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V O L. 103 . N. 6 . P A G. 533-539 . DICEMBRE 2012

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IMPAIRED WOUND  HEALING  IN  DIABETES:

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THE  RATIONALE  FOR  CLINICAL  USE  OF
IN R

HYALURONIC  ACID  PLUS  SILVER  SULFADIAZINE

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M. PROSDOCIMI, C. BEVILACQUA
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 MINERVA MED 2012;103:533-9

Impaired wound healing in diabetes:

the rationale for clinical use
of hyaluronic acid plus silver sulfadiazine

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M. PROSDOCIMI 1, C. BEVILACQUA 2

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O
IC
Diabetes-related chronic cutaneous lesions 1Pharmacologist, Padua, Italy
are a serious and common problem, as well 2Biologist, Abano Terme, Padua, Italy
as a major cause for hospital admissions,

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although no general consensus has been
reached on the best available treatment for
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this frequent pathological condition. The pri-
mary objective of this review is to analyze the
most recent evidence supporting the clinical
use of a formulation containing hyaluronic
E
ing the general clinical situation, on the basis
of the synergic effect to control infection and
accelerate the tissue repair process.
M
acid (HA) and silver sulfadiazine (SSD) in the Key words:  Wounds and injuries - Diabetes
diabetic patient. This formulation has been complications - Hyaluronic acid - Silver sul-
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widely used in cutaneous lesions of various fadiazine - Wound healing.

etiology, both acute and chronic. The mecha-
VA

nisms underlying tissue repair are altered in

the diabetic patient with respect to a healthy
individual, namely for a diminished response
of the keratinocytes and a reduced capacity
A bout 170 million people are currently
suffering from diabetes mellitus (DM). It
is estimated that by 2025, 300 million people
of the endothelial cells to form new vessels
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worldwide will have DM, and this will rise to

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(neoangiogenesis). Since HA favours the tis-

sue repair process through various mecha- 360 million by 2030, equaling to a worldwide
nisms, among these an increased angiogenic prevalence of more than 4%. An estimated
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response and an activation of the keratino- 15% of patients with DM will develop a dia-
cytes, its application in diabetic lesions is a
betic foot ulcer (DFU) during their lifetime
IN

rational choice. SSD has been widely used

in acute cutaneous lesions, particularly in
burns, where it is considered the “gold stand-
ard” by which other treatments are measured.
The efficacy of SSD in terms of antibacterial
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and foot complications account for approxi-
mately one-quarter of all hospital days for
diabetic patients. Furthermore, not only the

foot is frequently affected, it is also known

activity spectrum on various types of micro-
organisms, with a favourable safety profile,
supports the potential use of SSD in diabet-
ic lesions, where the presence of infection
caused by bacteria resistant to most available
antibiotics, but not to SSD, is rather frequent.
In conclusion, the combined use of HA and
SSD in the diabetic patient proves a rational
choice and is potentially capable of improv-
Corresponding author: C. Bevilacqua, Fidia Farmaceutici
Spa, Abano Terme, Italy. E-mail: cbevilacqua@fidiapharma.it
that diabetes is a leading cause of chronic
pressure ulcers involving other parts of the
body. For instance, Escandon 1 performed a
retrospective cohort study of patients with
chronic wounds, reporting that this condition
is characterized by a high mortality rate, ap-
proaching that observed in cancer patients.
Patients with chronic wounds have a remark-
ably high incidence of co-morbidities, dia-
betes being one of the most frequently ob-

Vol. 103 - No. 6 MINERVA MEDICA 533

PROSDOCIMI IMPAIRED WOUND HEALING IN DIABETES
served. Indeed, heart disease was the most
frequent co-morbidity (64%) and diabetes
was the second most frequent co-morbidity,
being present in 52% of patients.
Generally, there is a lack of consensus on
the best available treatment for this com-
mon condition, frequently not respond-
ing to interventions that in other patients
are quite effective. On the other hand, it is
known that a series of multiple mechanisms,
including decreased cell and growth factor
response, lead to diminished peripheral
blood flow and decreased local angiogen-
esis, all of which can contribute to lack of
healing. In other words, diabetic foot ulcers
and pressure ulcers do not heal properly
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because of the underlying pathology, even
if there is no local obstacle to tissue repair.
Furthermore, due to the fact that healing is
slow and response to infections by the im-
mune system is decreased, the probability
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to develop infections is relatively high. This
may pave the way for a chronic wound po-
tentially leading to pain, reduced motility
and, possibly, to amputation in a substantial
percentage of patients.
A local intervention focused on bacterial/
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fungal proliferation on one side and on wound
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repair on the other side would be a rational
choice for diabetic foot ulcer treatment. A
combination of silver sulfadiazine (SSD) plus
hyaluronic acid (HA) at a well defined ratio,
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namely 5:1, has been widely used in several
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countries for acute and chronic wounds since
1995 under various trade names, including Con-
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nettivina Plus, Bionect Plus Effidia Plus, Jalplast
Plus and Jaloplast Plus. A review paper focus-
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ing on the rationale of its clinical use in the gen-
eral population has been published recently.2
In this document, we will briefly analyze the
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evidence supporting the use of a local inter-
vention with SSD and HA in diabetic patients
with chronic skin lesions, on the basis of their
mechanism of action and of the reasons lead-
ing to impaired tissue repair in these patients.
Rationale for the use of SSD
Silver is a rational choice for the treat-
ment of DFUs, as it will be later discussed,
534 MINERVA MEDICA December 2012
but this concept is neither proven nor dis-
proved by well-designed clinical trials. A
Cochrane review 3 summarizes this con-
cept, after an extensive literature analysis,
as follows: “Despite the widespread use of
dressings and topical agents containing sil-
ver for the treatment of diabetic foot ulcers,
no randomised trials or controlled clinical
trials exist that evaluate their clinical ef-
fectiveness”. Furthermore, Peters et al. in
their recent review,4 specifically devoted to
diabetic foot infections, came to a similar
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conclusion, summarized as follows: overall,
there are currently no trial data to justify
the adoption of any particular therapeutic
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approach in diabetic patients with infection
of either soft tissue or bone of the foot.
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On the other hand, the presence of bac-
teria potentially responding to SSD in di-
abetic lesions is quite clear. In particular,
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one should consider that silver is gener-
ally active against many strains of bacteria
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resistant to most available antibiotics and
SSD has a clear-cut activity. Generally, sil-
ver prevents wound infection because of
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its toxic action against many microorgan-
isms, including several fungi.5, 6 The mecha-
nism has been described by several authors
and it is widely accepted that respiratory
chain and electron transport enzymes are
inhibited, due to its capability of interaction
with SH groups, fundamental for enzymatic
functions. Many salts can be used, but SSD
is the most frequently used, on the basis
of long-standing experience and clinical ef-
ficacy.7 In the 1960s, Fox et al.8 pioneered
the use of the compound by topical route,
based on the knowledge about topically
administered silver nitrate and sulfadiazine,
used since the 1940s by oral route. Clini-
cal studies focused initially on infections
caused by Pseudomonas 8 and were rapidly
confirmed by several groups, mostly work-
ing on burns.
In 1974, Fox and Modak 9 reported sys-
tematically several observations and pro-
posed a theory for SSD mechanism of ac-
tion, substantially acceptable also today. At
the concentration usually applied (1%) sul-
fadiazine does not work by itself, but rather
synergizes with low concentrations of sil-
IMPAIRED WOUND HEALING IN DIABETES PROSDOCIMI

Table I.—Activity of Sodium Sulfadiazine and Silver obtained from a large cohort of human
Sulfadiazine against P. aeruginosa and animal origin. Focusing the attention
Compound (conc) Observation on microorganisms affecting DFUs, re-
Silver Sulfadiazine (micromoles/ml) cent reports point out the difference in the
0.004 No Effect strains observed in different countries. Re-
0.006 No Effect ports from Western countries and Australia
0.008 No Effect have found that Staphylococcus aureus and
0.010 Growth inhibition
Sodium Sulfadiazine (micromoles/ml) β-haemolytic streptococci are the main caus-
0.2 No Effect ative pathogens and antecedent therapy is
0.4 No Effect likely to increase the chances of the wound
0.4 No Effect yielding both polymicrobial growth (often
0.6 Growth inhibition comprising both aerobic and anaerobic

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1.0 Growth inhibition
Gram-positive and Gram-negative bacteria)
and resistant organisms. On the other hand,
a recent report disclosing data obtained in

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Table II.—Synergic activity of Sodium Sulfadiazine India indicated that Gram-negative bacteria
and Silver Sulfadiazine against P. aeruginosa O were found to have always been dominant

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Compound (conc) in the wounds of patients with diabetic foot
Sodium Sulfadiazine Silver Sulfadiazine Observation infections, and that infection with poly-mi-
(micromol/ml) (micromol/ml) crobial multidrug-resistant Gram-negative

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0.1 0.006 Growth inhibition bacilli is common.13 Interestingly, drug-re-
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0.4 0.002 Growth inhibition sistant organisms are over-represented in

ver. Clinical efficacy is due to continuous

interaction with fluids at the wound site,
able to sustain slow release of silver from
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E
samples obtained from diabetic foot ulcers
in comparison with other sources. A recent
example of this type of observations refers
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to a study from a secondary care multidis-
ciplinary diabetic foot clinic in Melbourne,

the salt, and synergic activity against micro- Australia, representative of many such units,
VA

organisms exerted by the combination.
Tables I, II summarize some of the origi-
nal observations reported in the quoted
paper. Table I describes the dose-response
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where MRSA was isolated from 23% of the
samples, a very high prevalence.14 In any
case, the microorganism found in DFUs will
respond to SSD in a very large majority of

relationships of both compounds separate- cases, and it is expected that resistance will
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ly, while Table II shows two examples of be very rare. Considering that silver prepa-
synergic activity. Quoting the words of Fox rations are widely used and their toxicity
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and Modak on their in vitro data obtained is generally considered extremely unlikely,
against Pseudomonas Aeruginosa: “a sub- it seems that SSD application to DFUs is a
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inhibitory amount of NaSD (0.4) becomes
inhibitory upon addition of a non inhibito-
ry amount (0.002) of AgSD. Likewise, a sub-
inhibitory level of AgSD (0.006) becomes
M
rational choice, although one has to admit
that clinical evidence supporting its use is
limited.

inhibitory upon addition of approximately

one sixth the inhibitory level of NaSD”.
Considering the antibacterial spectrum,
silver inhibits growth of many bacteria re-
sistant to antibiotics and of many fungi,
as extensively reviewed.10 This concept is
even more enforced by recent reports 11, 12
describing a very low occurrence of silver
resistance in Methicillin-Resistant Staphylo-
coccus Aureus (MRSA) samples originally
Rationale for the use of HA
In a recent review, Krafts 15 described the
general process of tissue repair as a drama,
where the main characters are involved in
the migration and proliferation of cells, the
laying down of the extracellular matrix, and
the remodeling of collagen to form a dura-
ble scar. As an example of the drama ending

Vol. 103 - No. 6 MINERVA MEDICA 535

PROSDOCIMI IMPAIRED WOUND HEALING IN DIABETES
badly, the author specifically mentions diabe-
tes, suggesting that several systemic factors
may adversely affect the performance of the
tissue repair drama. Patients with diabetes
mellitus tend to have less granulation tissue
formation, less collagen deposition and de-
fects in collagen maturation, leading to slow
and ineffective wound healing, and indeed
it is well known that skin lesions heal very
slowly even in the absence of infection.16 The
reason for this is a matter of debate: Brem
and Tomic-Canic 17 indicated that 100 known
physiological factors contribute to wound
healing deficiencies in individuals with dia-
betes, thus outlining the attention for the is-
sue as understood from the literature. Figure
O
1, slightly modified from the original paper,
summarizes some key features of the defec-
tive repair process observed in diabetic pa-
tients, specifically keratinocyte migration and
angiogenesis.
O
It is interesting to mention that HA posi-
tively affects many of the factors consid-
ered deficient in diabetic patients, at least
in vitro, as recently described in our review
paper 18 as well as in the review paper by
Frenkel.19 In this document we will brief-
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VA
P
R
E
IN
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Figure 1.—Mechanisms of wound healing in healthy people versus people with diabetes. (Modified from Brem and
Tomic-Canic 2007).
536 MINERVA MEDICA December 2012
ly touch the fact that HA strongly affects
some of the mechanisms of fundamental
importance in the process of wound heal-
ing, namely angiogenic response, keratino-
cyte migration and macrophage function,
clearly altered in diabetes.
The process of new vessel formation, de-
fined as angiogenesis, is of crucial impor-
tance in the tissue repair cascade of events.
Endothelial cells are the most relevant cell
type involved in the process and stimula-
tion of their proliferation may represent
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the best way to allow rapid tissue repair.
Diabetes researchers have been chasing
the “angiogenesis stimulator” in many dif-
A
ferent ways, including the use of stem cell
application and growth factor. This search
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has been largely based on the experimen-
tal and clinical evidence of a defective an-
giogenic response in the phase of wound
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repair observed in diabetes.17 On the other
hand, it is quite reasonable that HA may
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positively affect endothelial cell prolifera-
tion also in the setting of diabetic lesions.
The action of HA on angiogenesis has been
M
specifically analysed in several papers, in-
cluding our recent review.18-21 When ap-
IMPAIRED WOUND HEALING IN DIABETES PROSDOCIMI
plied to wounds, HA is metabolized by spe-
cific enzymes and by free radicals, with the
formation of small fragments of less than
12 sugars, usually defined oligomers. There
is a paradigm that can be considered well
defined in vitro: HA oligomers promote en-
dothelial cell proliferation, while high mo-
lecular weight HA decreases proliferation.
Recent evidence gathered in experimental
animals using various models confirmed
that this paradigm is well substantiated also
in vivo. HA promotes angiogenesis mainly
by stimulating endothelial cell proliferation,
and it is generally accepted that CD44 is
the major receptor mediating this HA ac-
tion, although the importance of other
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transduction systems cannot be underesti-
mated, in particular of RHAMM (Receptor
for HyAluronan-Mediated Motility). Overall,
one can conclude that endothelial cells are
particularly sensitive to the activity of HA
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oligomers, capable of activating an “angio-
genesis program” interacting with cellular
receptors on the cell surface, with involve-
ment of both CD44 and RHAMM receptors.
Macrophages are fundamental in the
wound healing process 1) for the forma-
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tion of the granulation tissue; and 2) for
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the production of several key growth fac-
tors and mediators that keep fuelling the
repair process, thus macrophage activation
may be considered a key mechanism sup-
P
porting tissue repair. The critical role of
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macrophages is demonstrated also by the
fact that their depletion in wounds leads to
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a delay in wound healing. Diabetes causes
a substantial reduction of macrophage re-
IN
sponse to inflammatory stimulation,22 pos-
sibly a major reason explaining the defec-
tive repair process shown by these patients.
M
Keratinocyte activation is fundamental in
tissue repair and endogenous HA is impor-
tant for regulation of keratinocyte prolifera-
tion and differentiation in vivo, both under
homeostatic conditions and in response to
tissue trauma. In the last few years, substan-
tial scientific evidence on the effect of ex-
ogenous HA on keratinocyte responses has
become available, and it is now clear that
stimulation by HA induces a migratory and
proliferative phenotype of epidermal ke-
Vol. 103 - No. 6 MINERVA MEDICA 537
ratinocytes, considered an essential feature
of the tissue repair process after injury.23, 24
Furthermore, recent evidence indicate that
HA modulates genes that control keratino-
cyte metabolism, proteolysis and cytoskele-
ton, as indicated by experiments performed
to investigate the global gene expression,
with and without exogenous HA.25
Macrophage activation is probably one
of the key mechanisms by which HA pro-
motes tissue repair after injury. Noble et al.26
described that low-molecular weight forms
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of HA (<500 kDa), but not larger fragments,
induce inflammatory responses in inflam-
matory macrophages. Furthermore, it has
A
been described that HA fragment stimula-
tion of inflammatory gene expression is not
IC
dependent on CD44 in inflammatory macro-
phages. Instead, HA fragments use both Toll-
like receptor (TLR) 4 and TLR2 to stimulate
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inflammatory genes in macrophages. Sub-
sequently, several laboratories have found
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similar results with a variety of cell types,
supporting the concept that HA fragments
potentially generated at sites of inflamma-
M
tion, but not native high-molecular-weight
HA, can stimulate the production of inflam-
matory mediators by many cell types.26, 27
The presence of diabetes may change
several cellular responses, reducing the ca-
pability of the body to restore tissue integri-
ty, while HA improves the process of tissue
repair by acting on many cells involved in
the process at different stages. Endothelial
cells, macrophages, fibroblasts and kerati-
nocytes are sensitive to HA fragment ac-
tion, all of them modifying their properties
toward a more “repair-oriented” condition,
in sharp contrast with diabetes. These con-
siderations support the notion that exog-
enous HA may accelerate wound healing in
diabetes, thus removing one of the causes
leading to chronic skin lesions.
Conclusions
HA use in the clinical setting is well es-
tablished, indeed an overall positive effect
of HA can be expected in the healing of
chronic wound ulcers of various etiolo-
PROSDOCIMI IMPAIRED WOUND HEALING IN DIABETES
gies, burns, and epithelial surgical wounds,
no matter the form in which HA is deliv-
ered topically.28, 29 On the other hand, SSD
is considered a fundamental resource by
WHO, being part of the List of Essential
Drugs as 1% cream in the anti-infective cat-
egory.30 Furthermore, SSD has long been
recognized as the mainstay of topical burn
therapy, with broad antimicrobial proper-
ties and a relatively small side-effect pro-
file, indeed it continues to be the standard
by which other treatments are measured.7
Coupling the considerations regarding HA
activity on tissue repair in diabetes with
those supporting SSD application in various
types of wounds to control microbial pro-
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liferation, it appears that simultaneous ap-
plication of SSD and HA may be a rational
choice for the treatment of chronic lesions
affecting diabetic patients. Simultaneous ap-
plication is made possible by a formulation,
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commercially available in several countries
since 1995, containing HA and SSD at a 1:5
ratio, i.e. 100 g of the product contain 200
mg of HA and 1,000 mg of SSD, the same
concentrations that are present in the com-
mercially available formulations containing
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each product individually. This concentra-
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tion of HA does not reduce the antibacterial
activity of SSD on several microorganisms
in vitro.2 In the clinical setting, HA-SSD
long-standing use demonstrated excellent
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tolerability in a variety of patients with dif-
R
ferent conditions, including diabetes, in
several countries, as one would expect with
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the single component. With particular refer-
ence to patients with chronic lesions and
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diabetes, Peghetti et al.31 studied 127 hos-
pitalized patients with grade-2 and -3 pres-
sure sores, with a variety of co-morbidities,
M
including diabetes (11%). The authors ob-
served, at variance with the expected poor
outcome frequently observed in such popu-
lations, that a high percentage of patients
improved: improvement or complete heal-
ing of the pressure sores was observed in
67% of patients at early follow-up (10 days),
increasing to 76% and 87% at 20- and 35-
day controls, respectively. The Push tool
further improved in patients who carried
on treatment. On the other hand, clinical
538 MINERVA MEDICA December 2012
evidence of efficacy for the formulation in
DFUs is not available at present, although
it must be emphasized that practically no
intervention can be considered effective on
the basis of evidence-based medicine, due
to the variability of the underlying pathol-
ogy and the limited possibility of meaning-
ful clinical evaluation of the interventions.
The available evidence fully support the
rationale for clinical use of the formulation
here described in diabetic patients, on the
basis of the preclinical data available for
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each component in microorganisms, in ex-
perimental animals and in human cells in
vitro, as well as on the basis of clinical data
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obtained for each component and for the
combination product in patients with differ-
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ent pathological conditions.
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Riassunto
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Ridotta capacità riparativa delle ferite nel diabete:
la base razionale per l’uso dell’acido ialuronico as-
sociato alla sulfadiazina d’argento
M
Le lesioni cutanee croniche nel diabetico rap-
presentano un problema grave e frequente, sono
infatti una delle cause principali di ospedalizza-
zione, anche se manca un consenso generale su
quale sia il trattamento più appropriato per questa
diffusa condizione patologica. Obiettivo della ras-
segna è stata la analisi dei più recenti meccanismi
che sono alla base dell’uso clinico nel diabetico di
un prodotto contenente acido ialuronico (HA) e
sulfadiazina argentica (SSD), prodotto ampiamen-
te applicato in lesioni cutanee di varia origine sia
acute che croniche. I meccanismi della riparazione
tessutale sono alterati nel diabetico rispetto ad un
soggetto sano, principalmente per una ridotta ri-
sposta dei cheratinociti e per una ridotta capacità
di neoangiogenesi delle cellule endoteliali. Poiché
HA favorisce il processo di riparazione tissutale
attraverso vari meccanismi, tra cui una aumentata
angiogenesi ed una attivazione dei cheratinociti,
risulta dunque razionale applicarlo nella lesione
diabetica. SSD è largamente utilizzata nelle lesio-
ni cutanee acute, in particolare nelle ustioni, dove
è considerata “gold standard” con cui paragonare
nuovi trattamenti l’efficacia di SSD in termini di
spettro di attività su microorganismi di vario tipo,
con rare segnalazioni di eventi avversi, rendono
SSD potenzialmente molto utile nelle lesioni dei
pazienti diabetici, nei quali la comparsa di infezio-
ni causate da batteri resistenti a molti antibatterici,
ma non a SSD, è assai frequente. In conclusione,
l’uso della combinazione tra HA e SSD nel pazien-
IMPAIRED WOUND HEALING IN DIABETES PROSDOCIMI
te diabetico appare razionale e potenzialmente ca-
pace di condurre ad un miglioramento del quadro
clinico per l’effetto sinergico di controllo dell’infe-
zione e accelerazione del processo di riparazione
tessutale.
Parole chiave: Ferite e lesioni – Diabete, complican-
ze - Acido ialuronico - Sulfadiazina d’argento - Ri-
parazione tessutale.
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26. Noble PW. Hyaluronan and its catabolic products in
tissue injury and repair. Matrix Biol 2002;21:25-9.
27. Jiang D, Liang J, Noble PW. Hyaluronan in tissue injury
and repair. Annu Rev Cell Dev Biol 2007;23:435-61.
28. Chen WY, Abatangelo G. Functions of hyaluronan in
wound repair. Wound Repair Regen 1999;7:79-89.
29. Voigt J, Driver VR. Hyaluronic acid derivatives and
their healing effect on burns, epithelial surgical
wounds, and chronic wounds: A systematic review
and meta-analysis of randomized controlled trials.
Wound Repair Regen 2012;20:317-31.
30. WHO Model List of Essential Medicines [Internet].
Available at http://whqlibdoc.who.int/hq/2011/
a95053_eng.pdf [cited 2012, Nov 6].
31. Peghetti A, Bellingeri A, Pomponio G, Sansoni S,
Paladino D. Efficacia dell’acido ialuronico associato
alla sulfadiazina (Connettivina Plus) nel trattamento
delle lesioni da pressione: uno studio di coorte os-
servazionale prospettico. Professioni Infermieristiche
2009;62:67-77.
Received on October 30, 2012.
Accepted for publication on November 6, 2012.
 CONNETTIVINA PLUS
Acido ialuronico sale sodico + sulfadiazina argentica
Riassunto delle Caratteristiche del Prodotto
1. DENOMINAZIONE DEL MEDICINALE CONNETTIVINA PLUS 0,2 % + 1 % crema; CONNETTIVINA
PLUS 2 mg + 40 mg garze impregnate; CONNETTIVINA PLUS 4 mg + 80 mg garze impregnate;
CONNETTIVINA PLUS 12 mg + 240 mg garze impregnate D03AX05 Acido ialuronico sale sodico +
sulfadiazina argentica. 2. COMPOSIZIONE QUALITATIVA E QUANTITATIVA 2.1 Principi attivi Acido
ialuronico sale sodico, Sulfadiazina argentica. CONNETTIVINA PLUS 0,2% + 1% crema 100 g di crema
contengono: Acido ialuronico sale sodico 200 mg, Sulfadiazina argentica 1,00 g. CONNETTIVINA PLUS
2 mg + 40 mg garze impregnate ogni garza da cm 10x10 è imbibita con 4 g di crema, CONNETTIVINA
PLUS 4 mg + 80 mg garze impregnate ogni garza da cm 10x20 è imbibita con 8 g di crema,
CONNETTIVINA PLUS 12 mg + 240 mg garze impregnate ogni garza da cm 20x30 è imbibita con 24 g
di crema della seguente composizione percentuale: Acido ialuronico sale sodico 50 mg, Sulfadiazina
argentica 1,00 g 3. FORMA FARMACEUTICA Crema – garze impregnate 4. INFORMAZIONI CLINICHE
4.1 Indicazioni terapeutiche Profilassi e trattamento locale di piaghe, ulcere varicose e ustioni.
4.2 Posologia e modo di somministrazione CONNETTIVINA PLUS 0,2% + 1% crema: stendere
su tutta la sede della lesione uno strato uniforme di crema di 2-3 mm di spessore, una o due volte
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al giorno. CONNETTIVINA PLUS 2 mg + 40 mg garze impregnate, CONNETTIVINA PLUS 4 mg + 80
mg garze impregnate, CONNETTIVINA PLUS 12 mg + 240 mg garze impregnate: applicare una o
più garze medicate due o più volte al giorno a seconda dell’estensione delle lesioni. L’applicazione
deve continuare senza interruzione, fino a completa cicatrizzazione. 4.3 Controindicazioni
Ipersensibilità verso i componenti del prodotto o altre sostanze strettamente correlate dal punto di
vista chimico. 4.4 Speciali avvertenze e precauzioni per l’uso CONNETTIVINA PLUS deve essere
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utilizzata con cautela in soggetti che hanno manifestato precedenti allergie verso i sulfamidici
ed in presenza di insufficienza epatica o renale. 4.5 Interazioni con altri medicinali e altre
forme di interazione Enzimi proteolitici locali, applicati contemporaneamente a CONNETTIVINA
PLUS, possono essere inattivati dalla presenza di ioni argento. 4.6 Gravidanza e allattamento
Non esistendo esaurienti dati sperimentali sugli eventuali effetti collaterali del farmaco sul feto,
CONNETTIVINA PLUS non dovrebbe essere impiegata durante la gravidanza e nell’allattamento a
meno che, a giudizio del medico, il suo impiego sia indispensabile. 4.7 Effetti sulla capacità di
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guidare e di usare macchinari Il farmaco non interferisce sulla capacità di guidare e sull’uso di
macchine. 4.8 Effetti indesiderati A seguito di applicazione di CONNETTIVINA PLUS potrebbero
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raramente verificarsi reazioni di tipo locale, di modesta entità. Non sono mai pervenute segnalazioni
di reazioni avverse di tipo sistemico, infatti l’assorbimento percutaneo di CONNETTIVINA PLUS è
trascurabile. Tuttavia, poiché la somministrazione sistemica di sulfamidici può provocare reazioni
avverse quali insufficienza renale, epatite tossica, agranulocitosi, trombocitopenia e leucopenia,
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non si può escludere che il trattamento di estese parti del corpo con CONNETTIVINA PLUS
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possa dar luogo ad effetti indesiderati classici dei sulfamidici somministrati per via sistemica.
4.9 Sovradosaggio Non sono noti casi di sovradosaggio. 5. PROPRIETÀ FARMACOLOGICHE
5.1 Proprietà farmacodinamiche CONNETTIVINA PLUS è un’associazione di acido ialuronico e
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sulfadiazina argentica. L’acido ialuronico è un mucopolisaccaride acido che costituisce oltre il 50%
Connettivina Plus crema tubo da 25 gr
Connettivina Plus garze impregnate cm 10x10
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della sostanza fondamentale del derma; si ritrova inoltre in concentrazioni elevate nell’umor vitreo,
nel liquido sinoviale, nel funicolo ombelicale e nella cartilagine ossea. L’apporto locale di acido
ialuronico determina l’accelerazione del processo di cicatrizzazione delle lesioni. La sulfadiazina
argentica ha una notevole attività antibatterica su molti germi gram positivi e gram negativi e
su molte specie di funghi. Notevole è la sua attività su Pseudomonas aeruginosa e Enterobacter
pyogenes che sono i microorganismi più frequentemente riscontrabili nelle ferite ed ustioni
infette. Grazie all’azione complementare dei due componenti attivi, CONNETTIVINA PLUS previene
l’infezione secondaria e favorisce la cicatrizzazione delle lesioni. 5.2 Proprietà farmacocinetiche
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L’assorbimento di acido ialuronico e di sulfadiazina d’argento per via topica è clinicamente
insignificante. I livelli plasmatici di sulfadiazina sono nettamente inferiori alla soglia per rischi
di natura sistemica. Dopo applicazione cutanea di una dose terapeutica di CONNETTIVINA PLUS
risulta infatti assorbito mediamente solo l’1% della quantità di sulfamidico che viene assorbita dopo
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somministrazione orale di una dose terapeutica di sulfadiazina. 5.3 Dati preclinici di sicurezza
La DL50 - os e i.p. nel ratto e nel topo dell’acido ialuronico è > 200 mg/kg. La DL50 - os nel topo
della sulfadiazina è >10.000 mg/kg. Gli studi di tossicità cronica dell’acido ialuronico, eseguiti su
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varie specie di animali, non hanno evidenziato tossicità. La somministrazione a lungo termine di
sulfadiazina ha determinato nefrotossicità solo a dosi orali molto elevate. Tra i costituenti attivi di
CONNETTIVINA PLUS non si stabiliscono interferenze di alcun genere relativamente a eventuali
effetti tossici. L’associazione si è dimostrata priva di potere antigenico e dotata di ottima tollerabilità
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locale. 6. INFORMAZIONI FARMACEUTICHE 6.1 Lista degli eccipienti CONNETTIVINA PLUS
0,2% + 1% crema: Polietilenglicole 400 monostearato - estere decilico dell’acido oleico - cera
emulsionante - glicerolo - sorbitolo soluzione 70% - acqua depurata CONNETTIVINA PLUS 2 mg +
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40 mg garze impregnate, CONNETTIVINA PLUS 4 mg + 80 mg garze impregnate, CONNETTIVINA
PLUS 12 mg + 240 mg garze impregnate: Polietilenglicole 4000 - glicerolo - acqua depurata 6.2
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Incompatibilità Non sono note incompatibilità. 6.3 Validità Il prodotto è stabile per 36 mesi a
confezionamento integro. 6.4. Speciali precauzioni per la conservazione Non conservare al di
sopra di 30°C. 6.5. Natura e contenuto del contenitore e prezzo. Crema: tubo in alluminio da
25 g. Garze impregnate: busta singola sigillata di carta-alluminio-politene. Scatola da 10 garze
impregnate cm 10x10. Scatola da 10 garze impregnate cm 10x20. Scatola da 5 garze impregnate
cm 20x30. 6.6 Istruzioni per l’uso Nessuna particolare. 7. TITOLARE DELL’AUTORIZZAZIONE
ALL’IMMISSIONE IN COMMERCIO Fidia farmaceutici S.p.A. - Via Ponte della fabbrica, 3/A 35031
Abano Terme (PD) Tel ++39 049 8232111 - fax ++39 049 810653. Codice Fiscale n 00204260285.
8. NUMERO DELL’AUTORIZZAZIONE ALL’IMMISSIONE IN COMMERCIO CONNETTIVINA PLUS
0,2% + 1% crema: A.I.C. 028440030. CONNETTIVINA PLUS 2 mg + 40 mg garze impregnate:
A.I.C. 028440079. CONNETTIVINA PLUS 4 mg + 80 mg garze impregnate: A.I.C. 028440055.
CONNETTIVINA PLUS 12 mg + 240 mg garze impregnate: A.I.C. 028440067. 9. DATA DI PRIMA
AUTORIZZAZIONE/RINNOVO DELL’AUTORIZZAZIONE 15/11/1999. 10. DATA DI (PARZIALE)
REVISIONE DEL TESTO 13/06/2000.
Classe C RR prezzo al pubblico € 10,25
Classe C RR prezzo al pubblico € 11,40
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Cod. 0000000 Depositato presso AIFA in data 00/00/2012