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Send Orders for Reprints to [email protected]
Current Medicinal Chemistry, 2014, 21, ????-????
1
Condrosulf®: Structural Characterization, Pharmacological Activities and
Mechanism of Action
Nicola Volpi*
Department of Life Sciences, University of Modena and Reggio Emilia, Italy
Abstract: Condrosulf® is a pharmaceutical formulation containing chondroitin sulfate (CS) as an active component possessing high quality and purity and standardized properties. CS is currently applied as a SYSADOA (Symptomatic Slow
Acting Drug for Osteoarthritis) agent in Europe in the treatment of osteoarthritis (OA). Furthermore, Condrosulf® and
pharmaceutical grade CS have also been proven to possess structure-modifying effects belonging to the S/DMOAD
(structure/disease modifying anti-osteoarthritis drug) class. This review summarizes current knowledge on
CS/Condrosulf® structure and its properties, its pharmacological activity as proved by many clinical trials and metaanalysis studies and focuses attention on its mechanisms of action in the pathophysiology of osteoarthritic joint tissues.
Finally, future perspectives are discussed in connection with the possibility to apply new outcome measures, such as MRI
and biomarkers, which can yield important advances in the use of Condrosulf® as well as the development of new drugs
with different structures useful in particular for the treatment of inflammatory symptoms and able to retard the progression
of arthritis.
Keywords: Condrosulf®, chondroitin sulfate, glycosaminoglycans, osteoarthritis.
INTRODUCTION
®
Condrosulf (manufactured by IBSA, Institut Biochimique SA, Switzerland) is a drug containing CS as its
active component. CS is a natural heterogeneous polysaccharide belonging to the biomacromolecule family of GAGs. In
fact, CS as a component of various PGs not only located on
the ECM, such as cartilages, skin, blood vessels, ligaments
and tendons, but also at cellular level [1]. The CS polymer is
constituted of repeating non-sulfated and various sulfated
disaccharide residues formed of GlcA and of GalNAc linked
by (1->3) bonds. The various disaccharides are attached to
one another by (1->4) links [2]. Depending on the position
of the sulfate groups, C2 of GlcA (very rarely on C3), C4
and/or C6 of the GalNAc unit, different disaccharides and
CS with heterogeneous carbohydrate backbones and charge
density are known (Fig. 1). In fact, the various sulfated disaccharides constitute, in different percentages, the building
block sequence of CS polysaccharide backbone, in relation
to specific animal sources such as tissues, organs and biological fluids, and pathological conditions [3].
CS is a strong negatively charged polymer due to the
ionization of sulfate groups and of the carboxyl groups of
GlcA. As a consequence, CS-PGs of articular cartilage are
responsible for the ECM viscoelastic and gelling properties
due to their high degree of hydration [4]. However, recent
glycobiology studies suggest that the complex CS polysaccharide and its related macromolecular derived PGs possess,
along with their structural functions, the capacity to regulate
*Address correspondence to this author at the Department of Life Sciences.
University of Modena & Reggio Emilia. Via Campi 213/D. 41100 Modena,
Italy; Tel: 0039 (0)59 2055543; Fax: 0039 (0)59 2055548;
E-mail: [email protected]
0929-8673/14 $58.00+.00
many cellular and physiological processes, such as the development of central nervous system, cellular differentiation
and migration, cell division and morphogenes, wound repair,
infective events and growth factor activity [3, 5-8].
Fig. (1). Structures of typical disaccharides forming chondroitin
sulfate chains. Sulfate groups may be located in position 2 of the
glucuronic acid (and very rarely in position 3) or/and on the C4 and
C6 of the N-acetyl-galactosamine unit.
PHARMACEUTICAL GRADE CHONDROITIN SULFATE IS THE ACTIVE DRUG IN CONDROSULF®
CS is a natural biomacromolecule extracted and purified
from animal tissues generally by patented and property processes [2]. As a consequence, along with CS natural structural
complexity and heterogeneity (see below), factors such as
source material, manufacturing processes, purity and physico-chemical properties of the final product (and many others) contribute to its biological and pharmacological activity.
CS has a complex macromolecular structure and characteristics strictly related to the tissue, organ and species. As a
consequence, the determination of origin, structure and physico-chemical properties is a key point of CS quality. To date,
© 2014 Bentham Science Publishers
2 Current Medicinal Chemistry, 2014, Vol. 21, No. 1
commercial CS is generally produced from cartilages of bovine [9], porcine [9], chicken [10], or cartilaginous fishes
such as sharks [11] and skate [12, 13]. Moreover, other
sources are useful for CS production such as fish bones [14]
and a combination of the above mentioned raw material may
be used to produce CS having distinctive properties.
CS samples extracted from different sources have polysaccharide chains composed of various percentages of disaccharides bearing sulfate groups in different positions [15].
Biosynthetic processes generate a great heterogeneity of the
number and position of sulfate groups responsible for an
overall charge density variability and for the presence of
low- and/or highly-sulfated sequences inside the polymeric
backbone. Moreover, CS is biosynthetized as a polydisperse
macromolecule possessing different molecular mass values
not only depending on the source but also on physiological
and pathological conditions. The number of disaccharide
units and related molecular mass parameters are other key
factors influencing CS biological and pharmacological activities [16-19]. Finally, generally property manufacturing
processes may generate further alterations of the CS structure and physico-chemical properties, in particular molecular
mass and charge density values, together with the final products possessing various grades of purity. In fact, along with
the yield, CS quality and purity may vary according to the
extraction and purification processes and/or tissue sources.
Due to these variations, CS produced from animal tissues
may possess different biological properties and pharmacological abilities.
The evaluation of the CS origin, structure, physicochemical properties, its content and purity are of paramount
importance when preparations are manufactured for pharmaceutical and nutraceutical applications. As a consequence,
specific and sensitive analytical techniques such as accurate
and reproducible quantitative assays are required, along with
appropriate and highly purified reference standards of wellknown and standardized properties and structures [15, 20].
CS for pharmaceutical applications is under strict evaluation for quality, purity, content, structural characterization
and physico-chemical parameters generally by Pharmacopoeia analytical indications, validated and published procedures and assays [see References 15 and 20 for an overview
of the analytical approaches to pharmaceutical grade CS].
This feature is a key point to guarantee active ingredient
quality and therapeutic reproducibility, purity and safe use of
the drug. In fact, viruses or prions may be present in CS
samples [21, 22] related in particular to bovine, porcine and
chicken origin, and specific purification procedures are required for their possible elimination [22]. Moreover, proteins
and their fragments derived from chemical and/or enzymatic
treatment are generally present also in high concentration,
reaching 3-5% [15, 20, 23, 24]. This is also related to the
nature of CS as PG and to the difficulty to eliminate protein
residues covalently linked to the CS backbone. The presence
of proteins (and related fragments) poses the problem of possible IgG-mediated intolerances and IgE-mediated allergies.
Additionally, nucleic acids, DNA and RNA, and their fragments derived from chemical treatment are also generally
present [15, 20, 23-25]. Finally, KS was detected in batches
from shark cartilage, averaging ~16% of the total GAGs
Nicola Volpi
[26]. This is most important, considering that KS is immunogenic, being able to produce immunological responses in
humans [27, 28].
On the contrary, CS for nutraceutical preparations is not
subject to such strict regulations. In fact, in a recent study
[20], the CS content reported on the label specifications of
ten European products was found to conform to just four
samples analyzed. These results were found comparable with
those of other studies reporting poor CS quality and failure
to comply with the label claim such as a great CS source
variability in products present in USA, Korean and Japanese
markets [see 20 for review].
CLINICAL STUDIES
Many clinical trials have been performed to establish
Condrosulf®/CS dose regimen, safety and efficacy (Table 1).
In a study performed in 1996 [29], Condrosulf® was orally
administered for 3 months to 61 subjects affected by hip,
knee and/or finger joints OA. Concomitant NSAID-therapy
consumption was significantly reduced by 72% during the
three months of CS administration. This study demonstrated
an effective reduction in the daily NSAID use by concomitant CS treatment. No risk of worsening of the OA symptoms and no serious side effects were observed.
In another study carried out in 1996 [30], the efficacy of
CS was assessed compared to NSAID drug diclofenac sodium in a randomized, multicenter, double blind, double
dummy, medium/long term clinical trial in 146 patients suffering from knee OA. Lequesne index, spontaneous pain,
pain on load and paracetamol consumption were evaluated.
Compared to NSAID, CS was found to gradually reduce OA
symptoms, lasting even after the end of treatment. In fact,
subjects treated with the NSAID showed a rapid decrease of
clinical symptoms, rapidly reappearing at the end of treatment. On the contrary, the efficacy of CS appeared later in
time also continuing for a long time even after the end of
administration.
A trial performed in 1998 [31] confirmed the capacity of
Condrosulf® to stop femoro-tibial joint space narrowing acting as a SYSADOA drug. Four further reviews published in
the same year underlined a few key activities of Condrosulf®
such as its efficacy and tolerability [32], and its properties as
a SYSADOA [33, 34] and S/DMOAD molecules [35] (Table
1).
A double blind, prospective, placebo controlled multicenter clinical study was undertaken in 2001 to determine the
efficacy and safety of CS in patients suffering from
femorotibial OA [36]. A trend showing CS efficacy compared to the placebo was observed after 3 months of treatment and persistent post-treatment for another month. However, due to the non significant results, further investigations
were required by the authors to confirm this trend. A new
trial in 2002 evaluated the progression of finger joint OA by
measuring anatomical changes recorded by standard radiographs [37]. 34 patients were included in a double-blind,
randomized, placebo-controlled trial receiving Condrosulf®
and monitored for 3 years. Progressive OA was found to be
more limited in the CS treatment group and few patients developed erosive OA (Table 1).
Condrosulf®
The efficacy and tolerability of orally administered CS in
patients affected by knee OA were investigated in 2004 in a
3-month, twice-yearly, intermittent treatment [38]. OA was
evaluated by radiological progression of the medial femorotibial joint space width along with clinical and biological
tolerability. Oral CS was able to improve knee function and
to decrease pain. Moreover, the 3-month intermittent treatment twice a year also supported prolonged CS clinical efficacy associated with symptom-modifying agents for OA.
Finally, the capacity of CS to improve the femoro-tibial joint
space narrowing also suggested further evidence of its structure-modifying capacities in knee OA. A further trial performed in 24 patients having erosive OA of the hands [39]
evaluated the effect of 800 mg/die of CS/naproxen combination versus naproxen alone over a 2 years period. This study
confirmed the capacity of oral CS to improve some features
of erosive OA (Table 1).
A randomized, double-blind, placebo-controlled trial was
conducted in 2005 [40]. 300 patients affected by knee OA
received 800 mg Condrosulf® once daily for 2 years. The
primary outcome was considered as the joint space loss over
the 2 years period evaluated by the posteroanterior radiograph of the knee in flexion. Pain and function were included
in secondary outcomes. The authors observed a reduction in
the radiographic knee OA progression determined by longterm treatment with Condrosulf®. A 2-year, randomized,
placebo-controlled trial of CS treatment in patients suffering
from symptomatic knee OA was published in 2007 [41].
Pain, investigator's assessment and quality of life were found
to be slightly improved in patients treated with CS (Table 1),
even if it failed to reduce joint space loss.
CS was able to significantly improve knee joint swelling
in an exploratory post hoc analysis of GAIT in subjects affected by OA [42]. A further two-year trial was conducted in
2009 to assess the effect of Condrosulf® on the radiographic
progression of knee OA associated with the modification of
symptoms [43]. Condrosulf® was suggested to be a diseasemodifying agent in patients with knee OA by its long-term
combined structure-modifying and symptom-modifying capacities (Table 1). Four recent publications not only confirmed the efficacy and safety of CS as a SYSADOA in patients suffering from knee OA in the absence [44] and in the
presence of plantar psoriasis [45], but also its capacity to
improve hand pain and function in subjects suffering of OA
of the hand [46], as well as its protective effect on joint
structure [47] (Table 1).
Several other clinical trials have been performed with CS
in combination with other active compounds, especially
GlcN (Table 2). In particular, considering the large clinical
GAIT trial [48], exploratory analyses suggested that CS may
be active in a subgroup of patients affected by moderate-tosevere knee pain, further confirmed by subsequent studies
[49].
To date, the first meta-analysis study was performed in
2000 [50] in which 7 trials on 372 patients taking CS were
considered (Table 3). Several other meta-analyses of clinical
trials have been published since that first report (Table 3).
CS, alone or in combination with other agents, was able to
reduce joint pain and to slow down the rate of reduction of
joint space in patients suffering from OA. Contrary to these
Current Medicinal Chemistry, 2014, Vol. 21, No. 1
3
positive reports, data provided by only two meta-analysis
studies by Wandel et al. [51] and Reichenbach et al. [52]
showed a minimal or nonexistent benefit from CS administration. However, many criticisms have been addressed to
these studies, such as the huge heterogeneity between trials
[53] considering that treatment is known to vary in relation
to disease severity, as confirmed by Sawitzke et al. [49] and
the high variability in the origin, potency and purity of CS
samples used in the evaluated studies, as previously discussed. Meta-analysis based on no evidence of heterogeneity
across the trials showed positive effects of CS as a SYSADOA and S/DMOAD agent (Table 3).
CS MECHANISM OF ACTION
As an important biomacromolecule at cellular, tissue and
metabolic level, besides its conventional structural roles, CS
possesses many important biological functions. In fact, CS is
involved in inflammatory processes, cell proliferation and
differentiation, cell migration, tissue morphogenesis, organogenesis, infection and wound repair [3, 54, 55]. As far
as its pharmacological mechanism of action is concerned,
many studies have focused great attention on its antiinflammatory capacity in addition to other activities [7, 5661].
Inflammation is a protective systemic and local response
caused by physical damage or infection by microorganisms.
The main biological function of inflammation is to eliminate
the noxious factors, and to promote tissue repair and wound
healing. Inflammation also establishes memory enabling the
host to cause a rapid and highly specific response upon a
possible future contact [62] (Fig. 2). A complex network of
biochemical pathways, including catabolic factors/mediators
and cytokines established between the different joint tissues
and the cartilage, is involved in tissue changes and remodeling [61]. Along with the destruction of the articular cartilage,
synovial inflammation is developed as a secondary phenomenon related to multiple factors, and these modifications
are also correlated to the altered metabolism of osteoblasts.
The above illustrated clinical trials have demonstrated the
capacity of CS to reduce pain improving articular function,
to decrease joint swelling and effusion, and to prevent joint
space narrowing of the cartilages more effectively compared
to placebo. Accordingly, CS has been defined as a SYSADOA and S/DMOAD compound (see above reported studies
and related References). The beneficial effects of CS in patients affected by OA result from different activities, in particular the documented reduction of the NF-B nuclear translocation, decrease in the production of pro-inflammatory
cytokines IL-1 and TNF- and reduction in the expression
and activity of NOS-2 and COX-2 (Fig. 3). Moreover, other
documented activities of CS may contribute to its efficacy in
patients, such as its capacity to increase the synthesis of articular cartilage PG, reduce the apoptosis of chondrocytes
and the synthesis and/or activity of MMPs [59, 60].
Besides other receptors, toll-like receptors 1-13 (TLR113) are the most frequently activated membrane PRRs in
immune cells. The activation of TLR1-13 leads to the phosphorylation of extracellular signal-regulated kinases capable
to produce a molecular cascade inducing the release of NFB and its translocation to the nucleus [63]. Inside cell
4 Current Medicinal Chemistry, 2014, Vol. 21, No. 1
Table 1.
Nicola Volpi
Clinical Trials With Condrosulf® /Chondroitin Sulfate (CS) Under Investigation
Year
Study
N° of Patients Daily Dose
1996
Patients suffering from OA of the hip,
knee and/or finger joints were included
in this open, multicenter, phase IV
trial. Patients were treated with Condrosulf® for 3 months
61
1996
The clinical trial was performed in
comparison with diclofenac sodium in
a randomized, multicenter, double
blind, double dummy, medium/long
term clinical study in patients with
knee OA
146
1998
This is a double-blind, randomized,
placebo-controlled clinical trial for a
total study period of 12 months
1998
This was a multicenter randomized,
double-blind, controlled study performed to compare the efficacy and
tolerability of Condrosulf® in patients
with mono or bilateral knee OA
1998
Patients with OA of the knee were
treated with Condrosulf® in a randomized, double-blind, placebo-controlled
study, performed in two centers for a
6-month study period
1998
This trial assessed the clinical, radiological and biological efficacy and
tolerability of Condrosulf® in patients
suffering from knee OA. This was a 1year, randomized, double-blind, controlled pilot study on patients with
symptomatic knee OA
1998
This is a randomized, double-blind,
placebo-controlled trial carried out to
assess the S/DMOAD properties of
Condrosulf® in OA
2001
The efficacy and safety of CS per os
was assessed compared to the placebo,
in a double blind, randomized, parallel
group study, with 3 months’ treatment
followed by a 3-month post-treatment
period, in patients with femoro-tibial
OA
2002
This study evaluated the progression of
OA using scoring systems based on the
anatomical changes recorded in the
finger joints on standard radiographs.
34 patients were included in a randomized, double-blind placebo-controlled
trial receiving Condrosulf® and monitored for 3 years
Results
Key Feature
Reference
800 mg
A significant reduction of 72% in
the daily NSAID consumption by
Condrosulf® is effecconcomitant CS-therapy was obtive over 3 months vs
served with no risk of deterioration
NSAID/placebo
of the patients' symptoms and
serious side effects
[29]
1200 mg
The therapeutic response of CS
CS effective for 6
appeared later in time but lasted
months vs placebo, 3
for up to 3 months after the end of
months carryover
treatment.
[30]
800 mg
This study confirms the SYSACondrosulf® is able to
DOA effect of Condrosulf® with
stop femoro-tibial joint
an excellent clinical and biological
space narrowing
profile and tolerance
[31]
127
1200 mg
The treatment was very well tolerated also indicating that CS favors
the improvement of subjective
Condrosulf® is effecsymptoms, improving joint mobil- tive at 3 months vs
ity. 1200 mg CS as a single daily
placebo
dose does not differ from that of 3
x 400 mg daily dose
[32]
80
800 mg
Condrosulf® effective
over 6 months vs placebo
[33]
800 mg
The results obtained confirmed
that oral CS is an effective and
safe SYSADOA for the treatment
Condrosulf® effective
of knee OA. CS might also be able
over 1 year vs placebo
to stabilize the joint space width
and to modulate bone and joint
metabolism.
[34]
1200 mg
In the Condrosulf® group a signifiTreated patients were
cant decrease in the number of
protected against eropatients with new "erosive" OA
sive evolution
finger joints was observed
[35]
1000 mg
A trend towards the efficacy of CS
compared to the placebo with good All variables considtolerability after 3 months’ treat- ered tended towards
ment, and persistent post-treatment greater improvement in
efficacy for one month, was obthe CS group
served
[36]
1200 mg
Conventional radiographs used to score
OA was less progressive in the CS the progression of
treatment group and few patients
finger joint OA aldeveloped "erosive" OA
lowed the determination of the S/DMOAD
effect of Condrosulf®
[37]
110
42
119
130
34
The observed results strongly
suggested that CS/Condrosulf®
acts as a SYSADOA in knee OA
Condrosulf®
Current Medicinal Chemistry, 2014, Vol. 21, No. 1
5
(Table 1) contd….
Year
Study
N° of Patients Daily Dose
Results
Key Feature
Reference
Oral CS decreases pain and improves knee function. The 3-month
twice-yearly intermittent CS administration does support the
prolonged effect associated with
symptom-modifying agents for
OA
The inhibitory effect of
CS on the radiological
progression of medial
femoro-tibial joint
space narrowing suggests further evidence
of its structuremodifying properties
in knee OA
[38]
[39]
2004
This trial investigated the efficacy and
tolerability of a 3-month, twice-yearly,
intermittent treatment with oral CS in
knee OA patients
2004
The aim of this study was to evaluate
the effect of CS per os plus naproxen
versus naproxen over 2 years in patients with erosive OA of the hands
24
800 mg
Contrary to the treated patients, The partial efficacy of
the untreated group showed sig- oral CS in improving
nificant worsening in erosion and some aspects of erosive OA was conphysician and patient global asfirmed
sessment scores
2005
A randomized, double-blind, placebocontrolled trial, including patients with
knee OA treated with Condrosulf® or a
placebo once daily for 2 years. The
primary outcome was joint space loss
over 2 years. Secondary outcomes
included pain and function
300
800 mg
Long-term treatment with Condro- The clinical relevance
sulf® may retard radiographic
of the observed strucprogression in patients with OA of tural results has to be
further evaluated
the knee
[40]
2007
A 24-week, randomized placebocontrolled trial of CS in patients with
symptomatic knee OA measured on a
visual analogue scale
1000 mg
CS was slightly more
This study failed to show an effi- effective than the placacy of CS as regards the primary cebo on pain, investigator's assessment and
criteria considered
quality of life
[41]
2007
An exploratory post hoc analysis of
GAIT (Glucosamine/chondroitin Arthritis Intervention Trial) patients
1200 mg
Patients taking CS
This study suggested that the efwere observed to have
fect of CS on joint swelling oca statistically significurred more often in patients with
cant improvement in
milder pain
knee joint swelling
[42]
2009
Performed to assess the long-term
(two-year) effects, of Condrosulf® on
the radiographic progression of, and
symptom changes associated with,
knee OA
800 mg
The intent-to-treat analysis demCondrosulf® could be
onstrated a significant reduction in
an S/DMOAD agent in
minimum joint space width loss in
patients with knee OA
the Condrosulf® group
[43]
2010
The aim of this trial was to assess the
efficacy of CS on symptomatic knee
OA associated with psoriasis
800 mg
This study confirmed the efficacy
The use of CS could
and safety of CS as a SYSADOA
represent a special
in patients with knee OA and
benefit in patients with
showed that CS improves plantar
OA and psoriasis
psoriasis
[45]
2011
The symptomatic effects of highly
purified CS therapy in patients with
OA of the hands were evaluated
800 mg
CS improves hand pain and funcCS improves hand pain
tion in patients with symptomatic
and function in patients
OA of the hands and shows a good
with symptomatic OA
safety profile
[46]
2011
The effect of CS on cartilage volume
loss, subchondral bone marrow lesions,
synovitis and disease symptoms in
patients with knee OA was evaluated
69
800 mg
A joint structure proCS treatment significantly reduced
tective effect of CS
the cartilage volume loss in knee
was confirmed providOA starting at 6 months of treating new information on
ment, and subchondral bone marits mode of action in
row lesions at 12 months
knee OA
[47]
2012
This study evaluated the correlation
between clinical symptoms and cartilage volume through MRI in patients
with knee OA after 48 weeks of treatment with CS
43
1000 mg
120
307
1583
622
129
162
800 mg
The total cartilage volume increased in the CS group, as opposed to a loss in the placebo
CS acts as an
S/DMOAD in knee
OA
[44]
6 Current Medicinal Chemistry, 2014, Vol. 21, No. 1
Table 2.
Clinical Trials With Condrosulf®/Chondroitin Sulfate (CS) and Glucosamine (GlcN) Under Investigation
Year
Study
1999
This was a 16-week randomized,
double-blind, placebo-controlled
crossover trial of a combination of
GlcN, CS and manganese ascorbate
in degenerative joint disease of the
knee or low back
2001
The effect of GlcN and CS taken for
twelve weeks on subjects diagnosed
with capsulitis, disk displacement,
disk dislocation, or painful OA of the
temporo-mandibular joint was assessed
2006
This was a multicenter, double-blind,
placebo- and celecoxib-controlled
GlcN/CS Arthritis Intervention Trial
(GAIT) to evaluate their efficacy and
safety as a treatment for knee pain
from OA
2007
This was a double-blind, placebocontrolled, randomized clinical trial
lasting 12 months. Participants included patients with knee OA randomized to either the GlcN/CS or
placebo group
2008
2010
Nicola Volpi
This study was undertaken to evaluate the effect of GlcN/CS, alone or in
combination, as well as celecoxib
and placebo on progressive loss of
joint space width in patients with
knee OA
To evaluate the efficacy and safety of
GlcN/CS, alone or in combination, as
well as celecoxib and placebo on
painful knee OA over 2 years
N° of Patients
34
45
1583
89
572
662
Daily Dose
Results
Key Feature
Reference
1200 mg
Knee OA symptoms were
relieved as demonstrated by
the summary disease score,
patient assessment of treatment effect, visual analog
scale for pain recorded during
clinic visits and in a diary and
physical examination score
The combination
therapy relieves
symptoms of knee
OA
[74]
1200 mg
Subjects taking CS/GlcN
experienced improvements in
their pain as measured by one
index of the McGill Pain
Questionnaire and in the number of daily over-the-counter
medications needed
Additional studies are
required to evaluate
the clinical effectiveness of CS/GlcN
[75]
1200 mg
GlcN/CS did not
reduce pain effecOverall, GlcN/CS were not
tively in the overall
significantly better than the
group of patients with
placebo in reducing knee pain
OA of the knee.
by 20 percent. However, for
Exploratory analyses
patients with moderate-tosuggest that the comsevere pain at baseline, the rate
bination of GlcN/CS
of response was significantly
may be effective in
higher with combined therapy
the subgroup of pathan with the placebo.
tients with moderateto-severe knee pain
[48]
1200 mg
WOMAC function and pain
did not differ significantly
between the groups at 6- or 12month follow-up. There were
also no significant differences
between the groups in knee
strength
The GlcN/CS group
was not superior to
the placebo group as
regards function,
pain, or mobility
[76]
1200 mg
No statistically significant
differences in mean joint space
Knees with Kellwidth loss were observed in
any treatment group compared gren/Lawrence grade
2 radiographic OA
with the placebo group. Howappeared to have the
ever, a trend towards improvement with respect to the greatest potential for
placebo group was observed. modification by these
treatments
The power of the study was
diminished by the limited
sample size
[49]
1200 mg
Over 2 years, no
treatment achieved a
clinically important
difference in
WOMAC pain or
function as compared
with the placebo.
Adverse reactions
were similar among
treatment groups and
serious adverse
events were rare for
all treatments
[77]
Compared to the placebo, no
statistically significant differences were observed
Condrosulf®
Current Medicinal Chemistry, 2014, Vol. 21, No. 1
7
(Table 2) contd….
Year
Study
2014
A double-blind randomized placebocontrolled clinical trial with 2-year
follow-up was performed to determine the capacity of GlcN and/or CS
to reduce joint space narrowing and
pain in patients with symptomatic
knee OA
Table 3.
605
Daily Dose
800 mg
Results
Key Feature
The dietary supplement comGlcN/CS combinabination (GlcN/CS) resulted in
tion resulted in a
a statistically significant restatistically signifiduction of 2-year joint space cant reduction in joint
narrowing compared to the
space narrowing at 2
placebo
years
Reference
[78]
Meta-analysis of Clinical Trials With Condrosulf®/Chondroitin Sulfate (CS) Under Investigation
Year
Study
2000
The efficacy of CS in the treatment
of OA on the basis of a metaanalysis of controlled clinical trials
was evaluated
2003
N° of Patients
To assess the structural and symptomatic efficacy of oral CS/GlcN in
knee OA through independent
meta-analyses of their effects on
joint space narrowing
Agent
Size
Results
Reference
CS
7 trials of 372 patients taking
CS were enrolled in the metaanalysis
CS may be useful in OA but
further investigations in
larger cohorts of patients for
longer time periods are
needed to prove its usefulness as a SYSADOA
[50]
CS and GlcN
An exhaustive systematic
research of randomized, placebo-controlled clinical trials
published or performed between January 1980 and
March 2002. 1775 patients
were analyzed in 15 selected
studies
This study demonstrates the
structural efficacy of GlcN
and indistinguishable symptomatic efficacies for both
compounds
[79]
The symptomatic benefit of
CS is minimal or nonexistent.
Heterogeneity among the
trials made initial interpretation of results difficult, and
exploring sources of heterogeneity in meta-regression
and stratified analyses may
be unreliable
[52]
20 trials, 3846 patients,
contributed to this metaanalysis
2007
To determine the effects of CS on
pain in patients with OA.
CS
2007
To determine the short-term painrelieving effects of seven commonly used pharmacological agents
for OA pain by performing a systematic review of randomized placebo-controlled trials
CS (and other 6 commonly
used pharmacological
agents for OA pain)
In total, 14,060 patients in 63
trials were evaluated
CS had maximum mean
efficacies at 1-4 weeks
[80]
CS
A MEDLINE search was
conducted from 1996 through
2007 and five articles reporting results from three trials
were identified. One additional trial was identified
through review of presentations at annual rheumatology
meetings. There was no evidence of heterogeneity across
the trials and results were
pooled using a fixed effects
meta-analysis
This analysis demonstrates
that CS is effective in reducing the rate of decline in
minimum joint space width
in patients with OA of the
knee. CS may have a role as
an S/DMOAD agent in the
management of patients with
knee OA
[81]
2008
A meta-analysis of randomized
double-blind placebo-controlled
clinical trials to assess the efficacy
of CS as an S/DMOAD agent for
knee OA has been performed
8 Current Medicinal Chemistry, 2014, Vol. 21, No. 1
Nicola Volpi
(Table 3) contd….
Year
Study
2008
A MEDLINE database search was
conducted for appropriate metaanalyses published between 1997
and 2007
2010
The effect of GlcN, CS, or their
combination on joint pain and on
radiological progression of disease
in OA of the hip or knee was evaluated
2010
2010
2012
This analysis updated a published
meta-analysis of double-blind placebo-controlled randomized clinical
trials to assess the efficacy of CS as
an S/DMOAD for knee OA
This study assessed the structural
efficacies of daily GlcN and CS in
patients with knee OA
A meta-analysis of randomized
double-blind placebo-controlled
clinical trials to assess the efficacy
of CS as a SYSADOA in OA of the
knee was performed
Agent
Size
Results
Reference
CS
Five meta-analyses that limited their analysis to randomized controlled trials comparing CS with placebo or notreatment control arms have
been analyzed
Data provided by these metaanalyses indicate that CS has
a slight to moderate efficacy
in the symptomatic treatment
of OA, with an excellent
safety profile.
[82]
CS and GlcN
Direct comparisons within
trials were combined with
indirect evidence from other
trials by using a Bayesian
model that allowed the synthesis of multiple time points
Compared with the placebo,
GlcN, CS, and their combination do not reduce joint pain
or have an impact on narrowing of joint space
[51]
CS
A published meta-analysis of
randomized controlled trials
was updated to include data
from two new trials published
in peer-reviewed literature
and limited to randomized
clinical trials of 2-year duration. Data were pooled with
no evidence of important
heterogeneity
The results demonstrate that
CS is effective in reducing
the rate of decline in minimum joint space width in
patients with knee OA
[83]
CS and GlcN
Randomized controlled studies on the effects of long-term
daily GlcN and CS on joint
space narrowing in knee OA
patients using MEDLINE and
the Cochrane Controlled
Trials Register, were evaluated. Meta-analysis was performed using a fixed effect
model due to no betweenstudy heterogeneity. Six studies involving 1,502 cases
were included
This meta-analysis of available data shows that GlcN
and CS may delay radiological progression of OA of the
knee after daily administration for over 2 or 3 years
[84]
CS is effective on symptoms
A MEDLINE search was
in patients with OA of the
conducted up to October 2010
knee compared to the plaand two articles reporting two
cebo, and may therefore have
trials were identified. There
was no evidence of heteroge- a role in the management of
patients with knee OA of
neity across the trials and
Kellgren-Lawrence grades II
results were pooled using a
and III
fixed effects model
[85]
CS
nucleus, NF-B enhances the transcription activity of a variety of genes encoding chemokines, cytokines, adhesion
molecules, inflammatory-associated enzymes and inhibitors
of apoptosis [64]. Furthermore, NF-B is involved in lymphopoiesis and in the differentiation and activation of
macrophages, osteoclasts, dendritic cells and granulocytes
[65]. As explained above, the NF-B signaling pathway is
strictly related to the regulation of inflammatory responses
and survival of immune cells. As a consequence, the ability
of CS and oligosaccharides derived from it to interact with
TLR1-13 [66, 67] and CD44 strongly supports its ability to
reduce inflammatory responses. In addition, CS contributes
to maintaining ECM integrity by increasing the expression of
TGF-1 and the synthesis of HA and collagen II.
Along with its role in inflammation, as discussed above,
NF-B is a key signal in many other cellular processes, such
as cell proliferation and survival, cellular stress response,
innate immunity and inflammation, related to the development of different human diseases [68]. The paramount im-
Condrosulf®
Current Medicinal Chemistry, 2014, Vol. 21, No. 1
9
Fig. (2). Schematic representation of the process occurring during joint osteoarthritis progression. Published with permission from [61].
portance of NF-B in inflammatory responses raises the possibility that CS might also be effective in other chronic inflammatory processes or diseases deriving from autoimmune
responses (Fig. 4).
Fig. (3). Schematic representation of the capacity of chondroitin
sulfate (CS) to reduce the nuclear translocation of NF-B or
p50/p65 heterodimer by inhibiting reactive oxygen species and/or
the extracellular signal-regulated kinase 1/2 (Erk1/2) and p38 mitogen-activated protein kinase (p38MAPK). As a consequence, CS is
able to decrease the synthesis of proteolytic enzymes (matrix metalloproteases, MMP-3, -9, -13 and cathepsine B), of proinflammatory enzymes (such as phospholipase A2, PLA2, cyclooxygenase-2, COX-2, and nitric oxide synthase-2, NOS-2), and
of pro-inflammatory cytokines (TNF- and IL-1). Published with
permission from [60].
Besides studies at molecular and cellular levels and clinical trials, animal models have been extensively applied for
the evaluation of CS (and Condrosulf®) activity. Adjuvant
arthritis and CIA animal models have been extensively used
to evaluate CS efficacy (Table 4). For example, Bauerova et
al. [69] described the effect of two different doses of orally
administered Condrosulf®, 300 or 900 mg/kg daily, in an
adjuvant arthritis animal model. Condrosulf® was able to
significantly reduce the extent of arthritis and the consequences occurring in this chronic inflammatory processes, in
particular the oxidative stress. The anti-arthritic effect was
confirmed by the capacity of Condrosulf® to improve the
total antioxidant status, GGT activity, and to reduce the production of pro-inflammatory cytokines, CRP in plasma,
phagocytic activity and the intracellular oxidative burst of
neutrophils.
Fig. (4). Possible beneficial roles of chondroitin sulfate (CS) in
multiple autoimmune diseases. CS may act by inhibiting the nuclear
translocation of the nuclear factor-B (NF-B), and consequently,
the synthesis of pro-inflammatory cytokines, such as TNF- and
IL-1, and of pro-inflammatory enzymes, such as cyclooxygenase2 (COX-2) and phospholipase A2 (PLA2). Published with permission from [60].
CONCLUSIONS AND FUTURE PERSPECTIVES
On the basis of the above reported trials, Condrosulf® is a
structure-modifying agent which has proven efficacy in the
symptomatic treatment of knee, hand and hip OA. Moreover,
some meta-analyses of placebo-controlled, randomized trials in
knee OA patients have assessed the efficacy of Condrosulf®
(and CS) in relieving joint pain along with excellent tolerability and no serious adverse events.
10 Current Medicinal Chemistry, 2014, Vol. 21, No. 1
Table 4.
Nicola Volpi
Animal Models and Related Biological Effects of Orally Administered Condrosulf®/Chondroitin Sulfate (CS)
Year
Animal Model
Biological Effects
Reference
1993
Adjuvant arthritis
Inhibition of induced arthritis
[86]
1998
Chymopapain-induced cartilage degradation
Significantly higher cartilage PG content in CS
treated animals. Protective effect on the damaged
cartilage
[87]
2000
Type II collagen induced arthritis
Reduction of arthritis index and serum anti-collagen II
antibody titer in a dose-dependent manner. Significant
inhibition of hind paw edema, synovitis and destruction of the articular cartilage
[88]
2004
Type II collagen induced arthritis
Significant reduction of hind paw edema, anti-type II
collagen antibody and TNF-alpha
[89]
2008
Atherosclerosis aggravated by chronic-antigen-induced arthritis
CS administration reduced CRP and IL-6. CS administration reduced the nuclear translocation of NF-kB
[90]
Adjuvant arthritis
CS reduced the severity of arthritis and oxidative
stress. CS improved total antioxidant status and GGT
activity. CS reduced the production of proinflammatory cytokines, CRP, phagocytic activity and
the intracellular oxidative burst of neutrophils
[69]
2011
Clinical trials and studies on Condrosulf® have been performed using a highly pure active drug, CS, having specific
physico-chemical properties as approved by the various National Institutes of Health [70-72]. This is very important
considering that specific CS activities strictly depend on its
purity, structural characteristics and properties. Moreover,
CS is orally administered and different pharmacokinetic and
bioavailability parameters may change depending on its
structure and origin [17, 18, 73]. On these basis, CS of low
quality for content and properties would be unable to have
paragonable pharmacological effects compared to pharmaceutical grade CS. Finally, the same clinical efficacy would
not be obtained unless different CS preparations had a comparable purity and structural characteristics. Related to this,
Condrosulf® having a standardized structure and composed
of a highly purified CS not less than 95%, was used to assess
the long-term combined S/MOAD effect [43].
degradation associated with arthritic/OA disease. Condrosulf® (and CS in general) beneficial properties may be further improved with the "design" and development of new
drugs possessing different and peculiar structures and characteristics. Moreover, new targets to treat inflammation state
derived from arthritis/OA condition, as well as to potentially
retard the cartilage matrix degeneration, should be evaluated
as potential future CS applications.
New outcome measures and novel biomarkers will
probably yield important advances in the area of SYSADOA
and S/DMOAD as well as in that of the degree of disease of
different joint structures affected by OA. In fact biomarkers
may allow sensitive and specific quantification of disease
processes in the different structures of the joint to tailor CS
treatment to the target tissue. A future challenge would prove
the capacity of biomarkers to predict OA in the asymptomatic patient, as this would allow selection of appropriate
patients to receive early CS treatment to obtain maximum
benefit. As a consequence, an important step towards future
research with CS (and Condrosulf®) would be the identification
of groups of patients showing similar features of the disease,
in order to establish a more appropriate relationship between
the severity of the pathology and therapy.
ABBREVIATIONS
Many studies on CS mechanism of action indicate that it
might reduce the inflammatory state and consequent tissue
CONFLICT OF INTEREST
The author(s) confirm that this article content has no conflicts of interest.
ACKNOWLEDGEMENTS
Declared none.
CIA
=
Collagen-induced arthritis
CRP
=
C-reactive protein
CS
=
Chondroitin sulfate
ECM
=
Extracellular matrix
EULAR
=
European League Against Rheumatism
GAG(s)
=
Glycosaminoglycan(s)
GAIT
=
Glucosamine/chondroitin Arthritis Intervention Trial
GalNAc
=
N-acetyl-galactosamine
GGT
=
-glutamyltransferase
GlcA
=
D-glucuronic acid
GlcN
=
Glucosamine
Condrosulf®
Current Medicinal Chemistry, 2014, Vol. 21, No. 1
KS
=
Keratan sulfate
[18]
NF-B
=
Nuclear factor kappa-light-chain-enhancer
of activated B cells
[19]
NSAID
=
Non-steroidal anti-inflammatory drug
OA
=
Osteoarthritis
OARSI
=
Osteoarthritis Research Society International
PG
=
Proteoglycan
PRR
=
Pattern-recognition receptor
[20]
[21]
[22]
S/DMOAD =
Structure/disease
arthritis drug
modifying
anti-osteo
[23]
SYSADOA =
Symptomatic slow acting drug for osteoarthritis
[24]
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Received: February 26, 2014
Revised: August 20, 2014
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