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`
`VOLUME 31, NUMBER 5, SEPTEMBER/ OCTOBER 2013
`
`
`
`CONTENTS
`
`Commentary: Nails and the clinician
`Aditya K. Gupta and
`Antonella Tosti
`
`Nail anatomy
`David de Berker
`
`Nail surgery
`Eckart Haneke
`
`Nail pathology
`Josette Andre’,
`Ursula Sass,
`Bertrand Riclzert, and
`Anne Theunis
`
`Diagnosing onychomycosis
`Aditya K. Gupta and
`Fiona C. Simpson
`
`Therapies for the treatment of onychomycosis
`Aditya K. Gupta,
`Maryse Paquet, and
`Fiona C. Simpson
`
`Improved efficacy in onychomycosis therapy
`Aditya K. Gupta and
`Maryse Paquet
`
`Pediatric nail conditions
`Adam J. Wulkan and
`Antonella Tosri
`
`Cosmetic treatment of nails
`Zoe Diana Draelos
`
`507
`
`509
`
`516
`
`526
`
`540
`
`544
`
`555
`
`564
`
`573
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`
`Contents Cont’d
`
`Common nail disorders
`Avner Sliemer and
`
`C. Ralph Daniel III
`
`Onychoscopy
`Andre’ Lencastre,
`Ana Lamas,
`Daniel Sci, and
`Antonella Tosti
`
`Longitudinal melanonychias
`Nilton Di Clziacclzio,
`Beth S. Ruben, and
`Walter Reflcalevsky Laiireiro
`
`Nail tumors
`
`Bertrand Ric/iert,
`Pauline Lecerf,
`Marie Caucanas, aria’
`Josette Andre’
`
`Drug-related nail disease
`Bianca Maria Piraccini and
`Aurora Alessandrini
`
`578
`
`587
`
`594
`
`602
`
`618
`
`.
`,
`Nail abnormalities associated with systemic pathologies
`Martin N. Zaiac and
`Ashley Walker
`___%_____
`
`627
`
`CONTEMPORARY DERMATOLOGY
`
`_
`Letters to the Editor
`The Karabus affair will be repeated in the future for others going to
`practice in the United Arab Emirates
`
`.
`.
`Edward L. Keyes Resident Contest for Outstanding Case Reports
`Caretaker of the Skin
`_
`Gerhard Henrik Armauer Hansen (l84l—l9l2)——The l00th anniversary
`of the death of the discoverer of Mycobacteriurn leprae
`Dermatologic Disquisitions and other Essays
`Medical Student Dermatology Interest Groups
`
`IACD Officers page
`
`Dermatology Around the World
`
`IACD Membership Application
`
`651
`
`652
`
`653
`656
`
`661
`
`662
`
`664
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`Clinics in Dermatology (2013) 31, 555—563
`
` This material may be protected by Copyright law (Title 17 U.S. Code)
`
`Clinics in
`Dermatology
`
`Improved efficacy in onychomycosis therapy
`Aditya K. Gupta, MD, PhD, FRCPC“"b'*, Maryse Paquet, PhD'°
`
`“Departmeiit of Mediciiie, University of Toronto School ofMedicine, Toronto, Ontario, Canada
`b
`.
`.
`Mediprobe Research, 1710., London, Ontario, Canada
`
`
`
`Abstract The success rate of onychomycosis treatment is limited by several factors, including the access of
`the therapeutic agent to the fungal mass, the presence of conidia, and the susceptibility of the different
`infectious agents to the antifungals. Different strategies used to improve efficacy of the currently available
`antifungal treatments, their rationale, and the published evidence of their beneficial effects are reviewed. An
`improved efficacy was demonstrated for some of these strategies, such as combined oral and topical
`antifungal therapies, whereas most ofthem lack clear and direct evidence ofan increase in therapeutic success.
`© 2013 Elsevier Inc. All rights reserved.
`
`
`Introduction
`
`Despite the good therapeutic responses obtained with an
`appropriate treatment of onychomycosis, treatment failures
`or recurrences are frequent. To improve the short- and long-
`term efficacy outcomes, different treatment strategies have
`been developed. These strategies could be divided into five
`categories: (1) treatments based on the biological cycle of the
`fungus,
`(2) modified dosing regimens,
`(3) combination
`therapy, (4) technology to improve drug delivery, and (5)
`adjunct/prophylactic care.
`
`Treatments based on the biological cycle
`
`of the fungus
`
`Fungi exist under at least two forms: dormant conidia and
`growing hyphae. Under appropriate conditions, such as
`humidity and the presence of nutrients, the conidia could
`germinate and lead to the invasive hyphae phase. In turn, the
`
`* Corresponding author. Tel.: +1 519 657 4222; fax: +1 519 657 4233.
`E-mail ac/rli'e.vs.' agupta@execulink.com (A.K. Gupta).
`
`0738-O8lX/$ — see front matter (0 2013 Elsevier Inc. All rights reserved.
`littp://dx.doi.org/l0.1016/j.clindermatol.2013.06.010
`
`filamentous fungus can produce conidia through asexual
`reproduction.‘ Consequently, both hyphae and conidia are
`present in infected nails, and they have shown differential
`susceptibility to antifungals.3~3 Conidia have been shown to
`be less susceptible to the antifungal action of itraconazole
`and terbinafme than hyphae for dermatophytes4*5 and
`nondermatophyte molds.“
`Different strategies can be used to induce the germination of
`conidia and make the infectious agent more susceptible to the
`antifungal
`therapies. For example,
`it
`is believed that nail
`lacquers have the potential to induce the germination ofconidia
`by reducing transonychial waterloss.‘ Germination can also be
`induced by placing a piece of Sabouraud’s agar on the nail
`plate during topical
`therapy (boosted antifungal
`topical
`treatment [BATT]) or oral therapy (boosted oral antifungal
`treatment [BOAT]). In an open study treating 13 participants
`with a history of treatment failure or recur1'ence of der1nato—
`phyte onychomycosis, 5% amorolfine nail laquer was applied
`one weekly for 6 months. As an adjunct, participants applied
`sabourad agar with chloramphenicol and cycloheximide to the
`nail plate with sticking plaster for 24 hours every second day,
`for one week per month for two months. At the end of the
`6 months, 85% of the participants were mycologically cured.7
`In another open study, 10 participants with onychomycosis in
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`556
`
`A.K. Gupta, M. Paquet
`
`both big toenails received 3 pulses of itraconazole (400 mg
`daily, 1 week on, 3 weeks off) and applied a piece of agar as
`previously described on one big toenail the week following
`each itraconazole pulse. Seven months after the initiation ofthe
`BOAT, 90% of the toenails treated with the agar booster were
`mycologically cured compared to 60% ofthe toenails receiving
`only itraconazole.8 This method seems to improve efficacy
`outcomes, but it is associated with a risk ofoverstimulation and
`
`systemic spread of fungi not susceptible to the antifungal." It
`has been suggested that a broad spectrum antifungal should be
`used with a booster period limited to one week. '0 We feel that
`such a regimen should not be used, until
`there is more
`published evidence supporting the safety of this concept.
`
`Modified dosing regimens
`
`Dosing regimens ofantifungals may be modified based on
`their phannacokinetic and pharmacodynamic properties to
`improve their efficacy. For example, fluconazole has a short
`residual concentration in nails and a fungistatic activity.
`Its administration throughout the nail regrowth would,
`therefore, result in better efficacy than the limited suggested
`regimen. Higher efficacy was observed with treatments
`longer than 6 months compared to shorter treatments.‘ ‘ Ifwe
`hypothesize that allowing the antifungal concentration to rise
`and fall in a controlled pattern might lead to the germination of
`protected structures such as conidia, pulse regimens or
`supplementary therapy (“booster”) could be used to improve
`treatment efficacy.
`Few studies compared the efficacy of continuous and
`intermittent dosing regimens of a given antifungal.
`In a
`double-blind randomized clinical trial comparing 3 months
`of therapy with continuous and pulse itraconazole, there was
`no difference in efficacy between the two dosing regimens. 12
`In a meta-analysis of head-to—head comparison of continuous
`and pulse terbinafine, continuous regimens were slightly
`superior to pulse regimens for mycological cure, but not for
`complete cure.” Similar recurrence rates were previously
`observed for the two terbinafine regimens.” Pulse therapy
`does not seem to improve short- or long-term efficacy of
`systemic antifungals based on the data currently available.
`In supplementary or booster therapy, patients with poor
`mycological and/or clinical outcomes after treatment with
`three pulses of itraconazole or 12 weeks of terbinafine
`receive an additional pulse of itraconazole or 4 weeks of
`terbinafine between 6 to 9 months after initiation of the
`therapy.” In two studies using this strategy to improve the
`efficacy of the anti fungal treatments for toenail dermatophyte
`onychomycosis, a mycological cure rate of 64-78.1% for
`terbinafine and 56.7—62.7% for
`itraconazole was ob-
`
`served.l5"7 Because these mycological cure rates do not
`differ from the pooled cure rates obtained for studies not
`using booster therapy (terbinafine 76 j 3%; itraconazole 63 +
`7%)” the beneficial effect of the “booster” still needs to be
`proved.
`
`Combination therapy
`
`One of the factors contributing to treatment failure is the
`limited access to the fungal mass. Oral antifungals are known
`to accumulate in the nail bed and have limited access to the nail
`
`plate and lateral borders, whereas topical antifungals penetrate
`the nail plate and the lateral borders but not the deeper layers of
`the nail.9"9 The formation of a visible yellow, white, or orange
`longitudinal streak or patch (dermatophytoma), which is a
`collection of fungal hyphae, and the presence of debris greater
`than 2 mm due to subungual hyperkeratosis are poor prognosis
`factors and can also reduce the antifungal absorption.” Nail
`avulsion or debridement can help reduce the fungal mass and
`increase the penetration of antifungal. A combination of nail
`avulsion/debridement with antifungal, or topical antifungals
`with systemic antifungals should,
`therefore,
`improve drug
`penetration and therapy efficacy. A combination oftopical and
`systemic antifungal treatments or systemic treatments can also
`increase the therapy efficacy by acting in synergy, preventing
`drug resistance, or offering a broader spectrum of action
`against mixed infections.
`
`Nail avulsion combined with antifungals
`
`In the published literature, combinations of chemical or
`surgical nail avulsion with the following topical antifungals
`have been reported for the treatment of onychomycosis: l%
`bifonazole ointment,2"34 2% butenafine cream,” 1%
`ciclopirox ointment,2"26’27 8% ciclopirox nail
`lacquer,“
`topical clotrimazole, or econazole,28 1% fluconazole,” 2%
`ketoconazole cream,26*3°’3' 2% miconazole,” l% oxicona—
`zole cream,” and 1% terbinafine cream,” and the following
`oral antifungals: ketoconazole“ and terbinafine.35v36 Only
`one of these publications compared the combined therapy to
`antifungal monotherapy.” In this study, mycological cure
`was achieved in 82.8% of the participants treated with 40%
`urea/ 1% fluconazole nail lacquer compared to 62.8% cure
`with 1% fluconazole nail lacquer alone. This combination
`was successful at increasing efficacy, but it is difficult to
`detennine the benefit associated with the other combined
`
`treatments. Nail avulsion or traditional topical creams alone
`were generally associated with low success rates, and these
`combinations were generally promising. An increase in
`efficacy is also supported by a series of cases in which all
`patients who previously had treatment failures with mono-
`therapy of various topical treatments were disease free for at
`least 1.5 years after combined surgical avulsion with 2%
`ketoconazole or 1% ciclopirox cream under occlusion.“
`A study combining surgical avulsion and two different
`topical antifungals (2% ketoconazole and 1% oxiconazole)
`showed that a better efficacy outcome was obtained when the
`topical treatment was done under occlusion,” but this study
`also showed that the combination of surgical avulsion with
`topical antifungals was associated with low compliance and
`high dropout rate.
`In a study combining partial chemical
`avulsion with 40% urea and topical 2% miconazole,
`the
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`
`Improving onychomycosis therapy
`
`557
`
`
`Table 1 Mycological and complete cure rates for combination of debridement with antifungal therapy in comparative studies
`
`Reference
`
`Topical treatment Mycological cure Complete cure
`Onycho- Frequency of
`(KOH microscopy (mycological + clinical)
`mycosis
`debridement
`and culture neg)
`severity
`
`Oral treatment
`
`Malay 2009”
`
`250 mg terbinafine
`daily for 12 weeks
`
`Jennings 200637 Moderate None
`to severe At baseline, and
`weeks 6, 12, 2438
`0/27 (0%)§
`None
`Variable Every 3 months for
`9 or 12 months
`21/28 (77%)"
`8% ciclopirox daily
`for 9 to 12 months
`
`
`152/243 (62.6%)
`166/246 (67.5%)
`
`79/243 (32.5%)
`93/246 (37.8%)
`
`“ Negative culture with or without negative microscopy with PAS staining.
`
`achievement of complete cure inversely correlated with the
`percentage of infected area at baseline.” These observa-
`tions suggest that combining antifungals and nail avulsion
`has its limitations.
`
`therapy is normally used in onychomycosis
`Dual
`treatment, but few examples of successful
`triple therapy
`using nail avulsion with both topical and oral therapies have
`been reported. For example, dermatophyte onychomycosis
`in toenails has been mycologically cured with shorter oral
`griseofulvin or ketoconazole treatments combined with
`surgical avulsion and topical clotrimazole or econazole.”
`A triple therapy using partial chemical avulsion with 40%
`urea/ 1% bifonazole, followed by topical 1% bifonazole and
`oral griseofulvin, showed higher complete cure rate (43.7%)
`than double therapy obtained by replacing griseofulvin with
`placebo (l0%).33
`
`Debridement combined with antifungals
`
`A combination of debridement and 8% ciclopirox nail
`lacquer resulted in a significantly better mycological cure
`rate than debridement alone (Table 1).” The mycological
`and complete cure rates were not statistically different
`between treatment with systemic terbinafme alone and
`combined with debridement
`(Table l),37 but
`the two
`combined therapies resulted in significantly better partici-
`pant-assessed quality of life than monotherapies.39’4° The
`study comparing debridement alone versus debridement with
`topical antifungal showed that the thickness of the nail plate
`was significantly reduced in the combined therapy group,
`and the chance to achieve mycological cure was statistically
`higher in participants with a final nail thickness less than
`2 mm.”
`
`Topical and oral antifungals
`
`In comparative studies including participants with lunula/
`matrix involvement, a high percentage of nail surface
`involved, or Candida spp, an increase in efficacy has been
`observed with additional
`treatment with amorolfme or
`
`lacquer compared to monotherapies with
`ciclopirox nail
`systematic terbinafine or itraconazole (Table 2)4"45~47. In
`contrast, in a study not specifying the severity of onycho-
`
`mycosis, no difference was found between terbinafme
`monotherapy and its combination with one of the two
`topical antifungals (Table 2).“ It is worth noting that there is
`a risk of bias associated with these studies, as only one of the
`seven clinical studies was assessor blind,“ and none of them
`
`used a topical placebo for the group receiving oral treatment
`only. To our knowledge, no study compared the efficacy of
`oral terbinafine with and without topical
`terbinafine, but
`three single-ami studies reported the efficacy of pulse
`terbinafme combined with topical 1% terbinafine for the
`treatment of dermatophyte onychomycosis. These studies
`reported a complete cure rate of 65.2% to 77.3%.‘“"5° Based
`on all these studies, we can conclude that a combination of
`
`topical and oral antifungals does increase the efficacy of
`antifungal therapies for the treatment of onychomycosis.
`
`Two oral antifungals
`
`Dermatophytes, nondermatophyte molds, and yeasts iso-
`lated from patients with onychomycosis showed differential
`susceptibility to the three oral systemic treatments, terbinafme,
`itraconazole, and fluconazole.5"5" This differential suscepti-
`bility to antifungals suggests that a combined therapy of oral
`treatments might be more effective against mixed infection or
`resistant fungi. A synergic action between itraconazole and
`terbinafme on both conidia and hyphae has been reported“);
`thus, a combined therapy might result in better eradication of
`conidia and prevent the recurrence of infection.
`Two comparative studies investigated combined oral
`therapy with itraconazole and terbinafme for treatment of
`toenail dermatophyte onychomycosis. One study investigat-
`ed sequential administration of the two treatments,°° whereas
`the other investigated overlapping treatments“ (Table 3).
`Sequential treatments with pulsed itraconazole and terbina-
`line over 12 to 16 weeks resulted in higher cure rates than
`
`pulsed terbinafine alone, whereas overlapping but shorter
`(6 weeks)
`treatments with continuous itraconazole and
`terbinafme resulted in similar cure rates as pulsed itracona-
`zole or continuous terbinafme for 12 weeks (Table 3). These
`data suggest
`that
`the beneficial effects of combined
`treatments depend on the length of therapy. The sequential
`therapy did not reduce the relapse rate compared to the
`terbinafme monotherapy during the study (Table 3).
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`558
`
`A.K. Gupta, M. Paquet
`
`
`Table 2 Mycological and complete cure rates for combination of oral and topical antifungals in comparative studies
`
`
`
`Reference
`
`Complete cure
`Mycological cure
`Onycho-mycosis
`severity
`(KOH microscopy (mycological + clinical)
`
`and culture neg)
`
`Oral treatment
`
`Topical treatment
`
`Baran 200041
`
`Lecha 200242
`
`Matrix involvement 250 mg terbinafine
`(daily for 3 months)
`
`None
`5% amorolfine
`(weekly for 15 months)
`200 mg itraconazole None
`5% amorolfine
`(daily for 3 months)
`
`Matrix or > 80%
`surface area
`involvement
`
`(weekly for 6 months)
`None
`5% amorolfine
`(weekly for 6 months)
`
`None
`8% ciclopirox
`(daily for 9 months)
`None
`
`18/48 (38%)
`34/47 (72%)
`
`22/32 (59%)
`31/33 (94%)
`
`34/42 (8 1%) a
`40/43 (93%) “
`
`22/34 (65%)
`30/34 (88%)
`
`17/34 (50%)
`23/34 (68%)
`
`14/25 (56%)
`19/27 (70%)
`
`19/23 (82.6%)
`7/10 (70%)
`
`10/ 12 (83.3%)
`
`Rigopoulos 200343 >50% surface area
`involvement
`(Candida spp)
`
`Avner 200544
`
`Without lunula
`involvement
`
`400 mg itraconazole
`(daily for 1 week
`on/3 weeks off for
`2 months)
`250 mg terbinafine
`(daily for 4 months)
`
`Gupta 200545
`
`Lunula/matrix or
`> 60% surface area
`involvement
`
`250 mg terbinafine
`(daily for 3 months)
`
`Jaiswa1200746
`
`N/A
`
`Baran 200747
`
`250 mg terbinafine
`(twice daily for
`1 week/month for
`
`4 months)
`
`8% ciclopirox
`(daily for 12 months)
`None
`5% amorolfine
`(weekly for 4 months)
`8% ciclopirox
`(daily for 4 months)
`Matrix involvement 250 mg terbinafine
`58/129 (45%)
`None
`5% amorolfine
`71/120 (59%)
`(daily for 3 months)
`(weekly for 15 months)
`" Global cure = mycological + improvement (20%-100%).
`
`In conclusion, only a few studies address the beneficial
`
`effects of combined oral antifungal therapy. These studies
`included participants with culture-proved derrnatophyte
`onychomycosis and did not address the advantages of the
`combined therapy for mixed infection and/or for infections
`caused by nondermatophyte molds or yeasts.
`
`Technology to improve drug delivery
`
`Topical antifungals have several advantages over sys-
`temic antifungals, such as lower risk of drug—drug in-
`teractions and adverse events, but their efficacy is limited by
`poor absorption in the nail apparatus. Techniques aiming to
`improve drug delivery have been developed, and they can be
`generally divided into two groups: physical enhancers and
`chemical enhancers."2'64 Several of these enhancers are still
`under preclinical investigation.
`
`Physical enhancers
`
`Abrasion/etching of the nail surface
`
`The nail plate is made of about 25 sheets of keratinized cells
`structured into three layers: dorsal, intermediate, and ventral
`
`layers. These layers vary in thickness in a 325:2 ratio; they also
`vary in type ofkeratin and lipid content. The dorsal and ventral
`layers are thinner and are composed of harder skin-type keratin
`with some lipids (ventral > dorsal), whereas the intermediate
`layer is thicker and composed mainly of more flexible hair-
`type keratin with few lipids. The dorsal layer is the major
`barrier to drug penetration into the nail p1ate64‘66;
`thus, a
`strategy used to increase antifungal penetration is to abrade the
`nail surface by filing/debridement, which removes the dorsal
`layer and reduces the thickness of the p1ate.63’64 Modification
`of the nail surface with etchants, such as phosphoric acid and
`tartaric acid, decreases the thickness of the plate and increases
`its surface area. Consequently, it increases the adhesion of
`topical films and drug diffusion into the plate.°4'65»57 Indeed,
`Etching with phosphoric acid increased the in vitro permeation
`in the human nail plate of ketoconazole and terbinafine
`contained in extruded fil11is.68~69
`
`Microporation
`
`Microporation is the drilling of individual small holes
`(400 pm) with a handheld microcutting device PathFormer,
`which is FDA—approved for draining of subungual hemato-
`mas.63>64 This technique has been used in combination with a
`topical application of 1% terbinafine or a placebo in a clinical
`trial for the treatment of onychomycosis,7° but no study
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`
`Improving onychomycosis therapy
`
`treatment with and without
`compared topical antifungal
`microporation to investigate the improvement
`in the
`permeation of the antifungal by this technique.
`
`Phonophoresis
`
`In therapeutic phonophoresis, the energy of the pressure
`waves of ultrasound is transferred to the nail plate via
`coupling provided by the topical antifungal formulation. The
`exact mechanism of action responsible for enhanced drug
`delivery is not clear. It might involve the formation of gas
`bubbles when low-frequency ultrasound waves are applied in
`liquid and their collapse on the nail surface, a process named
`cavitation."2’71 A recent
`in vitro study using a novel
`ultrasound-mediated drug-delivery system for onychomyco-
`sis treatment and a dye in water as a drug—1nimicking
`compound showed increased permeability of canine nails
`compared to passive diffusion.”
`
`Iontophoresis
`
`Iontophoresis is the application of a small current to a
`biological membrane to increase the transport of molecules,
`such as antifungals, relative to passive diffusion. Iontopho-
`resis can increase drug delivery through two mechanisms:
`electroosmosis (co—transport with water) and electromigra-
`tion (ions fluxes). At physiological pH,
`the nail plate is
`negatively charged and permeable to positive charges
`(cations). During iontophoresis, an excess of cations at one
`electrode (anode) and negative charges (anions) at the other
`(cathode) is created, and a water flux from the anode to the
`cathode is induced. The charge imbalance is corrected to
`reach electroneutrality by fluxes of ions across the biological
`membrane in a mechanism called electromigration. Thus, a
`negatively and a positively charged antifungal compound
`will cross the membrane at
`the cathode and the anode,
`
`respectively. Due to the small size of the nails, drug delivery
`
`559
`
`is generally from one active electrode, and the other inactive
`electrode is attached to a nearby skin site. The transport of a
`compound is limited by its molecular size and competing
`ionized species. The best candidates to be delivered by
`electromigration are small, fully charged compounds in a
`formulation minimizing competitive ions and maximizing
`their
`ionized fractions. Neutral compounds could be
`
`cotransported by electroosmosis. In contrast to electomigra—
`tion, the role played by electroosmosis in the ungual drug
`delivery induced by iontophoresis is not clear.73
`Iontophoresis delivery of 4% terbinafme in a gel-based
`formulation (TPI—DF-507) showed increased permeability in
`vitro compared to passive diffusion in both normal and
`onychomycotic human nai1s.74=75 Terbinafine is distributed in
`all
`three layers of the nail plate when delivered with
`iontophoresis, whereas it is more concentrated in the dorsal
`layer with passive diffusion.74’7(’ In onychomycotic nails, the
`concentration achieved in the nail plates was also higher than
`the concentration achieved with daily oral terbinafine (250
`mg) for4 weeks.” Better efficacy outcomes (linear growth of
`new clinically unaffected nail and mycological improvement)
`were observed with iontophoresis compared to passive
`diffusion in a pilot clinical trial using 1% terbinafine gel
`patch for the treatment of onychomycosis.77
`
`Chemical enhancers
`
`The nail plate is composed of 0.1% to 1.0% lipids, ~80%
`keratin, and 7% to 30% water. Its impermeability and rigidity
`are due to the physical and chemical stability of disulfide and
`hydrogen bonds found between and within the protein keratins.
`Transungual drug delivery could be improved by increasing
`the hydration of the plate and/or chemically compromising the
`integrity of the nail plate.°3'“4-66-78 Chemical permeation
`enhancers can break the physical and/or chemical bonds of
`the nail keratin. Permeation enhancers cleaving disulfide
`bonds by reduction or oxidation include N-acetyl—l-cysteine,
`
`Table 3
`Mycological and complete cure rates for combination of oral antifungals in comparative studies
`Terbinafine
`
`Reference
`
`Mycological cure Complete cure Relapse
`Treatment sequence Itraconazole
`(KOH microscopy (mycological + rate during
`(supplemental
`treatment (1)
`between month
`and culture neg)
`clinical)
`the study "‘
`
`6 and month 12)
`
`treatment (T)
`
`Gupta 200160 I1T(T)
`12 to 16 weeks
`TTT(T)
`12 to 16 weeks
`
`200 mg twice daily for 250 mg twice daily for 54/75 (72%)
`7 days 1 week on,
`7 days 1 week on,
`3 weeks off
`3wecks off
`
`44/90 (48.9%)
`
`39/75 (52%)
`
`10/75
`
`29/90 (32.2%)
`
`11/90
`
`Gupta 2004“
`
`200 mg daily for
`7 days
`
`11 [I+T ] [I+T] T T
`6 weeks
`T
`12 weeks
`200 mg twice daily for
`III
`7 days
`12 weeks
`1 week on/3 weeks off_—
`
`250 mg daily for
`7 days
`250 mg daily for
`12 weeks
`
`24/39 (61.5%)
`
`31/40 (77.5%)
`
`22/33 (66.7%)
`
`“ Participants mycologically cured before week 48 who had a mycological relapse before the end of study at week 72.
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`560
`
`thioglycolic acid, sodium sulphite, and hydrogen peroxide,
`whereas permeation enhancers, hydrolyzing/denaturing kera-
`tin proteins,
`include urea and salicylic acid. Permeation
`enhancers can also be surfactants, such as sodium lauryl
`sulfate (SLS), polyethylene glycols (PEG), T