ANTIBACTERIAL AGENTS
Introduction
Topical antibacterial agents may be useful in:
Preventing infections in clean wounds,
In the early treatment of infected dermatoses
and wounds,
In reducing colonization of the nares by
staphylococci,
In axillary deodorization,
In the management of
acne vulgaris.
The efficacy of antibiotics in these topical
applications is not uniform.
Antibiotic-corticosteroid combinations
Topical
anti-infectives may contain
corticosteroids in addition to antibiotics.
In the treatment of secondarily infected dermatoses,
which are usually colonized with streptococci, staphylococci, or both,
combination therapy may prove superior to corticosteroid therapy alone.
Antibiotic-corticosteroid combinations may be useful
in treating diaper dermatitis, otitis externa, and impetiginized eczema.
Choice of antibiotic
The selection of a particular antibiotic depends on:
The diagnosis
In some cases, in
vitro culture and sensitivity studies of clinical samples.
Most skin infections are caused by group A β-hemolytic
streptococci, Staphylococcus aureus, or both.
Choice of antibiotic
The pathogens present in surgical wounds will be those
resident in the environment.
Information about regional patterns of drug resistance
is therefore important in selecting a therapeutic agent.
Multiple antibiotic preparations
Topical preparations containing multiple antibiotics
offer the advantages of efficacy in:
Mixed infections,
Broader coverage for infections due to undetermined
pathogens,
Delayed microbial resistance to any single component
antibiotic.
Bacitracin and gramicidin
Bacitracin and gramicidin are peptide antibiotics
They are active
against:
Gram -positive
organisms such as streptococci, pneumococci, and staphylococci.
Most anaerobic cocci,
neisseriae, tetanus bacilli, and diphtheria bacilli.
Bacitracin
Bacitracin is compounded in an ointment base alone or
in combination with neomycin, polymyxin B, or both.
Bacitracin is poorly absorbed through the skin
Therefore systemic
toxicity is rare
However allergic contact dermatitis is frequent.
Gramicidin
Gramicidin can cause systemic toxicity
It is therefore
only available for topical use,
Used in
combination with other antibiotics such as neomycin, polymyxin, bacitracin, and
nystatin.
The incidence of sensitization following topical
application is exceedingly low in therapeutic concentrations.
Mupirocin (Pseudomonic acid A)
Most gram-positive aerobic bacteria, including
methicillin-resistant S aureus, are sensitive to mupirocin.
It is very effective in the treatment of impetigo
caused by S.ureus and Group A β-hemolytic streptococci.
Mupirocin: Adverse effects
Intranasal mupirocin in Bactroban Nasal ointment for
eliminating nasal carriage of S aureus may be associated with irritation of
mucous membranes caused by the polyethylene glycol vehicle.
Mupirocin is not appreciably absorbed systemically
after topical application to intact skin.
Polymyxin B Sulfate
Polymyxin B is a peptide antibiotic effective against
gram-negative organisms, including Pseudomonas aeruginosa, Escherichia coli,
enterobacter, and klebsiella.
Most strains of proteus and serratia are resistant, as
are all gram-positive organisms.
Polymixin B Sulphate
Detectable serum concentrations are difficult to
achieve from topical application,
However, the total
daily dose applied to denuded skin or open wounds should not exceed 200 mg in
order to reduce the likelihood of neurotoxicity and nephrotoxicity.
Hypersensitivity to topically applied polymyxin B
sulfate is uncommon.
Neomycin and gentamicin
Neomycin and gentamicin are aminoglycoside antibiotics
Neomycin is effective against most gram-negative
organisms e.g. proteus, E.Coli, klebsiella, enterobacter (except
Pseudomonas) and some gram-positive organisms. Group A streptococci are
resistant.
Gentamicin is effective against most gram-negative
organisms (similar to neomycin), including Pseudomonas and many
strains of Staphylococcus aureus.
Neomycin and gentamicin
Gentamicin generally shows greater activity against P.
aeruginosa than neomycin.
Gentamicin is also more active against staphylococci
and group A β-hemolytic streptococci.
Widespread topical use
of gentamicin, especially in a hospital environment, should be avoided to slow
the appearance of gentamicin-resistant organisms.
Neomycin and gentamicin
Neomycin is available both alone and in combination
with polymyxin, bacitracin, and other antibiotics.
It is also available as a sterile powder for
topical use.
Gentamicin is available as an ointment or cream.
Neomycin and gentamicin
Topical application of neomycin rarely results in
detectable serum concentrations.
However serum
concentrations of 1-18 mcg/mL of
gentamicin are possible if the drug is applied in a water-miscible preparation
to large areas of denuded skin, e.g. in
burns patients.
Both drugs are water-soluble and are excreted
primarily in the urine.
Renal failure may
permit the accumulation of these antibiotics, with possible nephrotoxicity,
neurotoxicity, and ototoxicity.
Neomycin and gentamicin
Neomycin frequently causes sensitization, particularly
if applied to eczematous dermatoses or if compounded in an ointment vehicle.
When sensitization occurs, cross-sensitivity to
streptomycin, kanamycin, paromomycin, and gentamicin is possible.
Topical antibiotics used in acne
Introduction
Acne is the general name given to a skin disorder in
which the sebaceous glands become inflamed.
It is characterized by
pimples on the face, chest, and back.
It occurs when the pores of the skin become clogged
with oil, dead skin cells, and bacteria.
Acne vulgaris, the medical term for common acne, is
the most common skin disease.
Acne: Pathophysiology
While acne can arise at any age, it usually begins at puberty
and worsens during adolescence.
The sebaceous glands produce an oil called sebum,
the skin’s natural moisturizer.
These glands and the
hair follicles within which they are found are called sebaceous follicles.
These follicles open
onto the skin through pores.
Acne: Pathophysiology
At puberty,
increased levels of hormones cause the
glands to produce too much sebum.
When excess sebum combines with dead, sticky skin
cells, a hard plug, or comedo, forms that blocks the pore.
Comedones, may be closed (“whiteheads”) or open
(“blackheads”).
The dark pigmentation
in open comedones is caused by oxidation of sebaceous material or melanin
rather than by dirt, a common misperception
Role of bacteria in acne
Moderate and severe inflammatory types of acne result
after the plugged follicle is invaded by Propionibacterium acnes
This bacteria normally lives on the skin.
A pimple forms when the damaged follicle weakens and
bursts open, releasing sebum, bacteria, and skin and white blood cells into the
surrounding tissues.
Severe acne
Inflamed pimples near the skin’s surface are called papules;
when deeper, they are called pustules.
The most severe type of acne consists of cysts (closed
sacs) and nodules (hard swellings).
Scarring occurs when new skin cells are laid down to
replace damaged cells.
Sites of acne formation
The most common sites of acne are:
The face
Chest
Shoulders
Back
These are the parts of the body where the most
sebaceous glands are found.
Topical antibiotics used in acne
Several systemic antibiotics used in the treatment of
acne vulgaris have been shown to be effective when applied topically.
Currently, four antibiotics are so utilized:
Clindamycin
phosphate,
Erythromycin
base,
Metronidazole ,
Sulfacetamide .
Topical antibiotics used in acne: General
considerations
The effectiveness of topical therapy is less than that
achieved by systemic administration of the same antibiotic.
Therefore, topical therapy is generally suitable in
mild to moderate cases of inflammatory acne.
Clindamycin
Clindamycin has in vitro activity against
Propionibacterium acnes;
Approximately 10% of an applied dose is absorbed
Rare cases of bloody diarrhea and pseudomembranous
colitis have been reported following topical application.
Clindamycin
The
hydroalcoholic vehicle and foam formulation may cause drying and irritation of
the skin, with complaints of burning and stinging.
The water-based gel
and lotion formulations are well tolerated and less likely to cause irritation.
Allergic contact dermatitis is uncommon.
Clindamycin is also available in a fixed-combination
topical gel with benzoyl peroxide .
Erythromycin
In topical preparations, the base of erythromycin
rather than a salt is used to facilitate penetration.
Although the mechanism of action of topical
erythromycin in inflammatory acne vulgaris is unknown, it is presumed to be due
to its inhibitory effects on P acnes.
Erythromycin
One of the possible complications of topical therapy
is the development of antibiotic-resistant strains of organisms, including
staphylococci.
If this occurs in
association with a clinical infection, topical erythromycin should be
discontinued and appropriate systemic antibiotic therapy started.
Erythromycin
Adverse local reactions to erythromycin solution may
include a burning sensation at the time of application and drying and
irritation of the skin.
The topical
water-based gel is less drying and may be better-tolerated.
Allergic hypersensitivity appears to be uncommon.
Erythromycin is also available in a fixed combination
preparation with benzoyl peroxide for topical treatment of acne vulgaris.
Metronidazole
Topical metronidazole is effective in the treatment of
acne rosacea.
The mechanism of action is unknown, but it may relate
to the inhibitory effects of metronidazole on Demodex brevis or as an
anti-inflammatory agent by direct effect on neutrophil cellular function.
Oral metronidazole has been shown to be a carcinogen
in susceptible rodent species, and topical use during pregnancy and by nursing
mothers and children is therefore not recommended.
Metronidazole
Adverse local effects of the water-based gel
formulation include dryness, burning, and stinging.
Caution should be exercised when applying
metronidazole near the eyes to avoid excessive tearing.
Sodium Sulfacetamide
Topical sulfacetamide is available alone as a 10%
lotion and as a 10% wash, and in several preparations in combination with
sulfur for the treatment of acne vulgaris and acne rosacea.
The mechanism of action is thought to be inhibition of
P. acnes by competitive inhibition of p-aminobenzoic acid utilization.
Sodium Sulfacetamide
Sodium sulfacetamide is a p-aminobenzoic acid
inhibitor
It restricts folic
acid synthesis required for bacterial
growth
Approximately 4% of topically applied sulfacetamide is
absorbed percutaneously
Its use is
therefore contraindicated in patients having a known hypersensitivity to
sulfonamides.
ANTIFUNGAL AGENTS
Topical Azole Derivatives
The topical imidazoles, which currently include
clotrimazole, econazole, ketoconazole, miconazole, oxiconazole, and
sulconazole, have a wide range of activity against:
Dermatophytes-epidermophyton,
microsporum, and trichophyton
Yeasts- Candida
albicans and Pityrosporum orbiculare.
Topical azole antifungals
Combination therapy
Topical antifungal-corticosteroid fixed
combinations provide more rapid
symptomatic improvement than an antifungal agent alone.
Clotrimazole-betamethasone dipropionate cream
(Lotrisone) is one such combination.
Frequency of administration
Once- or twice-daily application to the affected area
will generally result in clearing of superficial dermatophyte infections in 2-3
weeks,
However the
medication should be continued until eradication of the organism is confirmed.
Frequency of administration
Paronychial and intertriginous candidiasis can be
treated effectively by any of these agents when applied three or four times
daily.
Seborrheic dermatitis should be treated with
twice-daily applications of ketoconazole until clinical clearing is obtained.
Adverse effects
Adverse local reactions to the imidazoles may include
stinging, pruritus, erythema, and local irritation.
Allergic contact dermatitis appears to be uncommon.
Ciclopirox olamine
This is a synthetic broad-spectrum antimycotic agent
with inhibitory activity against dermatophytes, candida species, and P
orbiculare.
It
inhibits the uptake of precursors
of macromolecular synthesis;
the site of action is
therefore the fungal cell membrane.
Ciclopirox olamine
Pharmacokinetic studies indicate that 1-2% of the dose
is absorbed when applied as a solution on the back under an occlusive dressing.
Ciclopirox olamine is available as a 1% cream and
lotion (Loprox) for the topical treatment of dermatomycosis, candidiasis, and
tinea versicolor.
Ciclopirox olamine
The incidence of adverse reactions has been low.
Pruritus and worsening of clinical disease have been
reported.
The potential for delayed allergic contact
hypersensitivity appears small.
Topical 8% ciclopirox
olamine (Penlac nail lacquer) has been approved for the treatment of mild to
moderate onychomycosis of fingernails and toenails.
Although well
tolerated with minimal side effects, the overall cure rates in clinical trials
are less than 12%.
Allylamines: Naftifine & Terbinafine
Naftifine hydrochloride and terbinafine (Lamisil) are
allylamines that are highly active against dermatophytes but less active
against yeasts.
They
selectively inhibit squalene epoxidase, a key enzyme for the
synthesis of ergosterol.
Allylamines: Naftifine & Terbinafine
They are available as 1% creams and other forms for
the topical treatment of dermatophytosis, to be applied on a twice-daily dosing
schedule.
Adverse reactions include local irritation, burning
sensation, and erythema. Contact with mucous membranes should be avoided.
Butenafine
This is a
benzylamine that is structurally related to the allylamines.
It also
inhibits the epoxidation of squalene, thus blocking the synthesis of
ergosterol, an essential component of the fungal cell membranes.
Butenafine is available as a 1% cream to be applied
once daily for the treatment of superficial dermatophytosis.
Tolnaftate
Tolnaftate is a synthetic antifungal compound that is
effective topically against dermatophyte infections caused by epidermophyton,
microsporum, and trichophyton.
It is also active against P orbiculare but not
against candida.
It is available
as a cream, solution, powder, or powder aerosol for application twice daily to
infected areas.
Tolnaftate
Recurrences following cessation of therapy are common,
and infections of the palms, soles, and nails are usually unresponsive to
tolnaftate alone.
The powder or powder aerosol may be used chronically
following initial treatment in patients susceptible to tinea infections.
Tolnaftate is generally well tolerated and rarely
causes irritation or allergic contact sensitization.
Nystatin & Amphotericin B
Nystatin and amphotericin B are useful in the topical
therapy of C albicans infections but ineffective against dermatophytes.
Nystatin is limited to
topical treatment of cutaneous and mucosal candida infections because of its
narrow spectrum and negligible absorption from the gastrointestinal tract
following oral administration.
Amphotericin B has a
broader antifungal spectrum and is used intravenously in the treatment of many
systemic mycoses and to a lesser extent
in the treatment of cutaneous candida infections.
Nystatin & Amphotericin B
The recommended dosage for topical preparations of
nystatin in treating paronychial and intertriginous candidiasis is application
two or three times a day.
Oral candidiasis
(thrush) is treated by holding 5 mL (infants, 2 mL) of nystatin oral suspension
in the mouth for several minutes four times daily before swallowing.
An alternative therapy for thrush is to retain
a vaginal tablet in the mouth until dissolved four times daily.
Nystatin & Amphotericin B
Recurrent or
recalcitrant perianal, vaginal, vulvar, and diaper area candidiasis may respond
to oral nystatin, 0.5-1 million units in adults (100,000 units in children)
four times daily in addition to local therapy.
Vulvovaginal
candidiasis may be treated by insertion of 1 vaginal tablet twice daily for 14
days, then nightly for an additional 14-21 days.
Nystatin & Amphotericin B
Adverse effects associated with oral administration of
nystatin include mild nausea, diarrhea, and occasional vomiting.
Topical application is nonirritating, and allergic
contact hypersensitivity is exceedingly uncommon.
Topical amphotericin B is well tolerated and only
occasionally locally irritating.
Hypersensitivity is very rare.
The drug may cause a temporary yellow staining of the
skin, especially when the cream vehicle is used.
Nystatin & Amphotericin B
Amphotericin B (Fungizone) is available for topical
use in cream and lotion form.
The recommended dosage in the treatment of paronychial
and intertriginous candidiasis is application two to four times daily to the
affected area.
ORAL ANTIFUNGAL AGENTS
Oral Azole Derivatives
The azole antifungals include the imidazoles and
triazoles.
These drugs have the same spectrum of antifungal
activity and share a common mechanism by inhibiting fungal CYPs that are
essential for ergosterol biosynthesis
Imidazoles
include clotrimazole, miconazole, ketoconazole, econazole, butoconazole,
oxiconazole, sertaconazole, and sulconazole
Triazoles include terconazole, itraconazole,
fluconazole, and voriconazole
Ketoconazole
Ketoconazole was the first imidazole derivative used
for oral treatment of systemic mycoses.
Patients with chronic mucocutaneous candidiasis
respond well to a once-daily dose of 200 mg of ketoconazole, with a median
clearing time of 16 weeks.
Most patients require long-term maintenance therapy.
Variable results have been reported in treatment of
chromomycosis.
Ketoconazole
Ketoconazole is quite effective in the therapy of
cutaneous infections caused by epidermophyton, microsporum, and trichophyton
species.
Infections of the glabrous skin often respond within
2-3 weeks to a once-daily oral dose of 200 mg.
Ketoconazole
Palmar-plantar skin is slower to respond, often taking
4-6 weeks at a dosage of 200 mg twice daily.
Infections of the hair and nails may take even longer
before resolving with low cure rates noted for tinea capitis.
Tinea versicolor is very responsive to short courses
of a once-daily dose of 200 mg.
Ketoconazole
Nausea or pruritus has been noted in approximately 3%
of patients taking ketoconazole.
More significant side effects include gynecomastia,
elevations of hepatic enzyme levels, and hepatitis.
Caution is advised
when using ketoconazole in patients with a history of hepatitis.
Routine evaluation of
hepatic function is advisable for patients on prolonged therapy.
Fluconazole
Fluconazole is well absorbed following oral
administration, with a plasma half-life of 30 hours.
In view of this long half-life, daily doses of 100 mg
are sufficient to treat mucocutaneous candidiasis;
Alternate-day doses are sufficient for dermatophyte
infections.
Itraconazole
Itraconazole is
effective for the treatment of onychomycosis in a dosage of 200 mg daily
taken with food to ensure maximum absorption for 3 consecutive months.
The plasma half-life of itraconazole is similar to
fluconazole, with detectable therapeutic concentrations remaining in the
stratum corneum for up to 28 days following termination of therapy.
Itraconazole
Recent reports of heart failure in patients receiving
itraconazole for onychomycosis have resulted in recommendations that it not be
given for treatment of onychomycosis in patients with ventricular dysfunction.
Additionally, routine evaluation of hepatic function
is recommended for patients receiving itraconazole for onychomycosis.
Adverse effects of azole antifungals
Administration of oral azoles with midazolam or
triazolam has resulted in elevated plasma concentrations and may potentiate and
prolong hypnotic and sedative effects of these agents.
Administration with HMG-CoA reductase inhibitors has
been shown to cause a significant risk of rhabdomyolysis.
Therefore,
administration of the oral azoles with midazolam, triazolam, or HMG-CoA
inhibitors is contraindicated.
Griseofulvin
Griseofulvin is effective orally against dermatophyte
infections caused by epidermophyton, microsporum, and trichophyton.
It is ineffective against candida and P orbiculare.
Griseofulvin's mechanism of antifungal action is not
fully understood, but it is active only against growing cells.
Griseofulvin
Following the oral administration of 1 g of micronized
griseofulvin, drug can be detected in the stratum corneum 4-8 hours later.
Reducing the particle size of the medication greatly
increases absorption of the drug.
Formulations that contain the smallest particle size
are labeled "ultramicronized."
Micronized griseofulvin
Ultramicronized griseofulvin achieves bioequivalent
plasma levels with half the dose of micronized drug.
In addition,
solubilizing griseofulvin in polyethylene glycol enhances absorption even
further.
Micronized
griseofulvin is available as 250 mg and 500 mg tablets
Ultramicronized drug is available as 125 mg, 165 mg, 250 mg,
and 330 mg tablets and as 250 mg capsules.
Griseofulvin: Dosing
The usual adult dosage of the micronized
("microsize") form of the drug is 500 mg daily in single or divided
doses with meals;
occasionally, 1 g/d is
indicated in the treatment of recalcitrant infections.
The pediatric dosage
is 10 mg/kg of body weight daily in single or divided doses with meals.
An oral suspension is
available for use in children.
Griseofulvin
Griseofulvin is most effective in treating tinea
infections of the scalp and glabrous (nonhairy) skin.
In general, infections
of the scalp respond to treatment in 4-6 weeks,
Infections of glabrous skin will respond in 3-4 weeks.
Dermatophyte
infections of the nails respond only to prolonged administration of
griseofulvin.
Fingernails may
respond to 6 months of therapy, whereas toenails are quite recalcitrant to
treatment and may require 8-18 months of therapy; relapse almost invariably
occurs.
Griseofulvin: Adverse effects
Adverse effects seen with griseofulvin therapy include
headaches, nausea, vomiting, diarrhea, photosensitivity, peripheral neuritis,
and occasionally mental confusion.
Griseofulvin is derived from a penicillium mold, and
cross-sensitivity with penicillin may occur.
It is contraindicated in patients with porphyria or
hepatic failure or those who have had hypersensitivity reactions to it in the
past.
Griseofulvin:Adverse effects
Its safety in pregnant patients has not been
established.
Leukopenia and
proteinuria have occasionally been reported.
Therefore, in patients
undergoing prolonged therapy, routine evaluation of the hepatic, renal, and
hematopoietic systems is advisable.
Coumarin anticoagulant activity may be altered by
griseofulvin, and anticoagulant dosage may require adjustment.
Terbinafine
Terbinafine is
quite effective when given orally
for the treatment of onychomycosis.
Recommended oral dosage is 250 mg daily for 6 weeks
for fingernail infections and 12 weeks for toenail infections.
Patients
receiving terbinafine for onychomycosis should be monitored closely with
periodic laboratory evaluations for possible hepatic dysfunction.
Viral infections
Viral infections of the skin are very common and
include:
Verrucae (warts)
Herpes simplex ,
Condyloma acuminatum –anogenital warts ,
Molluscum contagiosum,
Chicken pox.
Viral infections
Antiviral agents and their uses
ECTOPARASITICIDES
Introduction
Ectoparasite infections include lice infestation and
scabies
They can cause:
Disabling pruritus,
Secondary infection,
In the case of the body louse, transmission of
life-threatening illnesses such as typhus.
Topical and oral medications are available to treat
these infestations.
Lindane
Lindane (1% g-benzene hexachloride lotion) has been
used as a commercial insecticide as well as a topical medication.
It is highly effective in the treatment of
ectoparasites.
Lindane
Neurotoxicity, although a concern with the use of
lindane, is a rare side effect when the medication is used correctly.
However, the
FDA has defined lindane as a second-line drug in treating pediculosis and
scabies and has highlighted the potential for neurotoxicity in children and
adults weighing <110 lb.
Lindane
The lotion is applied in a thin layer from the neck
down,
It is left in place for 8–12 hours or overnight, and
removed by thorough washing at the end of the 8–12-hour period.
The treatment
may be repeated in 1 week.
Lindane: Special Precautions
To avoid problems with neurotoxicity:
The lotion should be
applied only in a thin coat to dry skin,
It should not be applied immediately after
bathing,
It should be kept away from the eyes, mouth, and
open cuts or sores.
A 1% lindane shampoo also is available for head and
body lice.
Permethrin
Permethrin, a synthetic derivative of the insecticide
pyrethrum,was obtained originally from Chrysanthemum cinerariifolium.
Neurotoxicity
associated with this compound is rare.
A 5% cream is available for the treatment of scabies.
This is used as an 8–12-hour
or overnight application.
A 1% permethrin cream rinse also is available
for the treatment of head lice.
Ivermectin
This is an antihelminthic drug used traditionally to
treat onchocerciasis,
It is also is
effective in the off-label treatment of scabies.
Because ivermectin does not cross the blood–brain
barrier, there is no major CNS toxicity.
Ivermectin
Ivermectin is given at a dose of 250–400 mg/kg, which
is repeated in a week.
Cure rates of 70% after one dose and 95% after two
doses given 2 weeks apart have been achieved
For treatment
of scabies outbreaks in large groups, this drug has obvious advantages as
compared with topical therapy.
Crotamiton
Crotamiton, N-ethyl-o-crotonotoluidide, is a scabicide
with some antipruritic properties.
Its mechanism of action is not known, and studies on
percutaneous absorption have not been published.
Crotamiton (Eurax) is available as a cream or lotion.
Crotamiton
For scabies treatment,
it is applied twice to the entire
body from the chin down at 24-hour intervals, with a cleansing bath 48 hours
after the last application.
Crotamiton is an effective agent that can be used as
an alternative to lindane.
Allergic contact
hypersensitivity and primary irritation may occur, necessitating discontinuance
of therapy.
Application to acutely
inflamed skin or to the eyes or mucous membranes should be avoided.
Sulfur
Although sulfur is nonirritating, it has an unpleasant
odor, is staining, and is thus disagreeable to use.
It has been replaced by more aesthetic and effective
scabicides but it remains a possible
alternative drug for use in infants and pregnant women.
The usual formulation is 5% precipitated sulfur in
petrolatum.
Malathion
Malathion is an organophosphate cholinesterase
inhibitor.
It is
hydrolyzed by plasma carboxylesterases much faster in humans than in insects,
thereby providing a therapeutic advantage in treating pediculosis.
Malathion is
available as a 0.5% lotion (Ovide) that should be applied to the hair when dry;
4–6 hours later, the hair is combed to remove the lice.
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