Preface - Condrosulf

Preface
Osteoarthritis (OA) is characterized by degeneration of articular cartilage, limited intra-articular
inflammation with synovitis, and changes in peri-articular and subchondral bone. Multiple factors are
involved in the pathogenesis of OA, including mechanical influences, the effects of aging on cartilage
matrix composition and structure, and genetic factors.
Since the initial stages of OA involve increased cell proliferation and synthesis of matrix proteins,
proteinases, growth factors, cytokines, and other inflammatory mediators by chondrocytes, research
has focused on the chondrocyte as the cellular mediator of OA pathogenesis. The other cells and tissues
of the joint, including the synovium and subchondral bone, also contribute to pathogenesis.
The adult articular chondrocyte, which normally maintains the cartilage with a low turnover of matrix
constituents, has limited capacity to regenerate the original cartilage matrix architecture.
Current pharmacological interventions of OA consist mainly of analgesics and non-steroidal antiinflammatory drugs (NSAIDs). Although these are the most commonly prescribed agents for this
condition, they may cause serious gastrointestinal and cardiovascular adverse events and do not seem
to affect the underlying structural cartilage damage.
Undoubtfully, a disease-modifying therapy would be more beneficial.
In recent years attempts have been made to influence cartilage loss in OA by therapy with such cartilage
constituents as chondroitin sulfate (CS).
Oral CS for treating OA has become widespread. Large-scale trials of high methodological quality have
demonstrated significant effects on OA-related symptoms, mainly pain. Additionally, treatment with CS
over 2 years can prevent the structural progression observed in OA.
This manuscript will focus on questions currently under study that may lead to better understanding of
mechanisms of OA pathogenesis and elucidation of the new effective strategies for therapy, with
particular emphasis on CS. The pharmacokinetics, pharmacodynamics and clinical uses of CS
(Chondrosulf®, Condrosulf®, Condrosan®, Condral®) will be considered.
1
Table of Contents
1
2
3
4
5
Composition and structure of normal articular cartilage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .3
1.1
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .3
1.2
General structure of articular cartilage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .3
1.2.1
Cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .3
1.2.2
Cartilage zonation and regional organization of the extracellular matrix . . . . . . . . . . . . . . . . . . . . . . . . . .3
1.3
SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .5
1.4
BOX. 1. What is chondroitin sulfate? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .5
Etiopathology of osteoarthritis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .6
2.1
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .6
2.2
Cartilage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .7
2.3
Synovial membrane . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .7
2.4
Articular joint tissue catabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .7
2.5
Anabolic and destructive mediators in OA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .8
2.6
SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .8
Pharmacokinetics of CS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .9
3.1
Bioavailability, distribution and target tissue orientation of CS: human studies . . . . . . . . . . . . . . . . . . . . . . . . .9
3.2
SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .14
3.3
BOX 2. How can chondroitin sulfate pass gastrointestinal membrane? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .14
Clinical studies with CS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .14
4.1
Establishment of dose regimen . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .14
4.2
SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .16
4.3
Carry-over effect of CS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .16
4.4
The SySADOA effect of CS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .18
4.5
SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .21
4.6
The DMOAD effect of CS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .21
4.7
SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .26
4.8
The overall evidence on clinical efficacy of CS: the meta-analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .26
4.9
Preliminary pharmacoeconomy studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .27
4.10 SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .27
4.11 Safety profile of chondroitin sulfate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .28
4.12 SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .29
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .30
Tradenames of chondroitin sulfate: Chondrosulf®, Condrosulf®, Condrosan®, Condral®
2
1
Composition and structure of normal articular cartilage
1.1
Introduction
Articular cartilage is a hyaline cartilage covering the subchondral bone in a diarthrodial joint. It has an articulating surface that
abuts the synovial joint cavity. By definition, hyaline cartilages contain only type II collagen and therefore are distinguishable
from fibrocartilages, such as meniscal cartilage. The latter contains mainly type I collagen and a relatively low content of the
proteoglycan (PG) aggrecan1. In conjunction with synovial fluid, articular cartilages provide an almost frictionless articulation
in a diarthrodial joint and serve to absorb and dissipate load.
1.2
General structure of articular cartilage
1.2.1
Cells
Articular cartilage in adults is a comparatively acellular tissue, with cell volume averaging only approximately 2% of the total
cartilage volume in human adults. The remainder is occupied by an extensive extracellular matrix that is synthesized by these
cells that are called chondrocytes. This contrasts to fetal and young immature (0-2 years) cartilages where cell volume is very
much higher during growth. With increasing age, there is a progressive decrease in cell content and in matrix synthesis, the
latter reaching its lowest point when the individual is 20 to 30 years. Cell density is at its lowest in the deep zone.
1.2.2
Cartilage zonation and regional organization of the extracellular matrix
1.2.2.1
Zonation
The organization of articular cartilage reflects its functional role. At its free surface, which is bathed by synovial fluid, the cells
and extracellular matrix are arranged differently to the rest of the tissue. Here, the chondrocytes are flattened and aligned
parallel to the surface.
Only at the articular surface these specialized chondrocytes synthesize a molecule called superficial zone protein.
Below the superficial zone is the midzone, where cell density is lower. This has the more typical morphologic features of a
hyaline cartilage with more rounded cells and an extensive extracellular matrix rich in the PG aggrecan. Here, the collagen
fibrils are of larger diameter and arranged more randomly. Situated between this zone and a layer of calcified cartilage is the
deep zone. Cell density is at its lowest but aggrecan content and fibril diameter are maximal, although collagen content is
minimal. The partly calcified layer provides a buffer with intermediate mechanical properties between those of the uncalcified
1
Aggrecan, or large aggregating proteoglycan, is a proteoglycan, or a protein modified with carbohydrates; the human form of the protein
is 2316 amino acids long and can be expressed in multiple isoforms due to alternative splicing. Along with type II collagen, aggrecan forms
a major structural component of cartilage, particularly articular cartilage.
Aggrecan consists of two globular structural domains at the N-terminal end and one globular domain at the C-terminal end, separated by
a large domain heavily modified with glycosaminoglycans. The two main modifier moieties are themselves arranged into distinct regions:
a chondroitin sulfate and a keratan sulfate region.
The linker domain between the N-terminal globular domains, called the interglobular domain, is highly sensitive to proteolysis. Such
degradation has been associated with the development of osteoarthritis. Proteases capable of degrading aggrecans are called
aggrecanases, and they are members of the ADAM (A Disintegrin And Metalloprotease) protein family.
3
cartilage and the subchondral bone. The chondrocytes in this calcified zone usually express the hypertrophic phenotype.
They reach a stage of differentiation that also is achieved in the physis and in fracture repair in endochondral bone formation.
These hypertrophic cells are unique in that they synthesize type X collagen and can calcify the extracellular matrix. Unlike in
bone formation, this calcified matrix is not resorbed fully in development and ordinarily resists vascular invasion. This interface
provides excellent structural integration with the subchondral bone.
1.2.2.2
Regional organization
In addition to this zonation, the matrix surrounding the chondrocytes of articular cartilage varies in its organization. All
chondrocytes are surrounded by a narrow (approximately 2 µm wide) pericellular region in which few collagen fibrils are
detected. At the ultrastructural level it is more amorphous in appearance. Here, numerous molecules are concentrated
including type VI collagen and the PGs decorin and aggrecan. A territorial region surrounds this pericellular region which is
present throughout the cartilage.
In the deep zone, there is a clearly identifiable third region of structure, distinguishable by the ultrastructure of aggregates
of the PG. This region is called the interterritorial region. It is the part of the matrix most remote from the chondrocytes.
Degradation products of aggrecan probably are most concentrated here, produced as a result of incomplete proteolysis and
retention of degradation products that retain binding for hyaluronan.
1.2.2.2.1 The macrofibrillar collagen network
Just as in other connective tissues with extracellular matrices, the endoskeleton of hyaline cartilages is composed of collagen
fibrils that form an extensive network throughout the territorial and interterritorial matrix. These fibrils vary in diameter, from
approximately 20 nm in the superficial zone to 70 to 120 nm in the deep zone. Type II collagen forms the bulk (approximately
90%) of the fibril. Collagen fibrils form from procollagen molecules that contain amino and carboxy propeptides. These are
removed by amino- and carboxy-proteinases as the fibril forms. The thrombospondin family member COMP can bind these
collagen molecules and type IX collagen. It therefore may play a role in fibril assembly whereby five collagen molecules are
brought together in register to form a microfibril.
Type IX collagen also is present in the fibril, being cross-linked to its surface in an antiparallel fashion. Its distribution may
be limited in the adult to pericellular sites. It has been reported to represent approximately 2% of the total collagen.
Type XI collagen is present within and on the surface of the fibril. It nucleates fibril self-assembly and limits lateral growth
of cartilage fibrils.
The small PG decorin also binds to collagen fibrils in the gap zone. In cartilage, its content essentially is equimolar with the
PG aggrecan. Decorin, similar to the other leucine-rich PGs fibromodulin and lumican can bind to collagen during fibril
formation and reduce the final diameter of the forming fibril. In the superficial zone and pericellular matrix, where decorin is
concentrated, collagen fibrils are at their thinnest.
1.2.2.2.2 Microfilamentous network
In the pericellular region, type VI collagen forms a highly branched filamentous network based on the formation of tetramers
that bind decorin. This network also seems to involve an association with hyaluronan 1 with which type VI collagen binds. These
microfilamentous structures are thought to exist mainly in pericellular sites where these molecules are most concentrated.
1.2.2.2.3 The macromolecular organization of the proteoglycan aggrecan
The other dominant structural organization of hyaline cartilages is that contributed by the PG aggrecan, which binds through
its amino terminal G1 globular domain to hyaluronan. Aggrecan has a core protein that contains a carboxyterminal G3 domain,
4
at least when it is synthesized and secreted from the cell. Aggrecan provides the compressive stiffness of cartilage. This is
achieved by hydration of the large numbers of chondroitin sulfate (CS) (see Box 1) and keratan sulfate chains that occupy the
core protein in the keratan sulfate and CS rich regions between the G2 and G3 domains. G2 marks the carboxyterminal end
of an interglobular domain stretching from G1. The hydration of aggrecan only is partial because the swelling of these
molecules is restricted by the collagen fibrillar network. It is this swelling pressure that endows cartilage with its compressive
difference, one of its special properties so important for the role that cartilage must fulfill in joint articulation. Hyaluronan can
reach up to 1 to 2 million in size.
In addition to an undefined interaction of hyaluronan with the macrofibrillar collagen network, hyaluronan also binds to
chondrocytes via the CD44 cell surface receptor. This structural relationship of the cell with its extracellular matrix, plays an
important role in linking chondrocyte metabolism to turnover of the extracellular matrix. The annexin V or anchorin CII receptor
also plays an important role in the binding of type II collagen to the chondrocytes. Other receptors known as integrins also
can bind type II collagen and these include the α 1 β1 and α 2 β1 receptors.
1.3
SUMMARY
The composition and structural organization of articular cartilage in the human adult reflects the very specialized role of this
tissue in articulation. There still is very much to learn although there has been enormous progress in the past 25 years, which
has resulted in the identification of many collagens and PGs and a host of other molecules.
1.4
BOX 1. What is chondroitin sulfate?
CS is a sulfated glycosaminoglycan (GAG) composed of a chain of alternating sugars (N-acetylgalactosamine or GalNAc and
glucuronic acid or GlcA) (Fig. 1). It is usually found attached to proteins as part of a PG (aggrecan). A chondroitin chain can have
over 100 individual sugars, each of which can be sulfated in variable positions and quantities. See Tab. 1 for further details.
O
COOH
O
OH
O
Fig. 1. Chemical structure of one unit in a CS chain. Chondroitin4-sulfate: R1 = H; R2 = SO3H; R3 = H. Chondroitin-6-sulfate: R1
= SO3H; R2, R3 = H.
H2 COR1
O
R2 O
O
HN
CH3
OR3
O
n
Understanding the functions of such diversity in CS and related GAGs is a major goal of glycobiology.
CS is an important structural component of cartilage and provides much of its resistance to compression.
CS is present not only in the extracellular matrix of cartilage, but also in normal human plasma, accounting for 77-80% of the
total serum GAG content (endogenous CS). The major site of metabolism for circulating CS is the liver, where it may partly
degrade to oligosaccharides and inorganic sulfate. Some of the GAGs are incorporated into cells, where they are catabolized
to low molecular weight products. Inorganic sulfate and intact CS are excreted in the urine (Baici et al., 1992).
CS biosynthesis is initiated by the addition of xylose to serine residues in the core protein of aggrecan, followed by sequential
5
addition of two galactose (Gal) residues and one GlcA residue. Chondroitin polymerization then takes place by alternating
GalNAc and GlcA, forming the repeating disaccharide region. Finally, sulfotransferases transfer sulfate residues to the different
positions of the repeating unit (Nadanaka, 1999).
Tab. 1. Different isoforms of CS.
Letter identification
Site of sulfation
Systematic name
Chondroitin sulfate A
carbon 4 of the GalNAc sugar
chondroitin-4-sulfate
Chondroitin sulfate C
carbon 6 of the GalNAc sugar
chondroitin-6-sulfate
Chondroitin sulfate D
carbon 2 of the GlcA and 6 of the GalNAc sugar
chondroitin-2,6-sulfate
Chondroitin sulfate E
carbons 4 and 6 of the GalNAc sugar
chondroitin-4,6-sulfate
CS was originally isolated well before the structure was characterised, leading to changes in terminology with time. Early
researchers identified different fractions of the substance with letters.
"Chondroitin sulfate B" is an old name for dermatan sulfate, and is no longer classified as a form of CS.
Chondroitin, without the "sulfate", has been used to describe a fraction with little or no sulfation. However, this distinction is
not used by all.
Although the name "chondroitin sulfate" suggests a salt with a sulfate counter-anion, this is not the case, as sulfate is
covalently attached to the sugar. Rather, since the molecule has multiple negative charges at physiological pH, a cation
is present in salts of CS.
Commercial preparations of CS typically are the sodium salt. Some Authors have suggested that all such preparations of CS
be referred to as "sodium chondroitin" regardless of their sulfation status.
2
Etiopathology of osteoarthritis
2.1
Introduction
In OA, articular cartilage, subchondral bone, and synovial membrane are the major sites of change in the course of the disease
process. OA is characterized by degradation and loss of articular cartilage, hypertrophic bone changes with osteophyte formation,
subchondral bone remodeling, and, at the clinical stage of the disease, chronic inflammation of the synovial membrane.
Prior to the onset of PG depletion and loss of cartilage, biosynthetic activity of the chondrocytes may lead to an increase in
PG concentration of the cartilage, resulting in thickening of the tissue during the earlier stages of OA. These new PG molecules
appear abnormal as their structure is significantly altered. Nevertheless, the repair process appears to keep pace with the
disease, and this response may be sufficient to maintain joint function for many years. As the disease progresses, however,
the degradative process eventually exceeds the anabolic, leading to a progressive loss of cartilage and eburnation of bone.
This appears to occur when the physiologic balance between the synthesis and degradation of the extracellular matrix favors
catabolism. At the clinical stage of the disease, an inflammatory reaction involving the synovial membrane is often present.
This process favors the synthesis of inflammatory mediators, which impact on cartilage matrix homeostasis by altering
chondrocyte metabolism to enhance catabolism while reducing the anabolism.
6
2.2
Cartilage
The alterations in OA cartilage are numerous and involve morphologic and synthetic changes of chondrocytes as well as
biochemical and structural alterations of the extracellular matrix macromolecules. Evidence has accumulated favoring an
important role for metabolic changes in these pathologic chondrocytes, with elaboration of pathologic factors causing matrix
degradation (Martel-Pelletier et al., 1999).
In the normal joint, there is a balance between the continuous processes of cartilage matrix degradation and repair. These
functions are performed almost solely by resident chondrocytes dispersed in their lacunae throughout the matrix, lasting a
lifetime under normal conditions. Chondrocytes function in response to cytokines and growth factor signals, and to direct
physical stimuli, which interact in a complex manner. The end result is a change in the rate of synthesis versus that of enzymatic
breakdown of the cartilage matrix, occurring both around the cells and at some distance.
Both autocrine and paracrine actions have been demonstrated in chondrocytes as well as in synovial lining cells. In OA, there
is a disruption of this homeostatic state. In most sites of OA change, the anabolic processes of these cells become deficient
relative to their catabolic influences (stage I). Focal repair responses are inadequate to maintain normal matrix integrity. At
the time of histologic appearance of OA lesions, the matrix has reached the critical point where its viscoelastic properties
become insufficient to withstand normal joint loads, and progressive cartilage loss may follow. Biomechanical factors then
assume a more prominent role.
2.3
Synovial membrane
As is well known, even if articular tissue destruction characterizes the OA condition, synovial membrane inflammation is
also of importance in the progression of cartilage lesions in this disease. In most patients with OA, focal or scattered sites
of synovial inflammation are detected (Goldenberg et al., 1982; Lindblad & Hedfors, 1987; Haraoui et al., 1991). OA
patients who have undergone either total knee or total hip replacement are often found to have a prominent inflammatory
synovitis that may resemble the inflammatory changes seen in rheumatoid arthritis (RA). Osteoarthritic synovial membrane
histology is quite heterogeneous. At one end of the spectrum there is marked hyperplasia of the synovial lining layer, with
a dense cellular infiltrate composed mainly of lymphocytes and monocytes. At the opposite end, the synovial membrane
is thickened by fibrotic tissue, with a very sparse cellular infiltrate. Cytokines in the synovial fluid are believed to originate
from increased synthesis by the membrane, but this is certainly not the primary cause of the synovitis. Synovial
inflammation in OA is almost certainly secondary and is related to multiple factors, including microcrystals, mechanical
stress, and enzymatic breakdown of OA cartilage, producing wear particles and soluble cartilage-specific degradation
products of macromolecules (stage II). Cartilage matrix components are released into the synovial fluid, then taken up by
synovial lining macrophages or, like keratan sulfate, escape into the blood (Lohmander, 1999). Proteolytic enzymes release
increased amounts of cartilage matrix fragments into synovial fluid, which can promote inflammation in the synovial
membrane. The inflammation, through the synthesis of mediators, creates a vicious circle, with increased cartilage
degradation and subsequent provocation of more inflammation (stage III).
2.4
Articular joint tissue catabolism
Biochemical changes in OA affect several cartilage components, including its major matrix constituents, i.e., PG aggregates
(aggrecan) and collagens. Aggrecans are probably the first cartilage constitutent to be affected, because they are progressively
depleted in parallel with the severity of the disease. At a certain stage of evolution of OA, the chondrocytes appear unable
to compensate fully for PG loss by increased synthesis, resulting in a net loss of matrix. The structure of the PG remaining in
the cartilage is altered in different ways (Rizkalla et al., 1992; Cs-Szabo et al., 1995; Malemud et al., 1995; Cs-Szabo et al.,
7
1997). Generally, the presence of aggregates appears to reduce the vulnerability of PGs to enzymatic attack. In OA,
proteases able to attack the PG monomer, particularly at the hyaluronic acid (HA)-binding region, have been demonstrated
(Tyler, 1985; Campbell et al., 1986; Martel-Pelletier, 1988; Sandy et al., 1991; Lark et al., 1997; Arner et al., 1999). Such
degraded fragments can rapidly diffuse from cartilage, leaving behind normal PG still capable of aggregation. This
important finding may explain why few breakdown products of PGs have been found in OA cartilage. As soon as the
degradation occurs, the products are either further degraded by chondrocyte enzymes or rapidly diffuse into the synovial
fluid. Alternatively, but not excluding the latter, the reduction in the HA content of OA cartilage, causing a diminution in
the size of the aggrecans as a result of facilitated diffusion of linear polymers, could favor a loss of PG breakdown products
from cartilage. PG degradation products have been identified in synovial fluid of patients with OA (Saxne and Heinegard,
1992; Sandy et al., 1992; Lohmander et al., 1993; Lohmander et al., 1993).
The decreased PG content of the matrix in association with damaged collagen structure (Pelletier et al., 1983) leads to
functional loss of normal matrix physiologic properties. Epitopes near the collagenase cleavage site of type II collagen fibers
have been detected in OA cartilage with the use of antibodies (Hollander et al., 1994). Moreover, the first damage to type II
collagen is seen in pericellular sites around chondrocytes, directly implicating the chondrocyte in this collagen alteration.
In addition to mechanical factors, evidence suggests a role for enzymatic pathways in OA cartilage matrix degradation. In RA,
the synovium is the most abundant source of degradative enzymes, but in OA, chondrocytes seem to be the prime source of
enzymes responsible for cartilage matrix catabolism.
The enzyme family identified as playing a major role in OA pathophysiology is the metalloprotease (Smith, 2006). However,
a role for other enzymes cannot be ruled out.
2.5
Anabolic and destructive mediators in OA
It is generally accepted that OA may occur as a general consequence of multiple causes, including inherited defects in
extracellular matrix molecules, biomechanical overloading and an imbalance in synovial homeostasis. Apparently the joint
has only a limited repertoire of reactions to various insults and the OA process may reflect a common response pathway.
It appears that at all stages of OA, independently from the initial cause, anabolic and catabolic mediators play a key role in
the destructive and repair processes in the osteoarthritic joint (Fig. 2). The net effect of these mediators depends not only on
their absolute quantities, but also on the presence of inhibitors such as soluble receptors, and the balance between the various
mediators and their inhibitors determines the overall outcome with regard to destruction and repair.
Importantly, the strict division into anabolic and catabolic mediators is somewhat arbitrary, because for many mediators both
catabolic and anabolic actions are reported and the exact roles of these mediators in the OA process are still an enigma.
2.6
SUMMARY
The pathophysiology of OA cartilage appears to be a mixture of both a degradative and a repair process. In the early stage
of OA the repair phenomena predominate, whereas in the later stages the attempted repair fails and full cartilage
destruction occurs.
Soluble mediators regulate both the degradative events and the repair response of the chondrocytes.
Catabolic mediators, such as IL-1 and TNF-α, are derived from chondrocytes and the synovial lining, which is activated by
cartilage degradation products. These mediators play a role in the activation of chondrocytes and the initiation and
progression of cartilage destruction, the latter most likely by stimulating the production of catabolic enzymes that are
capable of degrading matrix macromolecules.
Potentially, these factors could be applied to optimize the repair process. However, therapeutic application of these
8
factors will be complicated by the fact that chondrocytes in osteoarthritic cartilage have a deranged phenotype, which
results in altered responses to growth factors. The aberrant chondrocyte phenotype results in deviant production of matrix
molecules, which limits the capacity of these cells to reconstitute a normal cartilage matrix.
These considerations demonstrate that the application of anabolic factors to stimulate cartilage repair is a complex matter,
and that targeted stimulation of articular chondrocytes is a desirable goal for the future.
IGF-I
TGFBMPs
CDMPs
IL-4
IL-6, IL-10, IL-13
IL-1
TNFIL-17
IL-18
Catabolic
Anabolic
Regulatory
Fig. 2. Anabolic, catabolic and
regulatory mediators in OA.
Simplified scheme of the role of
anabolic, catabolic and regulatory
mediators in the synthesis and
degradation of articular cartilage
matrix molecules during the OA
process.
(BMP, bone morphogenetic protein; CDMP,
cartilage-derived morphogenetic protein;
IGF, insulin-like growth factor; IL, interleukin;
TGF, transforming growth factor; TNF,
tumour necrosis factor).
Matrix synthesis
Chondrocyte
Matrix degradation
3
Pharmacokinetics of CS
3.1
Bioavailability, distribution and target tissue orientation of CS: human studies
Conte et al. (1991) have administered CS to healthy volunteers by intravenous, intramuscular or oral route.
After intravenous administration of 0.5 g of CS, the plasma level decreased according to a two-compartmental open
model. The half-lives of distribution and elimination were 25.5±6.6 and 281±32 min, respectively. The volumes of central
and tissue compartments were 6.0±1.0 and 22.9±7.7 l, respectively.
9
Although one must be careful in extrapolating pharmacokinetic data, after intravenous administration of CS, the
central compartment had a volume slightly higher than that of plasma, a relevant tissue volume being also present.
This suggests that CS flows out from the vascular bed and reaches peripheral tissues.
In the study by Conte et al. (1991), more than 50% of the intravenously administered CS was excreted with urine during the
first 24h as high and low molecular weight derivatives.
After oral administration of 3 g of CS, a main peak (11.4±3.7 µg/ml), preceded by a lower peak, was observed after 190±21
min. The elimination half-life was 363±109 min.
The shoulder peak is probably due to gastric absorption of the compound. Acid polysaccharides, such as CS, might
enter easily through this route in conditions in which their negative charge is decreased by the
low pH value of gastric fluid.
The absolute bioavailability following oral administration, calculated from AUC of plasma concentration, was 13.2%. A peak
of oligo- and polysaccharides with a molecular weight lower than 5000 daltons, presumably derived from partial digestion of
exogenous CS into the intestinal lumen, was also present in plasma. Interestingly, the presence in human intestinal microflora
of the Bacteroides stercoris, which is able to degrade the CS, has been reported.
The specific intra-synovial targeting of CS, followed by an active influence on the composition of synovial fluid, was
demonstrated by Conte et al. (1995) in osteoarthritic patients, treated with 800 mg CS for 30 days.
Since one of the purposes of this study was the demonstration that orally administered exogenous CS reaches synovial fluid,
the synovial fluid, collected from 18 osteoarthritic patients who needed knee joint aspiration, was fractionated by gel
chromatography before and during CS treatment.
Interestingly, after 5 days of treatment, the molecular mass distribution of hyaluronan changed, with an increase of the high
molecular mass fractions, suggesting that not only a quantitative variation but also a qualitative change of this molecule took
place during CS treatment. The molecular mass of sulfated GAGs was also changed. The high molecular mass components,
markers of cartilage breakdown, decreased, whereas the low molecular mass molecules increased.
The study by Conte et al. (1995) suggests that at least a part of the low molecular mass material, present in joint synovial fluid
after 5 days of treatment, is exogenous CS. Therefore, CS reaches synovial fluid and cartilage (Box 2).
CS reaches synovial fluid and cartilage
The recent results obtained by Volpi (2002) and Volpi (2003) after oral administration of CS of bovine and ichthyic origin have
confirmed the pharmacokinetics of CS. A cross-over study was performed to assess the bioavailability of 4 g of CS from bovine
or fish cartilage after oral administration to 20 healthy male volunteers (25.2±2.1 year old). Blood samples were collected from
0.5 to 48 hours after drug intake, including a pre-dose sample. Pharmacokinetic parameters and the structure and properties of
plasma CS were determined by using new analytical tecniques. Additionally, the possible physiological regulation of plasma levels
of endogenous CS during the day was also assessed.
By using agarose-gel electrophoresis and HPLC analysis, the disaccharide composition of human plasma CS changed after the oral
exogenous fish and bovine CS administration. In fact, a significant decrease in the relative amount of non-sulfated disaccharide
was shown. While the 4-sulfated disaccharide fraction increased over the endogenous plasma component, the 6-sulfated and disulfated (only for CS of fish origin) disaccharides appeared in blood. At the same time, the mean charge density increased to a
maximum measured at 4 hours after bovine CS and between 8 and 12 hours after fish CS administration (Fig. 3).
10
Agarose-gel electrophoresis and HPLC
analisys of human plasma CS after oral
administration
0s
Absorbance at 232 nm
Subject 1
Predose, endogenous CS
4s
0
5
10
20
15
Retention time (min)
0,4
0,2
0
0
10
20
Time (h)
30
40
50
Absorbance at 232 nm
Sulfate to disaccharide
(charge density)
Sulfate to disaccharide
(charge density)
1
0,6
0,8
0,6
0,4
0,2
0
30
Subject 18
After 6 h of oral
administration of CS
1
0,8
25
Fig. 3. Agarose-gel electrophoresis and HPLC
analysis of fish and bovine CS in human
plasma after oral administration. A significant
decrease in the relative amount of nonsulfated disaccharide is evident. While the
4-sulfated disaccharide fraction increased
over the endogenous plasma component,
the 6-sulfated and di-sulfated (only for CS of
fish origin) disaccharides appeared in blood.
4s
0s
6s
2,6 dis
0
5
10
15
Time (h)
20
25
0
5
10
15
20
Retention time (min)
25
30
By using the same methodological approach, plasma concentrations of the endogenous CS were found to be constant
throughout the entire sampling period, indicating the absence of interfering factors (such as physical exercise) during the
clinical study and of any suppressing action of the drug on the endogenous CS production.
In spite of the high variability calculated for plasma CS concentrations at different times of administration (about 37% for
bovine and 42% for fish CS), exogenous CS was absorbed as a high molecular mass polysaccharide (more than 2.000 daltons
as determined by agarose-gel electrophoresis) together with low molecular mass products and monosaccharides, deriving
from a partial depolymerization and/or desulfation of the intact CS.
After administration of bovine CS, plasma CS concentrations increased (more than 200%) in all subjects with a peak
concentration after 2 hours, with the increase reaching significance from 2 to 6 hours, whereas, after administration of fish CS,
plasma CS levels increased (more than 120%) with a peak concentration at 8.7 hours, with the increase reaching significance
from 4 to 16 hours.
Also complex molecules possessing high molecular mass and charge density as CS can be absorbed orally,
reaching discrete plasma concentrations
The extent of absorption also depends on the kind of CS. In fact, in the studies by Volpi (2000 and 2003), after oral
administration of 4.0 g bovine CS, 5% of the dose was absorbed vs 2.5% after administration of the same dose of fish CS.
Absorption, bioavailability and pharmacokinetic parameters are markedly influenced by the structure and
chemo-physical characteristics of CS, particularly molecular mass and charge density
11
Ronca et al. (1998) have labeled CS with one residue of hydroxyphenyl propionate per 70 residues of chain sugars. The
molecule was then iodinated with 131I. The labeled CS (0.8 g in water; 50 µCi) was administered per os to four healthy
volunteers. Other four volunteers received 25 mg of CS (50 pCi) in gastroresistant capsules.
The plasma radioactivity was fractionated on the basis of molecular mass by gel filtration.
SPECT analyses of lower limbs as a function of the time after intravenous administration of CS-labeled 99mTc to two healthy
volunteers were also carried out (Ronca et al., 1998).
A rapid increase was observed after administration in water with a maximum at 1 h. The radioactivity was present to a
measurable extent after 24 h. After administration in gastroresistant capsules the CS peak was observed at 4h.
The plasma radioactivity, which appeared on a gel filtration column in the same position of labelled CS, was about 60-70%,
while about 30-40% of total radioactivity was observed in the same position of low molecular mass degradation products and
iodide.
Radioactivity observed in urine consisted of low molecular mass derivatives or iodide. However, high molecular mass CS and
depolymerized CS derivatives were present in urine collected in the first hours. Total radioactivity excreted in urine after 72h
was about 19% of the total CS for administration in water and 14% for administration in gastroresistant capsules. About 90%
of administered radioactivity was recovered in urine and feces after 72h with both administrations.
From plasmatic and urinary values, it appears that the bioavailability as high molecular mass CS was about 12% when the drug
was administered in water.
SPECT analysis of lower limbs as a function of time, after intravenous administration of 99mTc as sodium pertechnate or CS
labeled with 99mTc, showed that radioactivity was higher during the first 40 min in the thigh and in the calf as compared with
knee tissues. After this time the radioactivity progressively increased in the knee tissues and became much higher than in the
adjacent tissues (Ronca et al., 1998) (Fig. 4).
Fig. 4. (A) SPECT analysis of lower limbs 2h after intravenous
administration of 99mTc sodium pertechnate. (B) SPECT analysis of
lower limbs 2h after intravenous administration of CS labeled with
99m
Tc. (C) Difference between B and A (Ronca et al., 1998).
12
In human studies using commercially available products, CS is rapidly absorbed. The absolute bioavailability is 12%.
Exogenous CS electively concentrates in joints
The intrasynovial targeting of CS (Chondrosulf®, Condrosulf®, Condrosan®, Condral®) followed by an active influence on the
composition of synovial fluid, was demonstrated by Conte et al. (1995) in osteoarthritic patients, who were treated with
800 mg CS for 30 days.
A very important result of this study was the demonstration that orally administered exogenous CS reaches synovial fluid.
After 5 days of treatment, the molecular mass distribution of hyaluronan changes, with an increase of the high molecular
mass fractions, suggesting that not only a quantitative variation, but also a qualitative change of this molecule takes place
during CS treatment.
In another part of this study, some biochemical parameters (number of leucocytes, proteins, concentrations of sulfated
GAGs [SGAGs] and hyaluronic acid [HA], activity of N-acetylglucosaminidase [NAG]) were evaluated in the synovial fluid
of treated osteoarthritic patients and in control patients (not treated with CS).
No variations were observed in the patients who did not receive CS. Five days of CS administration led in the osteoarthritic
patients to a significant increase of concentration and molecular mass of hyaluronan and a decrease of a lysosomal enzyme,
N-acetylglucosaminidase. No significant differences in leukocyte count and protein content were detected (Tab. 2).
Tab. 2. Biochemical parameters in synovial fluid of osteoarthritic patients after
treatment with CS (800 mg/day) (Conte et al., 1995).
L e u k ocy te s
( 1 0 6/ m l )
P ro tei ns (m g/ml )
S G A G s ( mg / m l )
H A ( m g / ml )
N AG ( U / I )
Before treatment
(n = 8)
2.3 ± 1.6
31.9 ± 5.9
0.20 ± 0.08
1.7 ± 0.6
31.2 ± 4.4
After 5 days
of treatment (n = 8)
1.8 ± 1.6
31.4 ± 5.6
0.20 ± 0.09
2.0 ± 0.6*
20.1 ± 2.6*
Before treatment (n=5)
2.6 ± 1.5
30.3 ± 4.9
0.16 ± 0.06
1.8 ± 0.7
41.2 ± 6.8
After 10 days of
treatment (n=5)
2.0 ± 1.4
29.6 ± 1.8
0.17 ± 0.07
2.3 ± 0.6*
29.4 ± 3.3*
First synovial fluid
collection (n=5)
2.0 ± 1.2
35.0 ± 5.7
0.20 ± 0.03
1.8 ± 0.7
33.3 ± 5.0
Second synovial fluid
collection (after 5 days)
(n=5)
2.4 ± 1.4
35.5 ± 8.3
0.18 ± 0.04
1.8 ± 0.8
31.5 ± 3.7
Treated patients
Non-treated
patients
*p < 0.05
13
3.2
SUMMARY
CS is absorbed after oral administration partially as high molecular mass compound.
Following absorption, it is evident in general that the parent compound and its fragments can reach their targets of efficacy
- the joints.
There is further evidence that the joints, the joint cartilage and the synovial fluid are the preferred targets for orally
administered CS and its fragments.
Absorbed CS and its fragments are able to induce pharmacological effects in the joints and the joint cartilage - this is the basis
for their clinical efficacy.
3.3
BOX 2. How can chondroitin sulfate pass gastrointestinal membrane?
CS is absorbed both at the gastric and the intestinal level. Interestingly, Ronca et al. (1998) suggest that the high molecular
mass CS reaches the blood circulation through the lymphatic system and the thoracic duct together with the lipoproteins and
other macromolecules, avoiding in this way the first hepatic passage. A process of pynocitosis/endocytosis might be involved.
CS is not degraded by the contents of the stomach or small intestine or in any of the tissues, but degradation only takes
place in the contents of the colon and particularly the cecum. While CS is transported across the small intestine in low amounts
in the intact form, probably by the mechanism of pynocitosis/endocytosis, in the colon and the cecum, higher amounts of CS
are transported, but most of this is in the form of the degradation products. In the distal gastrointestinal tract, the molecule
is degraded presumably by the enzymes in the intestinal flora.
Bacteroides species have been identified and characterized from human intestine that are able to degrade GAGs (and CS)
due to the presence of various kinds of polysaccharide lyases such as heparin lyase and chondroitin lyase. The presence of
GAG-degrading organisms in human intestine supports results in which orally administered GAGs can result in the observation
of small oligosaccharides in the urine and plasma.
CS is absorbed as high molecular mass polysaccharide together with low molecular-mass polysaccharide chains
resulting from partial depolymerization and/or desulfation occurring in the distal intestinal tract
4
Clinical studies with CS
4.1
Establishment of dose regimen
The optimal daily dose of CS has been established by a dose-effect study (Pavelka et al., 1998).
The objective of this study was to test the dose-effect of CS at a dosage of 1200 mg vs 800 mg, 200 mg and placebo (PB)
over a three-month treatment period in patients with femoro-tibial OA. The duration of the study was 90 days. Assessments
of efficacy and tolerability were evaluated on days 0, 14, 42 and 90.
Primary efficacy criteria were Lequesne's algofunctional index of knee OA and spontaneous pain on Huskisson's Visual
Analogue Scale (VAS)2 of 100 mm, whereas secondary efficacy criteria were the global efficacy evaluation by the patients and
by the physician using a 4-point scale (poor - fair - good - excellent) and paracetamol consumption from day 15 to day 90.
14
A significantly decrease in mean values of Lequesne's algofunctional index of knee appeared within each treatment group
from day 14 onwards. The doses CS 1200 mg and CS 800 mg were significantly more effective than the placebo and than
the dose CS 200 mg. The results were evident from day 42 for CS 1200 mg, whereas for dose CS 800 mg the results were
only evident at day 90.
Statistical analysis confirmed that there was no difference between CS 200 mg and placebo, that the doses of CS 800 mg
and CS 1200 mg were significantly more effective than CS 200 mg and placebo and that there was no difference between
CS 800 mg and CS 1200 mg.
Knee joint pain evaluated with Huskisson's VAS decreased in a statistically significant manner within each treatment group
from day 14 onwards (Fig.5).
14
42
90
time (day)
10
5
Fig. 5. Dose-dependence of CS efficacy for
reduction of disability: variation of
Huskisson VAS (Pavelka et al., 1998). * P <
0.05; ** P < 0.01; *** P < 0.001.
Variation VAS
0
-5
-10
-15
**
*
-20
-25
-30
PB vs CS 200
PB vs CS 800
***
***
***
PB vs CS 1200
On day 14, there was only a statistical difference between the placebo and the highest CS dose (CS 1200 mg). At
this control visit, the groups treated with CS 800 mg and CS 1200 mg did not differ between themselves, but
their pharmacological effect was statistically different as compared to the lowest dose (CS 200 mg). The dose
of CS 200 mg did not achieve a statistically different result when compared with placebo both on day 42 and on
day 90. On the contrary, CS 800 mg and CS 1200 mg both showed a statistically significant difference to placebo group
and to CS 200 mg group at day 42 and maintained this difference also at day 90. CS 1200 mg
was more effective than CS 800 mg at day 42, but there was no difference between them at the end of the study
(day 90).
The difference in percentage of efficacy judgements reported as good/excellent by the patients became statistically
significant from day 42 onwards, suggesting that the patients receiving the two highest doses of CS were those most
satisfied with their treatment.
2
Huskisson's Visual Analogue Scale (VAS) is a patient-completed measure consisting of a 10 cm continuous line anchored at each end with
a statement representing the extremes of the dimension being measured, usually pain intensity. The subject indicates by a pen mark on the
line the present pain level.
15
Paracetamol consumption was statistically lower in the groups CS 800 mg and CS 1200 mg than in placebo and in CS
200 mg groups.
The overall tolerability judgement, expressed by both the physician and the patients, was reported as good/excellent in
most of the cases
Overall, the study by Pavelka et al. (1998) shows that CS was significantly more effective in the suppression of pain and
in improving function as compared with the placebo. This effect was delayed; in fact, the difference only became evident
starting from the control visit on day 42. The effect was dose-related, as doses of CS 800 mg and CS 1200 mg were more
effective than CS 200 mg, but there was no significant difference between CS 800 mg and CS 1200 mg daily. Only on day
14 was CS 1200 mg more effective than CS 800 mg.
Based on the results of this study, the following treatment can be recommended: CS 1200 mg for the first two weeks,
followed by CS 800 mg daily.
An other study carried out by Bourgeois et al. (1998) compared the efficacy and tolerability of a treatment with CS
1200 mg/day oral gel, a treatment with CS capsules at a dose of 3 × 400 mg/day vs placebo in patients with mono
or bilateral knee OA.
As result the single dose 1200 mg/day did not differ from the dose of 3 × 400 mg/day for all clinical parameters taken
into consideration (Lequesne's Index, spontaneous joint pain evaluated by VAS and the physician's and patient's overall
efficacy assessments). In CS groups, Lequesne’s Index and the spontaneous joint pain (VAS) showed a significant reduction
vs placebo-treated patients.
As there is no difference between the single daily dose of CS 1200 mg and the dose of 3 × 400 mg CS/day (Bourgeois
et al., 1998), taking into account patient compliance, the monodose seems to be the best choice (Pavelka et al., 1998).
4.2
SUMMARY
A prospective, randomised, double-blind, dose-effect study was performed comparing CS at different doses (1200 mg,
800 mg, 200 mg daily) with placebo in the treatment of femoro-tibial OA over a treatment period of three months. CS
1200 mg/day for the first two weeks, followed by CS 800 mg/day could be recommended as a therapeutic scheme.
No difference in treatment efficacy could be found if the total daily dose (1200 mg) of CS was administered in two or three
doses. Taking into account patient compliance, the monodose seems to be the best choice.
4.3
Carry-over effect of CS
A carry-over effect of CS was demonstrated by Osterwalder et al. (1990) in a multicentre, controlled, double-blind study,
in patients suffering from femoro-patellar chondropathy confirmed by arthroscopy. A group of patients (n = 18) received
400 mg CS orally twice daily for three months and 20 patients the same dosage of placebo. The treatment stopped after
3 months.
Type of pain, intensity of pain and situations triggering pain were recorded at the beginning of the treatment, after three
months treatment and after 6 months after start of the study (that means after three months without treatment). Pain
sensations were also evaluated if the mid and the margins of the patellae was pressed by finger.
After the three-month course of treatment, the pain in the group treated with CS was reduced by 39% and after six
months, without any further treatment, by 67% in comparison with baseline.
The aim of the study by Morreale et al. (1996) was that to assess the clinical efficacy of CS in comparison with the NSAID
diclofenac sodium (DS) in a long term clinical study in patients with knee OA.
This was a randomized, multicenter, double-blind, double-dummy study. Patients with knee OA (n = 146) were recruited
into 2 groups. During the first month, patients in the NSAID group were treated with 3 × 50 mg DS tablets/day and 3 ×
16
400 mg placebo (for CS) sachets; from month 2 to month 3, patients were given placebo sachets alone. In the CS group,
patients were treated with 3 × 50 mg placebo (for DS) tablets/day and 3 × 400 mg CS sachets/day during the first month;
from month 2 to month 3, these patients received only CS sachets. Both groups were treated with 3 × 400 mg placebo
sachets from month 4 to month 6.
Clinical efficacy was evaluated by assessing the Lequesne Index, spontaneous pain (using the Huskisson VAS), pain on load
(using a 4 point ordinal scale), and paracetamol consumption.
DS showed prompt and potent analgesic/antiinflammatory efficacy during the administration period; however, when
treatment was suspended, the clinical picture showed progressive regression toward the previous state, confirming that
NSAID are not able to modify the natural course of the disease (Fig. 6).
On the other hand, the intake of CS was associated with relatively slow variation in the symptoms (modifications being
evident from day 30 of the treatment), later presenting a global efficacy that was comparable to that of DS; however, the
therapeutic effects lasted longer, even after the suspension of treatment. Symptoms tended to reappear only towards the
6th (and final) month of the observation period (carry-over effect) (Fig. 6).
70
Diclofenac
60
CS
Fig. 6. Huskisson VAS (Morreale
et al., 1996).
VAS
50
**
40
30
**
**
20
10
0
0
10
20
30
45
60
90
120 150 180
time (day)
Other researchers examined the intermittent treatment of knee OA with oral CS in a one-year, randomized, double-blind,
multicenter study vs placebo (Uebelhart et al., 2004).
Patients received 800 mg daily of oral CS or placebo. Over one year, patients received intermittent courses of therapy,
alternating between three months of active therapy and three months off therapy.
The researchers also evaluated the carry-over effect of oral CS (pharmaceutical grade) after a three-month period of
treatment. The primary outcomes were pain and mobility of the patient; secondary outcomes were biomarkers and joint
space narrowing.
After one year, chondroitin produced a 35% decrease in Lequesne’s index. The decrease became significantly different
from placebo results at month nine. After one year, chondroitin also produced a 40% decrease on the VAS for pain.
These results present the possibility of using intermittent doses of CS to treat patients with OA.
17
4.4
The SySADOA effect of CS
The term "symptomatic slow-acting drugs for OA" (SySADOA) was coined more than a decade ago to designate medications
and/or nutritional supplements used to alleviate the manifestations of OA in the long-term. Their efficacy has always been a focus
of considerable skepticism.
However, a critical reappraisal of the available data, which include results of carefully designed clinical trials strongly, suggests a
therapeutic effect.
The effects of SySADOA need to be determined based, in particular, on treatment objectives (symptom relief, decreased use of
nonsteroidal antiinflammatory drugs and other conventional agents). In addition, the characteristics of the patients who are most
likely to benefit from SySADOA need to be identified.
In this context, several clinical studies with CS (Chondrosulf®, Condrosulf®, Condrosan®, Condral®), included in the SySADOA
category, have been performed and published in literature (see Tab. 3).
Clinical trials have demonstrated CS's beneficial effect for treating OA. For example, two six-months clinical trials involving patients
with OA of the knee (L'Hirondel, 1992) and of the hip (Conrozier and Vignon, 1992) showed significant improvement in the
symptomatology among members of the groups receiving CS (3 × 400 mg daily) compared with those receiving placebo.
In these studies validated parameters were used:
■
VAS of pain perception according to Huskisson;
■
Lequesne-index of functionality;
■
butt-heel distance;
■
consumption of analgesic and antiinflammatory drugs by the patient;
■
subjective assessment of therapeutic effect by the patient.
In another study, patients with knee OA were treated with CS in a randomized, double-blind, placebo-controlled study, performed
in two centres (Bucsi and Poor, 1998).
The efficacy and tolerability of oral CS capsules 2 × 400 mg/day vs placebo was assessed in a 6-month study period. Patients with
idiopathic or clinically symptomatic knee OA, with Kellgren and Lawrence radiological scores I-III, were included in this trial. Clinical
controls were performed at months 0, 1, 3 and 6.
Eighty patients completed the 6-month treatment period. Lequesne's Index and spontaneous joint pain (VAS) decreased constantly
in the CS group; on the contrary, slight variations of the scores were reported in the placebo group.
The walking time, defined as the minimum time to perform a 20-meter walk, showed a statistically significant constant reduction
only in the CS group (Fig. 7).
Fig. 7. Walking time (Bucsi and Poor, 1998).
27
20 m walking time
26
25
24
23
22
21
20
Placebo
*
CS
19
0
1
3
time (months)
18
6
Tab. 3 - Main Characteristics of the Clinical Trials in the Efficacy Assessment on Joint OA
Study type
Study number,
principal
investigator(s),
year of report
Target
indication
CS
daily dose
CS
formulation
Treatment
duration
CS
and total pts
evaluated *
Study
design
Dose-effect
Pavelka (1999)
Knee OA
200/800/1200 mg
sachets
3 months
105 / 140
R/DB/MC/DE/PBO
Bourgeois (1998)
Knee OA
1200 mg
capsules 3x400 vs
oral gel 1200 mg
3 months
83 / 127
R/DB/MC/DD/PBO
Trèves Verbruggen
(report 2002)
Knee OA
1200 mg
capsules 3x400 vs
oral gel 1200 mg
3 months
244 / 244
R/DB/MC/DD
Bocchi Manopulo
(1996)
Knee OA
1200 mg
sachets 400 mg
3 months
74/146
R/DB/MC/DD/PBO
Clinical
Bioequivalence
SYSADOA Effect
Efficacy
pivotal
Bucsi (1998)
Knee OA
800 mg
capsules 400 mg
6 months
39 / 85
R/DB/MC/PBO
Uebelhart (2004)
Knee OA
800 mg
sachets 800 mg
12 months
54 / 110
R/DB/MC/PBO
Kahan, Reginster,
STOPP trial (2008)
Knee OA
800 mg
oral gel 800 mg
2 years
309 / 622
R/DB/MC/PBO
Uebelhart (1998)
Knee OA
800 mg
sachets 400 mg
12 months
23 / 46
R/DB/MC/PBO
Kissling (report
1995)
Knee OA
800 mg
sachets 800 mg
12 months
29 / 56
R/DB/PBO
Heberden’s &
Bouchard’s OA
3 years
20 / 37
Wang (1992)
1200 mg
sachets 400 mg
2 years
18/34
Verbruggen (2002)
Finger joints OA
1200 mg
capsules 400 mg
3 years
44/222
R/DB/PBO
Michel (2005)
Knee OA
800 mg
2 years
150/300
R/DB/PBO
Gross (1983)
Knee OA
≥800 mg
tablets 800 mg
sachets 400 mg
40 weeks
45 / 45
open
Pagliano (1986)
Various OA sites
1600➝800 mg
sachets 400 mg
8 weeks
30 / 60
SB/PBO
Savoini (1986)
Various OA sites
1600➝800 mg
capsules 400 mg
8 weeks
30 / 30
open
Crivelli (1987)
Various OA sites
1600➝800 mg
capsules 400 mg
15 weeks
255 / 255
open
L’Hirondel (1992)
Conrozier, Vignon
(1992)
Knee OA
1200 mg
sachets 400 mg
3 years
63 / 125
R/DB/MC/PBO
Hip OA
1200 mg
capsules 400 mg
6 months
29 / 56
R/DB/MC/PBO
Patello-femoral
chondropaty
800 mg
sachets 400 mg
3 months
18 / 38
R/DB/PBO
12 months
114 / 206
R vs prospective
control group/SB
Efficacy
supportive
Other
efficacy
supportive
studies
Osterwalder (1990)
R/DB/PBO
Fasciani (1990)
OA
1200 mg
sachets / capsules
400 mg
Michel (2005)
Knee OA
800 mg
tablets 800 mg
2 years
150 / 300
R/DB/PBO
Kahan, Reginster,
STOPP trial (2008)
Knee OA
800 mg
oral gel 800 mg
2 years
309 / 622
R/DB/MC/PBO
DMOAD Effect
Efficacy
pivotal
Efficacy
supportive
Uebelhart (1998)
Knee OA
800 mg
sachets 400 mg
12 months
23 / 46
R/DB/MC/PBO
Uebelhart (2004)
Knee OA
800 mg
sachets 800 mg
12 months
54 / 110
R/DB/MC/PBO
*for efficacy; R=randomized; DB=double-blind; MC=multicentric; SB=single-blind; DD=double-dummy; DE=dose-effect; PBO=placebo-controlled
19
During the study by Bucsi and Poor (1998), patients belonging to placebo group reported a higher paracetamol
consumption, but this consumption was not statistically different between the two treatment groups.
Efficacy judgements were significant in favor of CS group. Both treatments were very well tolerated.
CS acts as a symptomatic slow-acting drug in knee OA
Recently, European League Against Rheumatism (EULAR) commissioned steering groups to review the scientific evidence
for the treatment of knee OA. Recommendations for treatment were developed as a result of this evidence-based review
and presented in 2003.
The final document produced by EULAR 2003 has recognized the efficacy of CS in the management of knee OA both for
pain reduction and functional improvement.
In its recommendations for managing knee OA, EULAR 2003 graded evidence for CS as 1A, the highest level of evidence.
In addition, EULAR 2003 graded the strength of its recommendation to use CS as treatment for knee as A, the highest
level of strength of recommendation (Tab. 4).
EULAR 2003 recommends to use CS for knee OA
Tab. 4. EULAR Recommendations 2003 (Knee Osteoarthritis).
Ty pe
In t e r v e n t i o n
Non-invasive
Drugs
Non-invasive, non drugs
Invasive, intra-articular
Ev i de n ce
R e c o m m en d a t i o n
Acetaminophen paracetamol
1B
A
Conventional NSAIDs
1A
A
Coxibs
1B
A
Chondroitin sulfate
1A
A
Glucosamine sulfate
1A
A
Topical NSAIDs
1A
A
Topical capsaicin
1A
A
Patient education
1A
A
Active physiotherapy
1B
A
Steroids
1B
A
One hip-specific placebo-controlled, randomized clinical trial was undertaken for CS, demonstrating that CS was
statistically better than placebo in reducing pain and improving function over 6 months of treatment (Conrozier et al.,
1992).
As CS has been demonstrated to effectively reduce pain and functional disability due to hip OA, EULAR 2005 graded
evidence for CS as 1B in the management of hip OA.
EULAR 2005 recommends to use CS for hip OA
20
4.5
SUMMARY
Concerning the SySADOA properties (Symptomatic Slow-acting Drug) it can be summarized that CS:
■
■
■
■
■
■
has already been investigated in many placebo controlled double-blind studies;
showed a SySADOA effect after oral administration of 3, 6 and 12 months;
reduces spontaneous joint pain (VAS);
increases overall mobility capacity (decreases Lequesne's index);
reduces consumption of NSAIDs;
is well tolerated compared to NSAIDs.
4.6
The DMOAD effect of CS
In recent years, attempts have been made to influence cartilage loss in OA by therapy with such cartilage constituents
as CS.
New clinical trials (see Tab. 5) have demonstrated that CS is able also to decrease structural damages in OA of the knee,
evidencing a SMOAD (Structure Modifying OA Drug) effect.
Tab. 5. Overview on clinical studies conducted with CS (Chondrosulf®, Condrosulf®, Condrosan®, Condral®).
S t ud y
N o . o f p at ie n t s
D ai ly d o s e
R e s u l ts
Uebelhart (1998)
46
800 mg
CS effective over 1 year vs placebo
Uebelhart (2004)
110
800 mg
CS effective for 12 months vs placebo
Verbruggen (2002)
222
1200 mg
CS effective over 3 years vs control vs placebo
Rovetta (2002)
24
800 mg
CS effective for 24 months vs control vs placebo
Michel (2005)
300
800 mg
CS effective over 2 years vs placebo
Kahan/Reginster (2008)
622
800 mg
CS effective over 2 years vs placebo
The aim of the study performed by Uebelhart et al. (1998) was to assess the clinical, radiological and biological efficacy
and tolerability of chondroitin 4- and 6-sulfate in patients suffering from knee OA.
This was a 1-year, randomized, double-blind, controlled pilot study, which included 46 patients of both sexes, aged 3578 years with symptomatic knee OA. Patients were treated orally with 800 mg CS per day or with placebo (PBO)
administered in identical sachets.
The main outcome criteria were the degree of spontaneous joint pain and the overall mobility capacity. Secondary
outcome criteria included the actual joint space measurement and the levels of biochemical markers of bone and joint
metabolism.
Treatment with CS significantly reduced pain and increased overall mobility capacity. Additionally, in a limited group of
patients CS induced a stabilization of the medial femoro-tibial joint width, measured with a digitized automatic image
analyzer, whereas joint space narrowing did occur in placebo-treated patients (Fig. 8).
21
minimum width (cm)
0.45
Placebo
CS
0.4
Fig. 8. Quantitative assessment
of the medial femoro-tibial joint
space narrowing using a
digitised automatic image
analyser: minimal femoro-tibial
width (Uebelhart et al., 1998).
0.35
0.3
0.25
0
12
time (months)
The metabolism of bone and joint assessed by various biochemical markers (osteocalcin, keratansulfate,
pyridonilin/deoxypyridonilin) also remained stable in the CS patients, whereas it was not the case in PBO patients.
Importantly, CS was well-tolerated in all patients.
Oral CS is an effective and safe symptomatic slow-acting drug for the treatment of knee OA. In addition, CS
might be able to stabilize the joint space width and to modulate bone and joint metabolism
The study by Uebelhart et al. (1998) was the first demonstration that a SySADOA, precisely CS, might influence the natural
course of OA in humans.
More recent clinical data provide further evidences that oral CS does also have structure modifying effects in knee OA
patients (Malaise et al., 1998; Uebelhart et al., 2004, Michel et al., 2005; Kahan et al., 2008).
In this context, a randomized, double-blind, placebo-controlled study on patients with knee OA was performed with the
aim of assessing the effect of CS (Chondrosulf®, Condrosulf®, Condrosan®, Condral®) as a Structure Modifying Drug in knee
OA (SMOAD), by measuring the progression of the minimum and mean joint space width over 2 years with the use of a
validated automatic image analysis of digitised X-rays (Uebelhart et al., 2004).
The primary study end points were the minimum and mean joint space width of the more severely affected compartment
of the target knee.
Patients who received placebo experienced significant reductions in the mean joint space width (-0.14 ± 0.61 mm mean
± SD; P < 0.001 compared with baseline) (Fig. 9) and minimum joint space width (-0.07 ± 0.56 mm; P < 0.05 compared
with baseline) (ITT analysis).
22
Mean joint space width
300 randomised patients: ITT analysis
3.1
3.04
3.00
Month 0
mm
3.0
3.04
Fig. 9. Study patients were randomly
assigned to receive either 800 mg CS or
placebo (PBO) once daily for 2 years. The
patients
receiving
placebo
had
progressive joint space narrowing, as
shown by the values of mean joint space
width. In contrast, there was no change
in mean joint space width for the patients
receiving CS (Michel et al., 2005).
Month 24
2.9
2.87
2.8
PBO
CS
p = 0.001
p = n.s.
Evolution
PBO vs CS
p = 0.04
In contrast, the loss of joint space was null in CS group (Fig. 9).
Similar results, with greater differences between the two groups, were obtained in patients who completed the 2-year
study (PP patients).
Therefore, as shown by this randomized, double-blind, placebo-controlled study, long-term treatment with CS is capable
to retard radiographic progression in patients with OA of the knee.
CS is statistically superior to placebo regarding:
minimum joint space width stabilisation (ITT/PP)
■ mean joint space width stabilisation (ITT/PP)
CS prevents joint space narrowing
■
Another clinical trial has demonstrated that CS is able to decrease structural damages in knee OA: the STOPP study
by Kahan et al. (2008).
STOPP is a multicentre, randomised, double blind, clinical study designed to evaluate the structure and modifying
properties of orally administered 800 mg chondroitin 4&6 sulfate (Chondrosulf®, Condrosulf®, Condrosan®, Condral®) vs
placebo (PBO) over 2 years continuously in patients with knee OA.
Six hundreds and twentytwo patients of either sex, aged between 45 and 80 years, affected by tibio-femoral knee OA,
defined by clinical and radiological criteria, were recruited in 4 European countries (France, Belgium, Switzerland, and
23
Austria) and North America. The symptomatic knee (VAS ≥ 30 mm) of each patient was selected as the target knee at the
time of enrolment. If both knees were symptomatic, the knee with the narrower joint space width was selected. If both
knees had the same joint space width, the most symptomatic knee was chosen.
Main exclusion criteria were the use of systemic or intra-articular injections of SySADOA or corticosteroids in the past
months.
All patients were treated with CS 800 mg/day or PBO for 2 years. As rescue medication only paracetamol 500 mg
(maximum 4 g/day) was allowed with the invitation to stop drug intake at least 24h before each visit. Concomitant
treatment with NSAIDs was limited in case of acute pain and had to be stopped at least 5 days before each visit.
Arthrocentesis was permitted for hydrarthrosis.
The patients receiving CS had a significantly lower progressive joint space narrowing (JSN) of approx. 2.4 fold in respect
to patients receiving PBO (P <0.01).
The PP analysis confirmed the results obtained by the ITT analysis.
CS (Chondrosulf®, Condrosulf®, Condrosan®, Condral®) 800 mg daily, taken continuously for 2 years,
slows down the radiological progression of knee OA
The data regarding the secondary efficacy parameters confirmed the trend in favour of CS with statistical significance at
several endpoints.
Percentage of responders, i.e., patients who obtained a pain decrease > 40% or 60% at 6 months of treatment, was
significantly higher in CS-treated group than in PBO counterpart.
Cumulative consumption of NSAIDs (expressed in grams of equivalent ibuprofen) was markedly lower in patients treated
with CS (-17% at 24 months of treatment) (Fig. 10).
Fig. 10. Cumulative consumption of
NSAIDs (expressed in grams of equivalent
ibuprofen) was markedly lower in patients
treated with CS.
Cumulative Consumption of NSAIDs
(in grams of equivalent ibuprofen)
CS
-17%
CS
-16%
210
(CS = chondroitin sulfate; PBO = placebo)
CS
-12%
180
150
120
90
60
30
0
1
3
6
9
12
CS
24
15
PBO
18
21
24
Month
The tolerability was very good in both treatment groups.
CS:
has a favourable pharmacological profile
■ reduces pain, thus confirming its SySADOA effect
■ shows a trend to reduce NSAIDs consumption
■ is as well tolerated as placebo
■
In this randomised, double blind, placebo-controlled study CS reduces the joint space narrowing in knee OA in comparison
to placebo as assessed by radiographic follow-up over 2 years. Long-term treatment with CS appears to delay radiographic
progression in patients with OA of the knee.
CS (Chondrosulf®, Condrosulf®, Condrosan®, Condral®) prevents joint space narrowing,
evidencing a SMOAD effect
The main aims in the management of hand OA until now were to relieve pain by mean of NSAIDs and to preserve hard
function by exercise.
Erosive OA characteristically involves the proximal and distal interphalangeal joints of the hands, with marked inflammatory
appearance and progressive destruction.
The aim of the study by Rovetta et al. (2004) was to evaluate the joint count for erosions in patients with erosive OA of
the hands, who were treated with CS plus naproxen vs naproxen over 2 years.
Joint count for erosions, Heberden and Bouchard nodes, Dreiser's algofunctional index and physicians' and patients'
global assessment of disease activity were studied.
A total of 24 patients (22 women and 2 men, mean age 53.0±6.0), suffering from symptomatic OA with radiographic
characteristics of erosive OA, were evaluated. The patients were divided into two groups of 12 patients each. The first
group took naproxen 500 mg only. The second group was treated with CS 800 mg orally plus naproxen 500 mg. Joint
counts, radiological hand examinations and assessment of disease activity were performed at baseline (T1), at 12 months
(T2) and at 24 months (T3). A less marked progression of erosions was observed in patients taking CS plus naproxen than
in patients taking naproxen only.
Although the disease was progressive and the number of affected joints significantly increased in all the patients when
compared with baseline, the administration of oral CS plus naproxen in patients with erosive OA of the hands was
associated with a better clinical course of the disease, which was well demonstrated by the improvement in patients'
assessment of their condition.
CS (Chondrosulf®, Condrosulf®, Condrosan®, Condral®) is currently the drug of choice for diminishing
joint damage in erosive OA of hands
In a randomized, double-blind, placebo-controlled study, Verbruggen et al. (2002) evaluated the effect of CS (3 × 400 mg/die), given
for a period of one year, on the clinical status of 222 patients suffering from OA of the finger joints. Poster-anterior roentgeno-graphies
of the inter-phalangeal joints were carried out at the start of the study and at yearly intervals. This enabled the investigators to document
the radiological progression of the anatomical lesions in the pathological finger joints over a 3-year period.
Interestingly, in the CS group it was observed a significant decrease in the number of patients with new 'erosive' OA finger joints.
25
As CS has been demonstrated to have marked DMOAD effects in hand OA, EULAR 2007 graded evidence for CS as 1B in the
management of hand OA.
EULAR 2007 recommends to use CS for hand OA
4.7
SUMMARY
Concerning the disease-modifying effect it can be summarized that CS:
• is able to stabilize the knee joint space width and to modulate bone and joint metabolism;
• reduce the progression of hands OA especially concerning the erosive phases.
This is the first demonstration of CS that a drug with SySADOA classification might also have the potential to slow down
the progression of OA in humans (DMOAD).
4.8
The overall evidence on clinical efficacy of CS: the meta-analysis
The aim of the meta-analysis by Leeb et al. (2000) was to evaluate the results of randomized controlled trials of CS in hip and
knee OA that complied at least partly with the guidelines for investigations of drugs in OA, and in which the study drug was
applied for at least 3 months.
Most of the reports on CS were not published in the mainstream rheumatology literature. For some of them flaws in their design
or small sample sizes were the reasons for exclusion from this meta-analysis; however, for other publications no such restrictions
were found. Overall, of a total of 16 publications found, 7 trials could be enrolled into the meta-analysis.
The results of this meta-analysis provide evidence for some efficacy, statistically significant as well as clinically relevant, of CS
concerning pain and amelioration of the functional situation in patients with hip and knee OA.
In these studies more than 700 patients (372 treated with CS and 331 controls) were analyzed. No study showing
lack of efficacy could be found and no investigation was evaluated on an intent-to-treat basis. There were only a
few dropouts, which were equally distributed between CS and placebo patients, indicating that the analysis may be sufficiently
valid.
Analysis of the available data, performed by Leeb et al. (2000), revealed that CS appeared superior to placebo in several aspects:
improvement of the algofunctional (Lequesne) index, reduction of pain, and reduction of NSAID or analgesic consumption,
considered a major response criterion in OA.
Combining the results with the fact that all selected studies had a double blind randomized parallel group design, CS appears
to affect OA positively. This was seen in each individual study, but also in combined analysis of percentage change from
baseline.
Patient's and/or physician's global assessment also had improved significantly in CS vs placebo treated patients. Other
variables, such as swelling, tenderness on pressure, pain at rest and on movement, number of flares over time,
and range of motion, were not available in many studies, but, when reported, also tended to favor CS.
Side effects were mild in all studies. They were recorded as the numbers of adverse events in patients who completed the trial.
Interestingly the frequencies of side effects were consistently higher in placebo groups compared to CS treated patients. Adverse
events in CS treated patients primarily affected the gastrointestinal tract, including epigastralgia (18 of 349 patients), diarrhea
(n = 7), and constipation (n = 2).
26
Based on a qualitative assessment of 7 studies it can be concluded that there is no safety issue to be reported
concerning the use of CS. The efficacy and risks associated with long-term use of NSAID and analgesics are well
documented.
The meta-analysis by Leeb et al. (2000) provides evidence for significant efficacy of CS on pain and function
in the treatment of OA compared to placebo in patients followed for 120 or more days
Since the meta-analysis by Leeb et al. (2000), new data, obtained from long-term prospective, welldesigned studies, using glucosamine or CS, have also assessed the activity of these compounds as structure modifying
agents.
Richy et al. (2003) performed a meta-analysis to re-evaluate, from the perspective of these new results, the evidence of
structural efficacy (i.e., a disease-modifying property or DMOAD effect) and of the symptomatic effects (or SySADOA
effect) of glucosamine and CS in knee and hip OA.
Unfortunately, in this meta-analysis by Richy et al. (2003), some very recent long-term studies, which have evaluated the
structural efficacy of chondroitin, were not considered (i.e., Uebelhart et al., 2004; Michel et al., 2005; Kahan et al., 2008).
Anyway, chondroitin was found to be effective on Lequesne index, VAS pain, mobility, and responding status. Safety was
excellent.
4.9
Preliminary pharmacoeconomy studies
Henry-Launois (1999) have performed a study with the aim of reassess the beneficial effects of CS on the number of
NSAIDs prescriptions and to ascertain the pattern of use of the product (i.e., to verify correct posology). The results
on the 11.000 patients followed in the study indicated that administration of CS did reduce the overall combined
prescription of NSAIDs without any extracharge to the health national system.
Prescription of CS (Chondrosulf®, Condrosulf®, Condrosan®, Condral®)
is pharmacoeconomically advantageous
4.10
SUMMARY
The meta-analyses have presented a lot of evidence that CS must be considered as a symptomatic slow-acting drug for
the treatment of OA (SySADOA).
The evaluation of clinical trials, which were conducted with a sufficient quality, have demonstrated that the efficacy of CS
treatment is consistent for pain and functional outcomes and have shown in general moderate to large effects for the
therapy of OA symptoms.
Results concerning the disease-modifying potential (DMOAD effect) of CS are available but not yet considered in the
available meta-analyses.
Prescription of CS is pharmacoeconomically advantageous
27
4.11
Safety profile of chondroitin sulfate
CS is known as a non-toxic substance, since it is a natural component of the connective tissue of both animal and man.
The drug has no genotoxic properties according to a battery of in vitro and in vivo mutagenicity tests. CS did not affect
fertility of rats, reproduction functions and no teratogenic properties at doses causing maternal toxicity.
In all clinical trials, mainly carried out in OA patients, CS has always been very well tolerated, with a limited number of
adverse events (AEs) and very rare serious adverse events (SAEs) reported, in most cases unrelated to the drug. No
statistically significant difference in the frequency of AEs between CS and placebo was seen in any of the placebocontrolled clinical trials.
Importantly, also the results of long-term clinical studies (6 to 36 months) have confirmed a total absence of toxicity of
CS orally administered at doses of 1 to 2 g/day.
On the post-marketing side CS (Chondrosulf®, Condrosulf®, Condrosan®, Condral®) has been available on several markets
(i.e. France, Switzerland, Italy, Hungary, Austria, Slovak Republic, Czech Republic, Mexico, Spain and Chile) for more
than 20 years, and millions of patients have been treated so far. Neither frequent nor concerning AEs had been received
during this long-time and extensive pharmacovigilance experience. This very safe profile is reflected in the CS patient’s
information leaflets currently approved in all countries, where the drug is on the market.
Only minor AEs were reported in the course of these studies: these occurred at the beginning of the treatment and
generally involved the gastrointestinal tract, e.g. nausea, gastric heaviness, epigastralgia, diarrhoea, etc. This may happen
to susceptible patients assuming a large single dose (e.g., 1200 mg) without food.
Few cases of cutaneous rash were reported, but their relation to the treatment could not be clearly demonstrated.
Worldwide sales of CS (Chondrosulf®, Condrosulf®, Condrosan®, Condral®), recorded during the last 3 years (PSUR, Nov
2004- Nov.2007), indicated that the total amount of treatment-days with all different formulations of CS ranges from more
than 450 millions (when posology is 1200 mg/day) to approximately 860 millions (when posology is 800 mg/day) and the
total number of treated patients range from 5 millions to more than 9.5 millions.
The doses used in the studies considered (800-1600 mg), that include the recommended doses for the treatment of OA
(800-1200 mg/day), did not modify significantly any of the laboratory blood and urine parameters evaluated.
Importantly, being not metabolized by enzymes from cytochrome P450, CS can not present drug interactions at this level
(Fig. 11). No evidence of drug-drug or drug-food interactions have been generated during the clinical studies.
28
SAFETY PROFILE
Fig. 11. Summary of safety
profile of CS.
■ The
tolerance of the product is very well documented; equivalent
to PBO and much higher than that of SD*
■ It
is not metabolized by enzymes from cytochrome P450
➔
It can not present drug interactions at this level
■
Pharmacosurveillance data, where no serious adverse events have been
reported, support the safety of the product
PBO= placebo; SD= sodium diclofenac
* Leeb BF., et al. Rheumatol 2000; 27: 205-211
Overall, medical review of the safety information on CS collected from clinical trials or spontaneously received from the
various worldwide markets in which the drug has been approved for use has never raised a flag of concern regarding
its safety, nor triggered any Regulatory Authority action to modify the precautions or warning sections of package
inserts.
4.12
SUMMARY
In terms of safety and tolerability, CS is virtually devoid of any adverse effect. Rarely, it may just cause some mild gastric
discomfort at time of administration. This may happen to susceptible patients assuming a large single dose (e.g., 1200
mg) without food.
Being not metabolized by enzymes from cytochrome P450, CS can not present drug interactions at this level.
The pharmacovigilance data on CS (Chondrosulf ® , Condrosulf ® , Condrosan ® , Condral ® ) support the safety of the
product, too.
29
5
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