I
`Photodynamic therapy for acne vulgaris: A critical
`review from basics to clinical practice
`
`Part II. Understanding parameters for acne treatment with
`photodynamic therapy
`
`Fernanda H. Sakamoto, MD,a,b Luis Torezan, MD,c and R. Rox Anderson, MDa
`Boston, Massachusetts, and Sao Paulo, Brazil
`
`Photodynamic therapy requires a photosensitizer, oxygen, and activating light. For acne, pilosebaceous
`units are "target" structures. Porphyrins are synthesized in vivo from 5-aminolevulinic acid (ALA),
`particularly in pilosebaceous units. Different photosensitizers and drug delivery methods have been
`reported for acne treatment. There are a variety of porphyrin precursors with different pharmacokinetic
`properties. Among them, ALA and methyl-ester of ALA (MAL) are available for possible off-label treatment
`of acne vulgaris. In addition, various light sources, light dosimetry, drug incubation time, and pre- and
`posttreatment care also change efficacy and side effects. None of these variables has been optimized
`for acne treatment, but a number of clinical trials provide helpful guidance. In this paper, we critically
`analyze clinical trials, case reports, and series of cases published through 2009. (J Am Acad Dermatol
`2010;63:195-211.)
`
`Learning objectives: After completing this learning activity, participants should be able to analyze
`photodynamic therapy using 5-aminolevulinic acid and its derivates for acne treatment, predict the
`effectiveness and outcomes of photodynamic therapy using different parameters and/or different
`porphyrin-related photosensitizers, and assess and manage the side effects of porphyrin-based photodynamic
`therapy for acne.
`
`Key words: adverse effects; 5-aminolevulinic acid; lasers; light; methyl 5-aminolevulinate; photochemo(cid:173)
`therapy; porphyrins; therapeutics.
`
`0 ver the past decade, several papers have
`
`been published about photodynamic ther(cid:173)
`apy (PDT) using 5-aminolevulinic acid
`(ALA) or methyl-aminolevulinate (MAL) for acne
`vulgaris. Despite the enthusiasm for new treatment
`alternatives, it is clear that there is no consensus
`
`From the Wellman Center for Photomedicine; Massachusetts
`General Hospital, Harvard Medical School, Boston, and the
`Departments of Dermatology at the Universidade Federal de
`Sao Paulo,b Escola Paulista de Medicina (UNIFESP-EPM), and the
`Faculdade de Medicina da Universidade de Sao Paulo (FMUSP),c
`Sao Paulo, Brazil.
`Funding sources: None.
`Conflicts of interest: The authors, editors, JAAD CME council
`members, and peer reviewers have no relevant financial
`relationships.
`Reprint requests: Richard Rox Anderson, MD, Wellman Center for
`Photomedicine, Massachusetts General Hospital, 55 Fruit St,
`BHX 630, Boston, MA 02114. E-mail: rranderson@partners.org.
`0190-9622/$36.00
`© 2010 by the American Academy of Dermatology, Inc.
`doi:10.1016/j.jaad.2009.09.057
`
`about treatment parameters to target of acne seba(cid:173)
`ceous glands.
`PDT drug delivery methods, choice of photosen(cid:173)
`sitizer, skin preparation, light sources, and light
`dosimetry/irradiance may affect efficacy and side
`effects. Understanding the science behind treatment
`methods may increase efficacy and long-term acne
`remission. This review is a critical analysis of all
`clinical papers on the subject of PDT for acne. Table I
`summarizes the clinical studies, case reports, and
`series of cases published through 2009 regarding
`PDT for acne.
`
`5-AMINOLEVULINIC ACID VERSUS
`5-AMINOLEVULINIC ACID DERIVATIVES
`Key points
`• 5-aminolevulinic acid (AIA) and AIA deriva(cid:173)
`tives have different mechanisms of cell
`uptake and transport
`• While AIA is hydrophilic, most AIA deriva(cid:173)
`tives are lipophilic, making it easier for pas(cid:173)
`sive cell transport. However, AIA derivatives
`
`195
`
`

`

`I
`Photodynamic therapy for acne vulgaris: A critical
`review from basics to clinical practice
`
`Part II. Understanding parameters for acne treatment with
`photodynamic therapy
`
`Fernanda H. Sakamoto, MD,a,b Luis Torezan, MD,c and R. Rox Anderson, MDa
`Boston, Massachusetts, and Sao Paulo, Brazil
`
`Photodynamic therapy requires a photosensitizer, oxygen, and activating light. For acne, pilosebaceous
`units are "target" structures. Porphyrins are synthesized in vivo from 5-aminolevulinic acid (ALA),
`particularly in pilosebaceous units. Different photosensitizers and drug delivery methods have been
`reported for acne treatment. There are a variety of porphyrin precursors with different pharmacokinetic
`properties. Among them, ALA and methyl-ester of ALA (MAL) are available for possible off-label treatment
`of acne vulgaris. In addition, various light sources, light dosimetry, drug incubation time, and pre- and
`posttreatment care also change efficacy and side effects. None of these variables has been optimized
`for acne treatment, but a number of clinical trials provide helpful guidance. In this paper, we critically
`analyze clinical trials, case reports, and series of cases published through 2009. (J Am Acad Dermatol
`2010;63:195-211.)
`
`Learning objectives: After completing this learning activity, participants should be able to analyze
`photodynamic therapy using 5-aminolevulinic acid and its derivates for acne treatment, predict the
`effectiveness and outcomes of photodynamic therapy using different parameters and/or different
`porphyrin-related photosensitizers, and assess and manage the side effects of porphyrin-based photodynamic
`therapy for acne.
`
`Key words: adverse effects; 5-aminolevulinic acid; lasers; light; methyl 5-aminolevulinate; photochemo(cid:173)
`therapy; porphyrins; therapeutics.
`
`0 ver the past decade, several papers have
`
`been published about photodynamic ther(cid:173)
`apy (PDT) using 5-aminolevulinic acid
`(ALA) or methyl-aminolevulinate (MAL) for acne
`vulgaris. Despite the enthusiasm for new treatment
`alternatives, it is clear that there is no consensus
`
`From the Wellman Center for Photomedicine; Massachusetts
`General Hospital, Harvard Medical School, Boston, and the
`Departments of Dermatology at the Universidade Federal de
`Sao Paulo,b Escola Paulista de Medicina (UNIFESP-EPM), and the
`Faculdade de Medicina da Universidade de Sao Paulo (FMUSP),c
`Sao Paulo, Brazil.
`Funding sources: None.
`Conflicts of interest: The authors, editors, JAAD CME council
`members, and peer reviewers have no relevant financial
`relationships.
`Reprint requests: Richard Rox Anderson, MD, Wellman Center for
`Photomedicine, Massachusetts General Hospital, 55 Fruit St,
`BHX 630, Boston, MA 02114. E-mail: rranderson@partners.org.
`0190-9622/$36.00
`© 2010 by the American Academy of Dermatology, Inc.
`doi:10.1016/j.jaad.2009.09.057
`
`about treatment parameters to target of acne seba(cid:173)
`ceous glands.
`PDT drug delivery methods, choice of photosen(cid:173)
`sitizer, skin preparation, light sources, and light
`dosimetry/irradiance may affect efficacy and side
`effects. Understanding the science behind treatment
`methods may increase efficacy and long-term acne
`remission. This review is a critical analysis of all
`clinical papers on the subject of PDT for acne. Table I
`summarizes the clinical studies, case reports, and
`series of cases published through 2009 regarding
`PDT for acne.
`
`5-AMINOLEVULINIC ACID VERSUS
`5-AMINOLEVULINIC ACID DERIVATIVES
`Key points
`• 5-aminolevulinic acid (AIA) and AIA deriva(cid:173)
`tives have different mechanisms of cell
`uptake and transport
`• While AIA is hydrophilic, most AIA deriva(cid:173)
`tives are lipophilic, making it easier for pas(cid:173)
`sive cell transport. However, AIA derivatives
`
`195
`
`

`

`196 Sakamoto, Torezan, and Anderson
`
`J AM AcAD DERMATOL
`AUGUST 2010
`
`need an extra step of metabolism to be
`converted
`into AIA
`and
`then
`into
`porphyrins
`• In general, high-dose photodynamic therapy
`with long incubation, high fluence red light
`activation works similarly for both AIA and
`AIA derivatives
`• Oral administration of
`AIA has been reported
`for
`acne
`treatment,
`but can be associated
`with systemic side ef(cid:173)
`fects and generalized
`phototoxicity
`
`C.:APSUL.E SUMMAR¥
`
`ors (S-amii:1olevulinic
`rs of At.A} delive
`orally ha\le beeA st
`· theraQy (PDT) af acne.
`• ROT for ac:ni has
`induding topical pre
`respl:J
`itions
`porp
`d light exposure.
`of ALA, such as methyl(cid:173)
`), ar,e converted 1·nt-o
`e to skin. Different
`occur among Al:.A
`Upo~hilicity and
`or:t mechanisms.
`• PoFpby:rin precursors require an
`incubation period fur metabolism.
`Longer ioc111bation times ( ~ 3 hours) are
`associated with long-term ac:Ae
`fiemissiom.
`• When used witn high-close conditions
`Uong incubation time, tiigh fluence red
`light exposme), AL#; P0T: and MAI.:. POI
`have been
`produce
`effects for
`ment.
`cus
`urces
`are mofe likely
`aceoos gland destruction
`blue light or pulsed light
`
`ts
`
`marketed by Galderma SA), but this compound has
`not yet been studied for acne. Other derivatives are
`not yet marketed.
`Mechanisms of ALA cell uptake involve trans(cid:173)
`membrane channels and active transport. ALA is a
`naturally occurring amino acid with a balance of
`hydrophilic and lipophilic properties that allows
`diffusion in and out of bio(cid:173)
`membranes.1 ALA is a largely
`hydrophilic
`zwitterion
`(a
`neutral molecule carrying
`both positively and nega(cid:173)
`tively charged groups) which
`facilitates plasma membrane
`penetration. 2 ALA
`esters
`were developed to increase
`drug penetration by adding
`aliphatic alcohols to the car(cid:173)
`bohydrate chains and modi(cid:173)
`fying the alkyl chain length,
`and to formulate new, pat(cid:173)
`entable molecules. However,
`if a highly lipophilic drug is
`added to a lipophilic vehicle
`(cream or ointment), it tends
`to be retained in the vehicle
`rather than partitioning into
`skin, and uptake is reduced. 1
`Those ALA derivatives with
`long lipophilic side chains
`may also suffer delay in up(cid:173)
`take because of retention in
`stratum corneum and/or a
`higher molecular weight. 1
`Figure 1 summarizes the lip(cid:173)
`ophilic properties of ALA and
`its derivates. 1 Ultimately,
`only the ethyl, propyl, and
`methyl esters of ALA have
`successfully improved por(cid:173)
`phyrin formation upon topi(cid:173)
`cal application to intact skin
`in vivo. 1·3 Some studies using
`the topical hexyl ester of ALA
`in skin failed, possibly be(cid:173)
`cause it was used within a
`lipophilic vehicle, suggesting
`that a hydrogel vehicle may
`be more appropriate for the more lipophilic esters. 1
`In addition to differences in uptake related to
`physicochemical properties, it was also observed in
`different cultured cell lines that uptake of ALA and its
`various esters follow different active transport path(cid:173)
`ways. 5-ALA is a beta amino acid that enters cells in
`part via active transport mechanisms, such as PEPTl
`
`In the United States and
`South America, 5-AIA is avail(cid:173)
`able in 20% hydroalcoholic
`solution
`and marked as
`Levulan Kerastick
`(Dusa
`Pharmaceuticals, Wilmington,
`MA) for treatment of actinic
`keratosis followed by blue
`light exposure. Methyl ami(cid:173)
`nolevulinate hydrochloride
`is the methyl-ester of ALA
`(MAL) in a cream formula(cid:173)
`tion. MAL
`is marketed as
`Metvix
`(produced
`by
`Photocure
`ASA,
`Oslo,
`Norway, and marketed by
`Galderma SA
`in Europe,
`Australia, and South America
`for the treatment of actinic
`keratosis and, depending on
`the country,
`for
`treating
`Bowen disease and superfi(cid:173)
`cial basal cell carcinoma) or
`as Metvixia (in the United
`States,
`marketed
`by
`Galderma SA for the treat(cid:173)
`ment of actinic keratosis
`with red light exposure). It
`is labeled either as 16% or
`16.8% concentration in differ(cid:173)
`ent countries, depending
`whether the hydrochloride
`is
`included
`in molecular
`weight. Lower concentrations of MAL (2, 4, and 8%)
`are being tested in phase I and phase II clinical trials
`for acne treatment, but no publications are available
`thus far. More recently, the hexyl-ester of ALA has
`been approved in Europe for bladder cancer treat(cid:173)
`ment (Hexvix 85-mg powder for intravesical use;
`produced by Photocure ASA, Oslo, Norway, and
`
`high in
`deepet pen
`to Rra
`compared
`sources.
`• Topical AL1\ PDT or MA:t POifi is often
`painful, causes inflammato~y side effects,
`and may cause residual ~hotosensitivity.
`
`

`

`Table I. Publications between 2000 and 2008 of 5-aminolevulenic acid and methyl aminolevulinate hydrochloride photodynamic therapy for the treatment
`of acne vulgaris
`
`llongcharu, 2000 18
`
`Itoh, 2000"'
`
`Itoh, 200123
`
`Goldman, 200335
`
`Pollock, 2004"
`
`Gold, 200426
`
`Taub, 2004 20
`
`Kimura, 2004 15
`
`Hong, 2005 ,.,
`
`Drug
`
`20% ALA topical
`
`20% ALA
`topical
`
`20% ALA
`topical
`
`20% ALA
`topical
`
`20% ALA
`topical
`
`20% ALA
`topical
`
`20% ALA topical Oral ALA
`I salicylic
`10 mg/kg
`acid peelings
`over 4 weeks
`No; not blinded
`assessment
`
`No; not blinded
`assessment
`
`20% ALA topical
`(only in acne
`spots)
`
`Yes (split-face ALA-
`PDT vs controls);
`blinded
`assessment (?)
`
`18
`
`51/Body
`
`8/Face
`
`Control
`group?*
`
`Yes; blinded
`assessment
`
`22/Back
`
`No. of
`patients/
`acne
`location
`Acne type
`
`Inflammatory,
`mild to
`moderate
`Pretreatment 70% lsopropyl
`alcohol
`
`Time of
`incubation
`
`3 hrs under
`occlusion
`
`Light
`sources
`
`Broad-spectrum
`(550-700 nm),
`150 J/cm2
`
`No. of PDT
`sessions
`
`Total
`follow-up
`time
`
`Two randomized
`groups: 1 vs 4
`sessions (1-wk
`apart)
`20 wks after
`the last
`treatment
`
`Yes (same
`No; not
`patients received blinded
`treatments
`assessment
`and controls);
`not blinded
`assessment
`10/Back
`
`15
`
`Inflammatory,
`mild to
`moderate
`Not mentioned
`
`3 hrs under
`occlusion
`
`Inflammatory,
`moderate to
`severe
`Cetaphil
`cleanser
`
`1 hr
`
`No (compared
`to blue light
`only group),
`not blinded
`assessment
`
`22 (12 blue
`light vs
`10 ALA-
`PDT)/Face
`Inflammatory,
`mild to
`moderate
`2% Salicylic
`acid cleanser
`
`15 min
`
`Yes (compared
`No; not
`blinded
`to rest of the
`face that was not assessment
`treated);
`not blinded
`assessment
`1/Face
`
`13/Face
`
`Inflammatory
`
`Not
`mentioned
`
`4 hrs under
`occlusion,
`light covered
`Pulsed excimer
`dye laser (635
`nm), 5 J/cm2
`
`3 Comedonal
`(NI); 10
`inflammatory
`Not
`mentioned
`
`4 hrs under
`occlusion,
`light covered
`Broad-spectrum
`(600-700 nm)
`halogen
`lamp at 17
`mW/cm2
`13
`
`5 nm, Diode laser
`Blue 417
`10 mW/cm 2
`(635 nm),
`,
`3.6 J/cm2
`25 mW/cm 2
`,
`15 J/cm2
`
`Inflammatory,
`moderate to
`severe
`Acetone scrub
`and alcohol
`scrub
`15-30 min,
`not
`standardized
`IPL (430-110 nm), Blue (417-420 nm) Metal halide
`3-9 J/cm2
`(540-800 nm),
`OR blue
`69.2 mW/cm 2
`heat
`417
`5 nm
`,
`(1.8-4.2 J/cm 2 at
`60-80 J/cm2
`10 mW/cm2
`) OR
`IPL (400-980 nm),
`18-25 J/cm2 +
`radiofrequency
`18-20J/cm2
`, no
`standardized
`fluences
`2-4 (4-8 wks
`apart), not
`standardized
`
`Intractable (?)
`
`Not mentioned
`
`4 hrs
`
`Inflammatory, mild
`to moderate
`
`70% lsopropyl
`alcohol
`
`4 hrs under
`occlusion, light
`covered
`Halogen lamp
`red (630
`63
`nm),
`30 mW/cm 2
`18 J/cm2
`
`,
`
`1
`
`1
`
`1
`
`2
`
`3 (1-wk
`apart)
`
`4 (1 wk
`apart)
`
`2 (2-4 wks
`apart)
`
`32 wks
`
`24 wks after
`the last
`treatment
`
`2 wks
`
`3 wks
`
`12 wks
`
`4-32 wks,
`not
`standardized
`
`12 wks
`
`24 mos
`
`Continued
`
`<"----
`~i~
`C
`,::..
`~ ►
`;;_~
`_w tJ
`zo
`C::: m
`:;; ►
`;.".: ?;'
`;,,
`...;
`"'o
`r
`
`a
`
`r::;
`;::i
`~
`::i:..
`;::i
`1%-
`&i
`0
`;:;
`....
`\0
`----.I
`
`

`

`Table I. Cont'd
`
`Hongcharu, 200018
`
`Hoh, 200040
`
`Itoh, 200123
`
`Goldman, 200335
`
`Pollock, 200441
`
`Gold, 2004 26
`
`Taub, 2004 27
`
`Complete
`remission,
`with no new
`lesions
`
`Four sessions
`better than 1.
`After 20 wks,
`reduction of
`·~ 50% of acne
`after 4 sessions
`(P < .05). --~30%
`reduction with
`only one session.
`Global acne
`improvement,
`sebum reduction,
`and
`autofluorescence
`statistically
`significant
`compared to
`other control
`sites
`
`100% of
`patients
`with some
`improvement;
`13/13 patients
`with no new
`lesions after
`mo; 5/13
`without new
`lesions after
`3 mos and
`6 mos all
`patients
`had new
`lesions
`
`68% (PDT)
`reduction of
`inflammatory
`lesions vs 40%
`(blue light)
`and 62%
`reduction
`of NI lesions.
`32% (ALA-PDTI
`vs 25% (blue
`only)
`improvement in
`severity of acne
`
`Recurrence
`
`New lesions
`after 3-6 mos
`
`Reduction of
`acne count
`from 11.6
`lesions to 3.6
`at the end of
`the study;
`lesions not
`evaluated
`
`20% of patients
`had no
`improvement
`with treatment;
`800/4 of patients
`showed 71.8% of
`improvement;
`lesions not
`mentioned
`
`27% of patients
`had no
`improvement
`with treatment.
`Results not
`comparable
`because of the
`lack of
`standardization
`
`Hong, 2005 42
`Kimura, 200415
`7.8% no changes; 41.9% (treated) vs
`31.4%
`15.4% (control)
`improvement;
`reduction
`60.8% marked
`of inflamed
`lesions.
`improvement.
`Average lesion
`Statistical
`count reduction
`difference when
`was 18%
`compared
`
`1 % recurrence
`in 1 or 2 mos;
`results not com(cid:173)
`parable because
`of the lack of
`standardization
`
`Most patients
`noted a increase
`in new lesions
`after 6 months
`
`Continued
`
`"'"' ~
`
`VJ
`:::,
`~ :::,
`;:i
`0
`}:i
`
`:::,
`:;:i
`~
`::i:..
`:;:i
`~
`~
`
`:;:i
`
`~ ,,.
`>
`>~
`§ 0
`C
`::i ('.;'
`2'3 ~
`0~
`
`t:M
`
`

`

`Santos, 200529
`
`Wiegell, 200612
`
`Wiegel!, 200613
`
`Alexi rules-
`Horfelt, 200614 Ar:menakas, 200628
`
`Rojanamatin,
`200630
`
`Akaraphanth,
`2007"3
`
`Yeung, 2007H
`
`Horfelt, 2007"9
`
`Drug
`
`20% ALA
`topical
`
`16.8% MAL
`
`20% ALA vs
`16.8% MAL
`
`16.8% MAL
`
`20% ALA topical
`+ conventional
`treatment or
`chemical peels
`
`20% ALA topical
`
`10% ALA topical
`only in acne
`spot
`
`20% ALA topical
`
`Not blinded
`assessment
`
`16.8% MAL
`topical; all
`patients used
`0.1% adapalene
`gel during the
`entire study
`No (IPL alone
`vs MAL l
`IPL vs
`control in a
`randomized,
`split-face
`study);
`blinded
`assessment
`
`23/Face
`
`14/Face: 9 cheek, 5
`back
`
`No (same
`patients
`received blue
`light alone
`and blue light
`ALA in a
`nonrandomized
`split-face study);
`not blinded
`assessment
`20/Face
`
`Inflammatory,
`moderate to
`severe
`Washing
`
`Inflammatory
`
`Mild to severe
`
`Not mentioned
`
`Washed with
`soap followed
`by alcohol
`scrub
`
`<"---.
`~i~
`C
`,::..
`~ ►
`;;_~
`_w tJ
`zo
`C::: m
`:;; ►
`;.".: ?;'
`;,,
`...;
`"'o
`r
`
`a
`
`r::;
`;::i
`~
`::i:..
`;::i
`1%-
`&i
`0 ..,,
`~
`....
`
`\0
`\0
`
`Control
`group?*
`
`No (split-face:
`IPL alone
`ALA);
`vs IPL
`not blinded
`assessment
`
`Yes; blinded
`assessment
`
`No (split-face);
`blinded
`assessment
`
`Yes (split-face);
`blinded
`assessment
`
`No (not
`randomized
`split-face
`study); not
`blinded
`assessment*
`
`No (all patients
`received some
`treatment);
`all patients
`continued
`conventional
`therapies; not
`blinded
`assessment
`
`13/Face
`
`No. of
`patients/
`acne
`location
`
`36 (21 treatment
`vs 15 control)/
`Face
`
`15/Face
`
`30/Face
`
`Acne type
`
`Inflammatory
`and NI
`
`Pretreatment Not
`mentioned
`
`Inflammatory
`
`Inflammatory
`
`Curettage l
`occlusive
`dressing
`
`Not
`mentioned
`
`Time of
`incubation
`
`3 hrs
`
`3 hrs under
`occlusion
`
`3 hrs under
`occlusion,
`light covered
`
`Inflammatory,
`moderate to
`severe
`Nodular and
`cystic lesions
`were pricked
`with 1-2 mm
`cannula
`3 hrs under
`occlusion
`
`14/Face
`19/Face; 1 ALA
`blue vs 14 ALA
`LP PDL
`vs 2 LP PDL
`only vs 2
`conventional
`treatments
`(4 patients of
`ALA
`LP PDL
`group received
`35% glycolic
`acid or 20%
`trichloroacetic
`acid peeling)
`Inflammatory
`and NI lesions,
`mild to severe
`Cetaphil
`cleanser
`
`Soap and
`water
`
`Inflammatory
`
`45 min
`
`30 min under
`occlusion
`
`1 hr
`
`30 min
`
`3 hrs under
`occlusion
`
`Continued
`
`

`

`Table I. Cont'd
`
`Light
`sources
`
`Santos, 200529
`IPL (cutoff
`filter, 560 nm),
`double pulse
`26-34 J/cm2
`
`Wiegell, 2006 l2
`
`Wiegell, 2006 13
`
`Noncoherent
`red (635 nm),
`37 J/cm2
`
`Noncoherent
`red (630 nm),
`37 J/cm2
`, 34
`mW/cm2
`
`2 (2 wks apart)
`
`2
`
`1
`
`8 wks
`
`12 wks
`
`12 wks
`
`No. of PDT
`sessions
`
`Total
`follow-up
`time
`
`Noncoherent
`red (635 nm),
`37 J/cm2
`
`2 (2 wks apart)
`
`12 wks
`
`Alexi rules-
`Horfelt, 2006 14 Annenakas, 200628
`LP PDL (595 nm,
`7.0-7.5 J/cm2
`,
`10 ms, 10-mm
`spot size), DCD
`30/30 blue
`(417
`5 nm),
`10 mW/cm2
`1-6 sessions
`(4 wks apart),
`no standardized
`protocol
`5-52 wks, no
`standardized
`protocol
`
`Rojanamatin,
`200630
`IPL (cutoff
`filter, 560--590
`nm), double
`pulse 25-30
`J/cm2
`
`Akaraphanth,
`2007"
`
`Blue LED
`5 nm),
`(415
`40 mW/cm 2
`48 J/cm2
`
`,
`
`3 (3-4 wks
`apart)
`
`4 (1 wk apart)
`
`Yeung, 200731
`IPL (530-750
`nm), single
`pass, double
`pulse, 10-ms
`delay, pulse
`2.5 ms,
`7.0-9.0 J/cm 2
`4 (3 wks apart)
`
`Horfelt, 200739
`
`Noncoherent red
`(600-730 nm), 50
`mW/cm 2
`, 50 or
`30 J/cm2 (cheek);
`50 or 70 J/cm2
`(back)
`
`1
`
`12 wks
`
`12 wks
`
`10 wks (cheeks); 20
`wks (back)
`
`ALA + IPL sites:
`23% poor
`response, 77%
`good or
`excellent results
`vs IPL only: 77%
`poor, 23% good
`results.
`
`68% reduction
`of inflammatory
`lesions vs 0% in
`controls
`.0023
`(P
`[control]) 92%
`improvement
`.64); NI
`(P
`lesions: no
`improvement.
`
`Mean of 59%
`reduction
`of inflammatory
`lesions
`for both MAL
`and ALA
`NI lesions:
`no difference
`75-83% clinical
`improvement
`
`54% (PDTI vs
`20% (control)
`reduction of
`inflammatory
`lesions
`.0006);
`(P
`NI lesions:
`reduction with
`no statistically
`significant 40%
`(PDTI vs 20%
`(control) clinical
`improvement
`
`LP PDL
`ALA
`group:
`clearance ~40-
`1000/o, but
`4 patients
`had additional
`chemical
`peels and
`maintained
`conventional
`treatment during
`the study.
`Clearance
`of 32-33% (LP
`PDL-only) vs
`17-200/4
`(conventional);
`results
`not comparable
`because
`of the lack of
`standardization
`
`65% (PDT-group) 100% showed
`vs 23% (IPL
`some
`group) vs 88%
`improvement;
`(control group)
`high and low
`reduction of
`light doses
`inflammatory
`showed similar
`lesions (no
`clinical
`statistical
`improvement,
`difference);
`the latter with
`NI lesions:
`lower side
`decrease of 38%
`effect rates
`PDT group
`vs 44% IPL vs
`increase
`of 15% in
`control group
`
`11 wks (16 wks
`of the
`beginning
`of the
`treatment)
`71.1% (blue
`All patients
`ALA)
`improved; 87.7%
`light
`(IPL
`ALA) vs
`vs 56.7%
`66.8% (IPL only)
`(IPL only)
`reduction of
`reduction of
`inflammatory
`inflammatory
`lesion (with no
`lesion
`(no statistical
`statistical
`difference)
`difference,
`p
`.092).
`Reduction
`in NI lesions
`was 80.5%
`(blue
`ALA)
`vs 71.3% (blue
`only) with no
`statistical
`difference.
`No significant
`difference in the
`lipid level
`
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`> Ei
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`
`

`

`J AM AcAD DERMATOL
`VOLUME 63, NUMBER 2
`
`Sakamoto, Torezan, and Anderson 201
`
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`
`transporter (in rat pancreatoma cells), 4 PEPT2
`transporter (in kidney cells), 5 carrier systems trans(cid:173)
`porting the beta amino acids (/3-transporters), and
`gamma-aminobutyric acid (GABA; in the human
`adenocarcinoma cell line WiDr), 6
`'7 It is unknown
`whether and to what extent different active transport
`mechanisms account for the striking biodistribution
`of ALA among different cell types in human skin,
`However, ALA esters were suggested to enter cells
`mainly by passive diffusion or endocytosis, 8 MAL
`does not seem to be taken up by /3-transporters, but
`by an active transport mechanism involving trans(cid:173)
`porters of nonpolar amino acids, when studied in
`colon adenocarcinoma cells, 9
`Even though in vitro porphyrin accumulation had
`been shown to be more effective for some ALA esters
`in comparison to ALA, when injected into mice, ALA
`derivatives resulted in a lower porphyrin concentra(cid:173)
`tion in the tumor compared to equimolar amounts
`of ALA, suggesting blood vessel retention of ALA
`derivatives, 10 Oral administration of ALA alkyl
`esters also show no advantage over 5-ALA, because
`these are quickly degraded in the gastric acidic
`environment 1
`The development of new ALA derivatives is
`promising, but the optimal photosensitizer for acne
`treatment is not yet defined, and clinical results are
`still pending for most of the ALA derivatives, Among
`all ALA derivatives, only MAL has been studied and
`introduced for treatment of acne outside the United
`States, but is not yet cleared by the US Food and Drug
`Administration for this indication,
`There may be important differences between MAL
`and ALA in practice, The role of occlusion after
`application has not been specifically tested for either
`of these topical medicines (hydroalcoholic solution
`vs, cream), While ALA is a water-soluble amino acid,
`MAL is a more lipid-soluble derivative, In theory,
`MAL may partition more easily into the lipid-rich
`milieu of sebum, but this has not been specifically
`tested, Depending on pH, the two molecules have
`different charges, The extra metabolic step of ester
`hydrolysis is also necessary to convert MAL to ALA,
`which appears to occur mainly in the intracellular
`space; tissue-cytoplasmic esterases in particular(cid:173)
`must hydrolyze the methyl ester to form ALA in situ,
`which is then converted to porphyrins, The heme
`synthetic pathway is complex, involving multiple
`cytoplasmic and mitochondrial steps that are sensi(cid:173)
`tive to substrate concentrations, Differences in the
`vehicles, uptake, charge, partitioning, and metabo(cid:173)
`lism plus the higher molecular weight of MAL may
`delay its onset of photosensitization compared with
`ALA, but this has also not been determined, A study
`comparing ALA and MAL for actinic keratosis has
`
`

`

`J AM AcAD DERMATOL
`AUGUST 2010
`
`Plasma
`Membrane
`
`202 Sakamoto, Torezan, and Anderson
`
`Log P Octanol I H2o
`0.0
`1.0
`
`- 1.0
`
`2.0
`
`3.0
`
`0
`
`5-ALA
`
`Methyl ester
`
`H3N •~o :
`0
`
`0
`
`H3N •~o /
`0
`
`0
`
`Ethyl ester
`
`H3N'~o_,,r-....
`0
`
`Butyl ester
`
`Pentyl ester
`
`Benzyl ester
`
`Hexyl ester
`
`Octyl ester
`
`0
`
`H3N •~o~ - - - ' " ,
`0
`
`Fig 1. Uptake of 5-aminolevulinic acid (ALA) and its derivatives depends on the partition
`between the aqueous and lipophilic environments, molecular weight, and specific transmem(cid:173)
`brane transport. Log P octanol/Hzo describes partitioning between octanol (lipophilic) and water
`(hydrophilic) media. ALA and its methyl ester have negative values, meaning that they are
`hydrophilic. For them, passive diffusion through cell membranes is difficult, and uptake occurs
`by specific receptors. All the other esters shown are more lipophilic. Intermediate lipophilicity
`allows most of them to cross biologic membranes, but the largest octyl ester of ALA is inhibited
`from cell uptake. (Modified with permission from Lange. 1
`)
`
`shown that ALA is more efficient for porphyrin
`formation, although MAL was more selective for
`the lesions. 11 Similar comparative studies for seba(cid:173)
`ceous glands were not performed. Neither of the
`drug formulations has been specifically optimized
`for use in acne treatment; it is likely that both could
`be improved.
`
`Comparative efficacy
`Similar studies of "high-dose" (long incubation
`time and high fluence red light exposure) have also
`verified similar efficacy when the MAL was used for
`acne therapy. 12
`14 Wiegell and Wulf12
`13 reported a
`-
`•
`significant 68% reduction in inflammatory lesions
`after 12 weeks of treatment, and a control group did
`not improve.
`
`The same group compared topical 20% ALA with
`16% MAL in a randomized, split-face, blindly as(cid:173)
`sessed study followed for 12 weeks after one PDT
`session (3 hours of incubation followed by irradia(cid:173)
`tion of red light). 13 There was 59% average reduction
`of inflammatory lesions with no statistical difference
`between the two drugs. Pain during treatment was
`similar for both photosensitizers, but was more
`intense after 24 hours in the ALA sites. This was felt
`to be consistent with more intense and homoge(cid:173)
`neous porphyrin fluorescence found in the ALA(cid:173)
`treated areas, suggesting that ALA may cause greater
`porphyrin synthesis in the epidermis. One hypoth(cid:173)
`esis is that MAL is more selective for sebaceous gland
`uptake because of its lipophilic properties. However,
`this is speculative, and it is not yet known whether
`
`

`

`J AM AcAD DERMATOL
`VOLUME 63, NUMBER 2
`
`Sakamoto, Torezan, and Anderson 203
`
`the two agents induce different porphyrin distribu(cid:173)
`tions under various application conditions, It is
`equally plausible that faster uptake and metabolism
`of ALA into protoporphyrin IX may explain its more
`intense fluorescence and greater side effects in this
`study,
`Potentially, a shorter period of incubation or a
`lower ALA concentration would produce the same
`intensity and distribution of porphyrins as MAL, with
`the same side effect rates and efficacy for the treat(cid:173)
`ment of acne, A larger clinical study comparing these
`drugs in a dose response manner is needed, At
`present, they appear to be largely equivalent.
`
`Oral or topical photosensitizer?
`While using oral ALA, Kimura et al15 observed a
`92% rate of improvement of acne according to
`nonblinded observers, The oral administration of
`ALA can lead to systemic adverse effects not unlike
`acute variegate porphyria, acute intermittent por(cid:173)
`phyria, or the 8-ALA dehydratase deficiency por(cid:173)
`phyria in which systemic ALA levels are elevated, 16
`Those include generalized photosensitivity requiring
`prolonged photoprotection, hepatotoxicity, nausea,
`and vomiting, 17 although only nausea was observed
`in Kimura et al's study, 15 in which the ALA dose was
`limited to 10 mg/kg, Similar to topical application of
`ALA, 18 an acneiform eruption occurring 3 to 4 days
`after treatment was also observed after oral ALA
`administration 15 and red light exposure for PDT
`Because of these side effects and lack of an approved
`formulation, oral ALA remains experimental and is
`rarely used outside of Japan,
`
`WHICH LIGHT SOURCES, AND WHAT
`DOSIMETRY AND IRRADIANCE?
`Key points
`• Deeper penetrating (red) light wavelengths
`are more likely to reach and activate por(cid:173)
`phyrins in sebaceous glands
`• Continuous, high-intensity red light sources,
`including lasers, broad spectrum, and light(cid:173)
`emitting diode sources, have shown best
`results in long-term follow-up studies using
`either ALA or MAL for photodynamic ther(cid:173)
`apy of acne
`• There is no consensus about optimal light
`dosimetry and irradiance
`
`Photons, the fundamental quanta of light, interact
`with matter by scattering and absorption, Both of
`these interactions limit the penetration of light into
`20 In the visible light spectrum, scattering and
`skin, 19
`,
`absorption generally decrease with
`increasing
`wavelength, Longer wavelengths (red) therefore
`
`400
`
`Wavelength (nm)
`500
`
`600
`
`300
`25
`
`2
`t5
`
`e
`~
`
`C
`0
`
`~ e
`0
`"' 05
`~
`0
`
`0
`
`500
`
`I 1000
`
`C
`0
`;
`~ QJ
`; 1500
`0.
`
`2000
`
`Fig 2. Porphyrin absorption bands exist from 300 to 650
`nm and can be excited by numerous sources, which have a
`range of clinical utility. The figure shows wavelength(cid:173)
`dependent penetration of light into human skin, with
`arrows indicating the approximate 50% optical penetration
`depth. IPL, Intense pulsed light (source); KTP, potassium(cid:173)
`titanyl-phosphate; Nd, neodymium; PDL, pulsed dye laser;
`YAG, yttrium-aluminum-garnet.
`
`penetrate deeper than shorter (blue) wavelengths,
`20
`a phenomenon also known as the Tyndall effect. 19
`,
`Facial sebaceous glands are part of the follicular unit
`and are located approximately 0.5 to 1.0 mm from
`the cutaneous surface. 21 Because of the deep loca(cid:173)
`tion of sebaceous glands, stimulation of the photo(cid:173)
`sensitizer for acne treatment requires light sources
`with wavelength(s) sufficiently long and with suffi(cid:173)
`cient irradiance to induce photodynamic effects on
`the targets22 (Fig 2).
`Porphyrins are tetrapyrrole molecules, with a
`maximum absorption band in the blue light spec(cid:173)
`trum, the Soret band ( 405-415 nm). Somewhat
`weaker absorption bands, so-called Q-bands, are
`located in the green ( ~506 nm to ~540 nm), yellow
`