2.1 Normal
Saline - NaCl 0.9%
Normal saline (from here will be mentioned as
saline) consisting of sodium chloride (NaCl) diluted
in sterile water with concentration of 0.9% (9g/L of water). Saline is commonly
used for i.v. injection to treat dehydration or for
external use such as wound irrigation. In wound irrigation, saline itself
doesn't provide any significant benefit compared to sterile water. Saline being
an easy to use antiseptic is preferred for wound irrigation (Beam JW, 2006).
2.2 Chlorhexidine
Chlorhexidine is a biguanide antiseptic with 2 common formulations: (a)
chlorhexidine gluconate (CHG) in alcohol based formulation and (b) chlorhexidine digluconate (CHD) in
water based formulation. Chlorhexidine is worked in a physiological pH (pH:
5.5-7.0) by releasing a chlorhexidine cation from chlorhexidine salt.
This cation is readily adsorbed by negatively charged
bacterial cell walls, causing membrane disruption. Due to its pH dependent
mechanism of action, chlorhexidine can be deactivated by other skin cleansers
(Deck and Winston, 2012).
The antimicrobial
activity of chlorhexidine is effective against a broad spectrum of pathogens but
especially effective against gram positive cocci such as Staphylococcus aureus. Chlorhexidine is
also effective against gram negative rod and cocci such as Pseudomonas aeruginosa but not to the extent of its effect against
positive gram bacteria (Payne et al, 1999). Routine usage of chlorhexidine has
also proven to be effective against sporal bacteria
due to its persistent effect, resulting in a similar effect such as alcohol
disinfection but requiring longer time (McDonnell and Russell, 1999).
Chlorhexidine is not effective against viral infection (Deck and Winston, 2012)
and not recommended against MRSA due to developed resistance (Cookson et al,
1991).
Since its invention in
1946, chlorhexidine has been used in the medical world as an antiseptic.
Chlorhexidine has been used for hand wash and pre-operative disinfection but use
of chlorhexidine in wound treatment is limited for wound irrigation (Russel, 2003). Chlorhexidine failed to provide any other
benefit in wound healing process other than its antiseptic properties and might
even prove detrimental if used in cases other than for irrigation (Main, 2008).
Chlorhexidine can't be used for middle ear surgery and neurosurgery due to its
neurotoxicity (Deck and Winston, 2012).
2.3 Povidone-iodine
Povidone-iodine
(PVP-1) is an iodophore antiseptic commonly used for
topical disinfection. As its name suggest, PVP-1 is a chemical complex of povidone, hydrogen iodide and iodine. The bacteriocidal action of PVP-1 is attributed to the presence
of free iodine provided in PVP-1, while povidone
bonded to iodine provides a slow release of free iodine to reduce toxicity and
side effect. Free iodine will alter membrane structure and prevent hydrogen
bonding of pathogens. It has a broad spectrum of antiseptic activity and is
frequently used for treating minor wound and surgical disinfection (Cooper,
2004). PVP-1 is effective against a broad spectrum of bacteria including gram
positive, negative and even MRSA. Aside from bacteria, PVP-1 is also effective
against other kind of pathogen including mycobacteria, yeast,
dermatophyte, encapsulated and unencapsulated
virus and protozoa. PVP-1 is also effective against bacterial spore in a
prolonged application (Deck and Winston, 2012).
PVP-1 doesn't provide
any benefit in wound healing process compared to other antiseptics such as PHMB
(polyhexamethylene biguanide)
and silver. Even so, PVP-1 doesn't cause as much pain during dressing change
compared to silver dressing. In general, wound healing process using PVP-1 takes
around 2-3 weeks (Kramer et al, 2018). Further, PVP-1 shows anti-inflammatory
activities which help the wound healing process (Bigliardi
et al, 2017). Usage of PVP-1 for longer than 7 days is not recommended because
prolonged use of PVP-1 may alter thyroidal function. If there is no other option
for antiseptic dressing, routine thyroid function test should be conducted in a
prolonged use. Extra attention should be given in application for pregnant
woman, infant ageing less than 6 months and patient with thyroid disease.
Contraindications for PVP-1 include hypersensitivity, hyperthyroid goiter, dermatitis herpetiformis, undergo radioiodine therapy or peritoneal
lavage (Kramer et al, 2018).
2.4 Silver
Sulfadiazine
Silver sulfadiazine (SSD) is a topical
antibiotic commonly used for wound dressing, especially to prevent infection in
burns. Antibiotic property of SSD is attributed to the presence of silver ions
and sulfadiazine released when in contact with aqueous environment such as
bodily fluid in burn wound. Silver ions are readily absorbed by bacteria and
bind to negatively charged proteins and nucleic acids resulting in disruption of
cell membrane and internal function. Sulfadiazine also helps by inhibiting dihydropteroate synthase enzyme (Cooper, 2004).
The antibacterial
activity of silver is effective against both gram positive and negative bacteria
(Hermans, 2006). Due to the universal antibacterial mechanism
of silver by causing proton leakage, silver also shows broad spectrum of
antimicrobial activity against yeast and virus. Silver is especially effective
in preventing the colonization of P.
aeruginosa that frequently infect burn wound (Fong et al, 2005).
Complimenting antimicrobial property of silver, SSD also showed positive
properties to help in wound healing process. In pig with clean wound,
application of SSD dressing increased the epithelialization rate by 28% (Geronemus et al, 1979). Usage in human showed increase in
quality of care by reducing the number of bacterial count, increased healing and
decrease in pain. Silver is also capable of inhibiting wound odor and secretion (Kramer et al, 2018).
Silver nanoparticles
are also known to have anti-inflammatory properties which help in wound healing
process (Wong et al, 2009). Due to its activation mechanism, silver is best used
for healable wound with high risk of colonization such as burn wound. Silver is
not recommended to be used for maintenance wound because the main goal of the
treatment is to reduce moisture which will prevent the activation of silver's
antimicrobial activity (Sibbald et al, 2017). However,
silver is not recommended to be used for longer than 14 days or as a prophylaxis
(Kramer et al, 2018). Side effect that may occur during usage of SSD can be
caused by reaction towards sulfonamide. These
reactions include blood diascariasis,
hypersensitivity, steven-johnson syndrome, toxic
epidermal necrolysis and
exfoliative
dermatitis. Reaction can also occur in gastrointestinal tract, liver, central
nervous system and kidney. Usage of SSD in patient with G6PD deficiency can
cause hemolytic reaction (Caffee
and Bingham, 1982).
2.5
Polyhexamethylene-Biguanide
Polyhexamethylene-biguanide (PHMB) is
a biguanide antibiotic used for disinfectant and
antiseptic. PHMB is a polymer with positive charge which helps to deliver the
active component to the negatively charged bacterial wall. This will cause the
loss of fluidity in bacterial cell wall, causing the dissolution of bacteria. It
is essentially a better version of chlorhexidine, providing the same efficacy
but with better safety and tolerability (Kramer et al, 2018). PHMB is effective
against a broad spectrum of pathogens including positive and negative gram
bacteria, yeast and virus (Sibbald et al, 2017).
Further, PHMB is able to prevent and treat infection from bacteria that commonly
infect wounds such as P. aeruginosa, S. aureus and even MRSA (Fabry et al, 2013).
In addition to its
antimicrobial activity, PHMB also helps in the process of wound healing (Sibbald et al, 2017). During both in vitro (Hubner et al, 2010) and in vivo studies (Perez et al, 2010)
PHMB is able to destroy biofilm and speed up wound healing process as reflected
in an increased capillary density and increase in arteriole diameter (Goertz et al, 2011). PHMB also showed anti-inflammatory
activities in wound healing process (Gentile et al, 2012). PHMB has a wide array
of formulation and application. PHMB is commonly available in the form of
solution, hydrogel and for wound dressing (Eberlein
and Assadian, 2010). PHMB is best used for chronic
exudative wound with a high risk of bacterial colonization (Sibbald
et al, 2017). PHMB foam dressing formulation is especially effective when used
in conjunction with negative pressure wound treatment in treating diabetic ulcer
and burn wound (Eberlein T and Kanis J, 2014). Side effect rarely occurs in PHMB usage but
may include hypersensitivity. Aside from hypersensitivity, contraindication
results if given to pregnant woman with less than 4 months old pregnancy (Kramer
et al, 2018).
2.6 Dalethyne
Olive oil is composed of 98% triglycerides,
including predominantly mono unsaturated oleic acids, their anti-inflammatory
properties being proven to be essential for skin maintenance. Dharshan developed Dalethyne based
on rearrangement of the structure of olive oil based on substituent variation
and reported 18 different dalethyne derivatives by varying the side chains of
the parent scaffold (Darshan, 2018a). These 18
compounds have been categorised into four different groups, namely peroxide,
aldehyde, iodine and anisidine.
Iodine, peroxide, and
anisidine are compounds that play a role in the
epidermis and dermis level and work in cleaning the wound area (killing
bacteria), so that a conducive environment is created for the repair process.
Peroxide has the ability to trigger the performance of macrophages and
neutrophils, which play a role in engulfing bacterial cells, dying cells, and
dead cells. In the process, the macrophages will secrete pro-inflammatory
cytokines such as IL-6, TNF-α, and IL-18 which in turn maximize the inflammatory
response in the body. The three cytokines play essential role in the
inflammatory process and the wound area is cleared of dead bacterial cells and
body cells in a faster time than without assistance of the cytokines. IL-6 will
trigger an acute phase response, where this process will trigger the formation
of fibrin to cover the wound area, so that bacteria cannot enter the wound (Desborough
2000). Of the four types of compounds contained in Dalethyne,
only the aldehydic compounds are able to infiltrate and work in the
hypodermic layer. When a wound occurs, the released ATP or extracellular ATP in
the injured tissue has reduced ability to trigger the wound healing process. So,
the presence of the aldehyde in the hypodermic area will trigger extracellular
ATP, so that more ATP will be released from the surrounding cells through the
process of sugar metabolism. High ATP can induce the body's response to injuries
by activating the release of the growth factors such as TGF-α, EGF, βFGF etc.
The higher the ATP in the environment, the higher is the growth factor level.
EGF and βFGF will promote reepithelialization
and induce collagen and keratin synthesis (Laato et
al., 1987). TGF-β, TNFα, and IL-1 will enter hypodermis and trigger collagen
synthesis. Collagen in the hypodermis will rise to the upper layer.
Subsequently, the growth factors trigger the occurrence of angiogenesis and
granulation. The increase in collagen concentration in the dermis and epidermis
layer is conducive to the initiation of repair processes such as
epithelialization, fibroplasia and neovascularization (Velnar
et al., 2009).
In chronic wounds,
necrotic tissue around the wound causes inhibition in the process of repairing
the wound (because the body is unable to do autolysis), so the tissue needs to
be debrided. Accumulates dead cells, pathogens, and exudates take place in the
necrotic tissues. Debridement resulting from effective application of topical
drugs to chronic wounds has a positive impact facilitating induction of a
process of wound repair. However, the negative impact of debridement is to open
the entry pathway of bacteria into the blood vessels, which affects other
complications. MRSA is also found in areas of chronic injury, especially in
necrotic tissue in diabetic foot disease, while entry of the bacteria into the
blood vessels leads to sepsis (Bowling et al.; 2009). The use of Dalethyne may
minimize areas treated with debridement and having a broad-spectrum
antibacterial abilities (can kill groups of bacteria that are resistant to
antibiotics such as ESBL, KPC, and MRSA) without causing resistance, dalythene can work effectively in healing skin due to
chronic wounds. Herewith, we summarized some studies both experimental (in vivo
and in vitro) as well as clinical study in involving the use of Dalethyne as
antiseptic and wound healing agent.
2.6.1
Antiseptic action of dalythene
Several studies have been conducted to explore
the antiseptic activities of Dalethyne ranging from in silico, in vitro and in vivo studies.
In silico analysis:
Dalethyne cream
facilitates the wound healing process by activating the molecular mechanism
involved in the wound healing process. Dalethyne has been predicted to be able
to lower inflammatory agents such as MMP-9 and COX-2. It is also able to reduce
oxidative stress, modulate the expression of growth factors (FGF-2 and TGF-βl)
and inflammation mediators (IL-lβ and IL-6) (Darshan,
2018a).
According to the
docking result of the 18 Dalethyne derivatives, methyl 8-octadecanoate has a
conducive inhibitory activity against C. albicans and P.
aeruginosa. Methyl palmitate has a good activity
against HSV-1 (Herpes simplex viruses) and methyl-6, 6-dimethoxyoctanoate shows
excellent against HPV-1 (Human papillomavirus). Dalethyne exerts potential
activity against Candida
albicans
and Candida glabrata
by inhibiting the fungi’s enzymatic activity resulting in malnutrition of the
pathogen. Dalethyne also exhibits good inhibitory potential against bacteria
especially Peudomonas aeruginosa
and MRSA. Dalethyne showed little activity against HSV-1, HSV-2 and HPV-16 but
showed most promising action against HSV-1 (Darshan
observation, Report UI. Study in Silica of Dalethyne against Wound Healing
Bacteria).
Based on the variance
of bacteria tested, Pseudomonas aeruginosa,
Escherichia coli and Klebsiella Pneumonia constituted the gram-negative
bacteria group, while MRSA, Staphylococcus
aureus,
Streptococcus
pyogenes and Aerococcus viridans constituted the gram-positive
bacteria group. It has been reported that Methyl linoleate
can inhibit four bacteria namely,
Staphylococcus aureus (with penicillin binding protein mechanism and
sortase
mechanism), Streptococcus pyogenes, Aerococcus viridans, and
Escherichia coli. Again, Methyl myristate shows
activity by inhibiting bacteria like
Staphylococcus aureus with DNA gyrase B
mechanism, Streptococcus pyogenes, Aerococcus viridans, and
Escherichia coli. On the other hand, Dimethyl azelate
can inhibit MRSA, Staphylococcus aureus
with penicillin binding protein mechanism and Klebsiella neumonia. Methyl 11-eicosanoate is also
capable of inhibiting bacteria like
Pseudomonas aeruginosa, Staphylococcus
aureus
with penicillin binding protein mechanism and Klebsiella neumonia. From 18 Dalethyne compounds, 13
compounds have been found to inhibit 7 bacteria (gram-negative and
gram-positive), thereby exhibiting excellent potential as broad-spectrum
antibacterial agent (Darshan observation, In silica study of wound healing mechanism, antibacterial,
antifungal and antiviral activities of Dalethyne).
In vitro studies analysis:
Dalethyne is
effective against a wide array of pathogens commonly found in wound infection.
Dalethyne is able to inhibit the formation and destroy biofilm produced
pathogens, requiring lower concentration to inhibit bacterial growth compared to
inhibition or destruction of biofilm (Darshan
observation, Effectivity of Dalethyne against
biofilm). As an antiseptic, Dalethyne is effective against Pseudomonas aeruginosa, MRSA, Clostridium pefringens,
Candida albicans,
Staphylococcus aureus
and Streptococcus
pyogenes. Dalethyne at the 30 % concentration has a phenol
coefficient value to Salmonella typhi
bacteria of 3.63, while for Staphylococcus
aureus bacteria of 4.44. These results prove that Dalethyne at 30%
concentration has antiseptic effects against Salmonella typhi bacteria 3.63 times
better than phenol, while for
Staphylococcus aureus bacteria its ability is 4.44 times better than that of
phenol. The results for the percentage of bacteria killed indicate that this
compound is most effective to eliminate
Pseudomonas aeruginosa and
Clostridium
perfingens. Its effectiveness for Candida albicans
is not as good as to bacteria mentioned before since it takes long contact time
to be able to give effect as expected (Darshan KS,
2018b, c). Dalethyne is also effective against other multiple drug resistant
organisms such as ESBL E. coli, ESBL K. pneumonia and
Carbapenem
resistant K. pneumonia (Darshan observation, Dalethyne:
effectiveness study on microbes which cause nosocomial infection an in vitro
study).
In vivo study analysis:
Dalethyne has been
tested on incised wound on rat infected with clinical isolate of bacteria
including: S. aureus, S. epidermidis, S. pyogenes, P.
aeruginosa, A.
baumanii, MRSA, ESBL E. coli,
ESBL K. pneumonia, Carbapenem resistant K. pneumonia and candida fungus. Topical application of Dalethyne on
infected wound incision resulted in 0 mortality by day-7, together with
increased macroscopic and microscopic wound healing. Increased microscopic wound
healing is indicated by perfect epithelialization, sufficient fibroplasia,
increased vascularization and no scar by day-7. Infection had lengthened the
inflammation period, distracted the fibroplasia and neovascularization process,
resulting in longer duration of wound healing process (Darshan
observation, Dalethyne effectivity
study on infected incised wound of rattus norvegicus)
2.6.2 Wound healing
In studies conducted on rat, topical
application of Dalethyne product on incised skin provided faster wound healing
compared to placebo. Placebo consisted of vehicle cream without Dalethyne. In
placebo group, erythema and edema still occurred on
the 3rd day, while the incised wound has dried up on the 6th
day and was covered in crustae. In Dalethyne group,
erythema and oedema was abated on the 3rd day, while majority of the incised
wound closed up on the 6th day. Dalethyne increased the rate of erythema and edema abatement and wound closing compared to placebo. In a
study conducted on rat, topical application of Dalethyne on incised wound on rat
tend to increase macroscopic and microscopic wound healing by day-7. Microscopic
wound healing indicated by perfect epithelialization, sufficient fibroplasia,
increased vascularization and no scar was left by day-7 (Darshan observation, Dalethyne
acute toxicity study on the incised wound healing rattus
norvegicus).
2.6.3 Toxicity and Clinical studies
Several in vivo studies have been conducted to
explore the possible toxicity and side effect caused by topical application of
Dalethyne. On study of intramuscular LDSO acute toxicity using 4ml/kg BW dose,
intramuscular injection of Dalethyne in rat's thigh did not cause any side
effect or mortality (Darshan observation, LDSO Acute
toxicity study of intramuscular injection of Dalethyne) Topical application of
Dalethyne on incised wound inn rat didn't cause any mortality until day-7.
Further, topical application of Dalethyne product on rabbit's intact skin
doesn't cause irritation or hypersensitivity reaction and also no internal organ
toxicity on both intact and incised skin. The acute skin irritation study of
Dalethyne in all 3 doses of concentration (20%, 30% and 40%) in rabbit showed no
sign of skin irritation, similar to control/vehicle (glycerine) (Darshan
observation, Acute
skin irritation study of Dalethyne in rabbit). Further, clinical study has been
conducted for the usage of Dalethyne in human. Dalethyne could be used for grade
0-1 diabetic foot ulcer, dry skin, acne and mild burn.
3.
CONCLUSION
The present review provides a precise summary
of the various wound healing agents that are traditionally used for the
treatment of wounds. In addition, a comparison table has been presented in the
present review to determine the wound healing potential of the Dalethyne
derivatives over the traditionally known components. The antiseptic action of
the compounds have also been analysed in the present review which adds to the wound healing
potential of the different components. Most of the traditionally known
components exhibit limitation in inhibiting all the bacteria that are commonly
known for infecting the wounds. However, the Dalethyne derivatives have been
found to exert potential against all the commonly identified bacteria that have
been indicated in infecting wounds. Further, observations from different types
of studies as well as clinical trial analysis indicates that the Dalethyne
derivatives have proved to exhibit potent anti-microbial as well as antiseptic
action which in turn accounts for the improved wound healing potential of the
Dalethyne derivatives.
Acknowledgements
This review work has
been sponsored and funded by the PT. Dermozone Pratama, Jakarta, Indonesia.
Conflict of Interest
The author has none
to declare.
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