Accepted: 18 April 2018

DOI: 10.1111/jocd.12670

ORIGINAL CONTRIBUTION

The efficacy and tolerability of 5-aminolevulinic acid 5%

thermosetting gel photodynamic therapy (PDT) in the
treatment of mild-to-moderate acne vulgaris. A two-center,
prospective assessor-blinded, proof-of-concept study

Stefano Maria Serini MD1 | Maria Vittoria Cannizzaro MD2 | Annunziata Dattola MD2 |
Virginia Garofalo MD2 | Esther Del Duca MD2 | Alessandra Ventura MD2 |
Massimo Milani MD3 | Elena Campione MD2 | Luca Bianchi MD2

1
Outpatient Dermatology Service Milan,
Milan, Italy
2
Dermatology, University of Rome Tor
Vergata, Rome, Italy
3
Medical Department, Cantabria Labs Difa
Cooper, Caronno Pertusella, Italy
Correspondence
Massimo Milani, Medical Department,
Cantabria Labs Difa Cooper, Caronno
Pertusella, Italy.
Email: massimo.milani@difacooper.com
Summary
Background: Acne vulgaris is a chronic inflammatory skin disease, commonly trea-
ted with topical or systemic drugs, according to the severity of the condition. Reti-
noids and antibiotic compounds are considered cornerstone approaches in this
condition. However, low adherence to the therapy and the issue of bacterial resis-
tance undermine the efficacy in the long term. Photodynamic therapy (PDT) with
20% aminolevulinic acid (ALA) has shown to be effective in the treatment of inflam-
matory acne. Skin tolerability, however, could be a limiting factor for a widespread
use of this approach. A new formulation of 5% ALA in thermosetting gel has been
recently available. This formulation allows a more convenient application procedure
without occlusion and better and more efficient release of the active compound in
comparison with traditional ALA formulations like creams or ointments.
Study aim: To evaluate in a two-center, assessor-blinded, prospective, proof-of-
concept study, the efficacy, and tolerability of red-light (630 nm) PDT with a new
5-ALA “low-dose” topical gel formulation (5%) in the treatment of inflammatory
mild-to-moderate acne vulgaris (AV).
Subjects and methods: A total of 35 subjects with moderate AV of the face (mean
age: 24  8 years, 13 men and 22 women) were enrolled, after their written
informed consent. The primary outcome was the evolution of GAG (Global Acne
Grade System) score at baseline and after an average of three, 630-nm, 15-minute,
PDT sessions, performed every 2 weeks. GAG score was also calculated in a follow-
up visit 6 months after the last PDT session. Skin tolerability was assessed during
PDT sessions with a patient-reported discomfort level evaluation score from 0 (no
discomfort at all) to 3 (severe discomfort).
Results: At baseline, the GAG score was 21  6. After the last PDT session, the
GAG score evaluated in a blinded fashion (digital photographs) was significantly
reduced to 6.5  5.7, representing a 70% reduction (P = .0001, Wilcoxon test;
mean difference 14.9; 95% CI of the difference: 12.1-17.6). At the follow-up visit,

J Cosmet Dermatol. 2018;1–7. wileyonlinelibrary.com/journal/jocd © 2018 Wiley Periodicals, Inc. | 1

2 | SERINI ET AL.

the GAG score was 6.7  6.8. The 5% ALA thermosetting gel Red-light PDT was in
general very well tolerated with a discomfort mean level score of 0.5  1.
Conclusion: This proof-of-concept study supports the efficacy of 5% ALA ther-
mosetting gel red-light PDT in inflammatory acne of the face with a relevant clinical
improvement of inflammatory lesions with a very good tolerability profile. Clinical
improvement was maintained in the medium term (Trial Registration Number:
ISRCTN66066651).

KEYWORDS
acne, aminolevulinic acid, photodynamic therapy, thermosetting gel

1 | BACKGROUND photodynamic killing of P. acnes could sterilize sebaceous follicles;

Acne vulgaris (AV) is a chronic inflammatory skin disease that mani-
fests as open and closed comedones as well as inflammatory papules,
pustules, and nodules localized on the face and trunk.1 The patho-
genesis is multifactorial and includes inflammation, increased sebum
production, and obstruction of the pilosebaceous unit, followed by
2
overgrowth of Propionibacterium acnes (P. acnes). Several studies
have shown that P. acnes can also induce skin inflammation by acti-
vating Toll-like receptor (TLR)-2 and TLR-4, which in turn trigger the
production of inflammatory cytokines such as interleukin (IL)-1, IL-8,
3
and IL-12. Retinoids and antibiotic compounds are considered a
cornerstone approach in this condition.4 However, adherence to the
therapy and the issue of bacterial resistance weaken the efficacy in
the long term.5 Photodynamic therapy (PDT) is a procedure that was
6
first used for the treatment of actinic keratoses. Photodynamic ther-
apy (PDT) has emerged also as a new option for dermatologists in
7
the treatment of moderate and severe acne. The principle of PDT is
that specific wavelengths of light irradiation combined with local or
8
systemic use of photosensitizer generate oxygen and free radicals.
Blue-light (405 nm) and Red-light (630 nm) lamps are commonly
used in PDT and they are now increasingly used for treatment of
acne vulgaris.9 PDT involves the application of a photosensitizing
chemical, 5-aminolevulinic acid (5-ALA) which, when exposed to vari-
ous lights, results in excitation of the photosensitizer (protopor-
phyrin, PpIX) and consequent production of a reactive oxygen
species that leads to cytotoxicity.10 PpIX is a photosensitizer that
accumulates not only in the epidermal cells but also in the piloseba-
ceous units.11 When intense visible light is delivered on the ALA-
treated skin, PpIX is excited into a triplet state, which reacts with
oxygen to produce singlet oxygen, causing membrane damage and
cell destruction. ALA is taken up selectively in sebaceous glands and
12
is processed to porphyrins. In fact, topical ALA may directly enter
hair follicles, where sebaceous glands actively synthesize and retain
PpIX. In addition, P. acnes contains endogenous PpIX.13 Topical ALA-
PDT may therefore have several modes of action for acne treatment.
In 2000, Hongcharu and colleagues were the first to use red-light
PDT for acne in the USA.14 The use of ALA with red-light PDT lamps
in acne was adopted in several clinical trials.15,16 Direct photody-
namic injury of sebaceous glands could inhibit sebum production;
follicular obstruction could be reduced by changing keratinocyte
shedding and hyperkeratosis.17 Moreover, an anti-inflammatory and
immune-regulatory effect has been supposed. ALA-PDT, indeed,
exerts its role by decreasing TLR2 and TLR4 expression.18 A new for-
mulation of 5% ALA in thermosetting gel has been recently avail-
able.19 This formulation allows a more convenient application
procedure without occlusion and better and more efficient release of
the active compound in comparison with traditional ALA formula-
tions like creams or ointments.20 This gel contains a peculiar poly-
mer, poloxamer 407, which is liquid at room temperature and
becomes a semi-solid (gel) when in contact with the skin (ie, temper-
ature >25 Co; thermosetting gel: a sol-gel temperature-dependent
state transition formulation).21 The gel is easy to apply on the skin.
In addition, this formulation has shown in vitro a more complete ALA
release in comparison with conventional cream and ointment vehi-
cles. This gel increases porphyrin accumulation in nude mouse skin.22
So far, no clinical data are available regarding efficacy and local toler-
ability of 5% ALA thermosetting gel in the treatment of acne.
2 | AIM OF THE STUDY
We investigated the efficacy and tolerability of 5% 5-ALA ther-
mosetting gel with red-light PDT in the treatment of mild-to-moder-
ate acne vulgaris.
3 | SUBJECTS AND METHODS
3.1 | Study design
We performed a two-center, prospective, assessor-blinded, proof-of-
concept trial.
3.2 | Subjects
Subjects of both sexes affected by mild-to-moderate acne of the
face referring to two outpatient clinics in Milan (SMS, Outpatient
Dermatology Service) and in Rome (Department of Dermatology,
University of Rome “Tor Vergata”) were enrolled after their written
SERINI ET AL.
informed consent. The study protocol was evaluated and approved
by the Investigational Review Board (University Tor Vergata, Rome)
(Trial Registration Number: ISRCTN66066651). The study took place
between October 2016 and January 2018. Main inclusion criteria
were as follows: patients affected either by non-inflammatory (mi-
cro-comedonic) or inflammatory acne vulgaris (papulo-pustolar) of
the face and trunk; age over 18 years old, not pregnant; contraindi-
cated or unresponsive to conventional acne treatments, including
oral and topical antibiotics and/or isotretinoin. Exclusion criteria
were as follows: presence of other acute skin diseases other than
acne vulgaris, topical acne treatment in the past 2 weeks or systemic
retinoids in the past 6 months, history of keloids, or photosensitivity
disorders. Pregnant and lactating women were also excluded.
(A)
(a)
F I G U R E 1 A, Subject at baseline (a)
and after 3 ALA 5% thermosetting gel PDT
sessions (b). B, Fluorescence imaging
pictures of 3 (a,b,c) subjects after 5% ALA
thermosetting gel incubation (120 min)
(B)
(a)
(c)
| 3
3.3 | PDT procedures
A 5% ALA thermosetting gel that does not necessitate occlusion was
chosen for the study. Patients were treated every other week for a
total of three sessions for each patient. The 5% ALA gel (2 mL per
application) was applied to the entire face by the investigator. Dur-
ing the ALA incubation period of 120 minutes, patients were kept
away from sunlight, to avoid early activation of the photosensitizer.
Before and after the topical application of 5% ALA gel, the presence
of PpIX was examined under the illumination using a UV LED or
Wood light in the dark (Figure 1B). Patients were irradiated using a
630 nm red-light source (S632 portable lamp Alpha Strumenti,
Melzo, Italy) at 25 mJ for 15 minutes on average. The standard
(b)
(b)
4 |
distance from the lamp to the skin area to be treated was 15 cm.
Immediately after light irradiation, cold water was applied to minimize
redness and pain, if necessary. In general, three PDT sessions, each
performed every 2 weeks, were done (average number of PDT ses-
sions: 2.7; range: 2-6). Patients were examined, and digital pho-
tographs were taken at every visit for an assessor-blinded evaluation
of clinical evolution of GAG score. Assessment of skin tolerability and
the appearance of adverse effects were carried out after each PDT
session. The number of acne lesions (including comedones, papules,
pustules) was recorded by the same dermatologist for all patients
using the GAGS score (global acne grading system score) according to
23
Doshi. Follow-up visits, to evaluate safety and tolerability profiles,
were carried out after 2 and 4 weeks after the last PDT session. A
final clinical evaluation follow-up visit was performed 6 months after
the last PDT session with the evaluation of GAG score.
3.4 | Study outcomes
The primary outcome of the study was the evolution of the GAG
score at baseline and after the last PDT sessions. GAG score was
also evaluated at the follow-up visit 6 months after the last PDT
session. The GAG score was calculated using high-definition, digital-
ized color pictures by an assessor unaware of time pictures
sequences. A secondary outcome was the evaluation of skin tolera-
bility after each PDT session with a patient-reported discomfort level
evaluation score from 0 (no discomfort at all) to 3 (severe discom-
fort). This evaluation was performed in an open fashion.
3.5 | Statistical analysis
Statistical analysis was performed using GraphPad Statistical Soft-
ware (GraphPad Software, Inc., La Jolla, CA, USA). Continuous vari-
ables were expressed as mean  standard deviation (SD). The
primary outcomes of the study were to evaluate the GAG scores
using paired nonparametric test (Wilcoxon test) comparing baseline
values with GAG values after PDT and at follow-up visit. In view of
the proof-of-concept nature of the present trial, a formal sample size
calculation was not performed. We decided to enroll at least 30
evaluable subjects.
4 | RESULTS
In all, 35 subjects (13 men and 22 women; mean age 24  8 years),
affected by mild-to-moderate acne vulgaris of the face and trunk,
were included in the study after written consent was given. Table 1
shows the patients’ characteristics at baseline. Red fluorescence gen-
erated from PpIX was observed after the topical application of 5%
ALA gel starting from the first incubation hour. On the other hand,
post-light irradiation UV exam showed the absence of PpIX fluores-
cence. All patients completed the study. At baseline, the GAG score
was 21  6. After 3 PDT sessions, the GAG score evaluated in a
blinded fashion was significantly reduced to 6.5  5.7, representing a
SERINI ET AL.
T A B L E 1 Subjects’ characteristics at baseline
Sex (Men/women) 13/22
Age, mean  SD, years 24  8
GAG score, mean  SD 21  6
Fitzpatrick Photo type Type 3: 24 (68%); Type 2:9 (32%)
History of acne, years, mean  SD 8
Previous history of acne therapy
Yes/no 29 (83%)/6(17%)
Topical 29 (83%)
Systemic 24 (68%)
70% reduction (P = .0001, Wilcoxon test; mean difference 14.9; 95%
CI of the difference: 12.1-17.6). At the follow-up visit, the GAG score
was 6.7  6.8 (P = .0001, Wilcoxon test vs. baseline; mean difference
14.7; 95% CI of the difference: 11.9-17.5) (Figure 2). Figures 1A and
3A and B show subjects before and after PDT therapy. The product
was very well tolerated during the PDT procedures. No major side
effects were reported, itching, burning, pain, during or after the irradi-
ation. The 5% ALA thermosetting gel PDT was in general very well
tolerated with a discomfort mean level score of 0.5  1.
5 | DISCUSSION
The therapeutic approach of acne could be challenging.24 Topical
and systemic retinoids and antibiotics are the mainstay acne treat-
ment.25 However, their efficacy in the medium and long term could
be undermined by the reduced compliance or adherence in the case
of retinoids treatments or by the gradual appearance of bacterial
resistance in the case of antibiotics use.26 In moderate/severe acne
subjects, the use of oral retinoids could be limited or contraindi-
cated.27 Photodynamic therapy (PDT), with 20% aminolevulinic acid
or 16% methyl-aminolevulinic acid, using artificial light sources like
405 or 630 nm lamps or natural sources (daylight PDT) are emerged
as an alternative treatment option in acne vulgaris.28 ALA is trans-
formed in protoporphyrin IX (PpIX), the photosensitizer substance
which has a broad activation spectrum (405-640 nm). The absorption
spectrum of PpIX is maximally activated at 410 nm (blue light) with
other peaks at 505-580 and at 635 nm.29 Therefore, many different
light sources can be used for ALA-PDT. Blue light (405 nm) is the
most potent wavelength for activation of endogenous PpIX compo-
nents of Propionibacterium acnes. However, blue light has a poor
depth penetration into the skin (about 1 mm). In contrast, red light
(635 nm) can penetrate deeper (about 3 mm). For this reason, in our
study, we have used a 630 nm red-light source. Red-light PDT is
considered very effective in inducing inhibition and destruction of
sebaceous glands.30 Acne could respond well to photodynamic ther-
apy using topical porphyrin precursors.31 The principle of PDT is the
use of a sensitizer substance, in general applied topically in the skin
area to be treated, a source of irradiation and a consequent forma-
tion of free radical derivatives which could have microbicidal
SERINI ET AL. | 5

action.32 Skin tolerability, however, could be a limiting factor for a

wide spread use of this approach.33 Incubation time and concentra-
tion of the photosensitizer could be correlated with relevant skin
side effects.34,35 In our study, 5% ALA gel PDT has demonstrated to
be an effective and safe alternative in the treatment of inflammatory
and non-inflammatory acne vulgaris, especially for patients recalci-
trant or contraindicated to conventional treatments. The application
of the gel without occlusion facilitates the use and improved the
patients’ compliance. The low (ie, 5%) concentration of ALA formula-
tion used in this trial in comparison with traditional “high-concentra-
tion” ALA formulations (ie, 20%) could improve the skin tolerability
without losing clinical efficacy. Moreover, this treatment can be a
useful alternative not only as first line, but also to help keeping the
isotretinoin or antibiotic results during the summer season when oral
acne treatments are no longer utilized. Some limitation should be
taken into account in evaluating our results. First, the relatively

F I G U R E 2 Evolution of GAG scores at baseline, after last PDT small sample size and the study design we chose (not double blind).
session and at follow up (6 months). Baseline vs. Last PDT: However, this should be considered a proof-of-concept trial and the
P = .0001, Wilcoxon test. Baseline vs Follow up: P = .0001, present results should be confirmed in a larger patients’ population.
Wilcoxon test. Last PDT vs follow-up: NS To increase the internal validity of our study, we adopted an

(A)
a b

(B)
a b

F I G U R E 3 A, Subject at baseline (a)

and after 3 ALA 5% thermosetting gel PDT
sessions (b). B, Same subject at the
12 months Follow UP visit (a: right chick;
b: frontal view)
6 |
assessor-blinded method (blinded evaluation of subject pictures for
the GAG score calculation) with the aim to reduce the potential bias
of the uncontrolled open study design. A strong aspect of our study
is the relatively long follow-up period (6 months) we adopted. It is
interesting to observe that the clinical improvement obtained after
PDT treatment sessions was practically fully maintained at the fol-
low-up. The relative long-lasting effects of ALA-PDT could be due to
the prolonged reduction in sebum production observed after PDT in
acne subjects.36
6 | CONCLUSION
This proof-of-concept study supports the efficacy of 5% ALA ther-
mosetting gel red-light PDT in inflammatory acne of the face with a
relevant clinical improvement of inflammatory lesions with a very
good tolerability profile. Clinical improvement was maintained in the
medium term. Further studies, including a larger number of patients,
are needed to substantiate our findings.
ORCID
Massimo Milani http://orcid.org/0000-0001-7559-1202
REFERENCES
1. Williams HC, Dellavalle RP, Garner S. Acne vulgaris. Lancet.
2012;379:361-372.
2. Cordain L, Lindeberg S, Hurtado M, Hill K, Eaton SB, Brand-Miller J.
Acne vulgaris: a disease ozrf Western civilization. Arch Dermatol.
2002;138:1584-1590.
3. Vowels BR, Yang S, Leyden JJ. Induction of proinflammatory cytoki-
nes by a soluble factor of Propionibacterium acnes: implications for
chronic inflammatory acne. Infect Immun. 1995;63:3158-3165.
4. Zaenglein AL, Thiboutot DM. Expert committee recommendations
for acne management. Pediatrics. 2006;118:1188-1199.
5. Ross JI, Snelling AM, Carnegie E, et al. Antibiotic-resistant acne: les-
sons from Europe. Br J Dermatol. 2003;148:467-478.
6. Ericson MB, Wennberg AM, Larko € O. Review of photodynamic ther-
apy in actinic keratosis and basal cell carcinoma. Ther Clin Risk
Manag. 2008;4:1.
7. Riddle CC, Terrell SN, Menser MB, Aires DJ, Schweiger ES. A review
of photodynamic therapy (PDT) for the treatment of acne vulgaris. J
Drugs Dermatol. 2009;8:1010-1019.
8. Sharman WM, Allen CM, Van Lier JE. Photodynamic therapeutics:
basic principles and clinical applications. Drug Discovery Today.
1999;4:507-517.
9. Elman M, Lebzelter J. Light therapy in the treatment of acne vulgaris.
Dermatol Surg. 2004;30:139-146.
10. Vrouenraets MB, Visser GW, Snow GB. Basic principles, applications
in oncology and improved selectivity of photodynamic therapy. Anti-
cancer Res. 2003;23:505-522.
11. Jun MS, Choi HS, Han I, Kim M, Kim JC. In vitro and ex vivo proto-
porphyrin IX expression induced by 5-aminolevulinic acid in human
pilosebaceous unit. J Dermatol Sci. 2005;40:68-70.
12. Dierickx CC. Photodynamic therapy of pilosebaceous units. In: Calza-
vara-Pinton PG, Szeimes RM, eds. Comprehensive Series in Photo-
sciences. New York, NY: Elsevier; 2001;2:271-282.
SERINI ET AL.
13. Ramstad S, Le Anh-Vu N, Johnsson A. The temperature dependence
of porphyrin production in Propionibacterium acnes after incubation
with 5-aminolevulinic acid (ALA) and its methyl ester (m-ALA). Pho-
tochem Photobiol Sci. 2006;5:66-72.
14. Hongcharu W, Taylor CR, Aghassi D, Suthamjariya K, Anderson RR,
Chang Y. Topical ALA-photodynamic therapy for the treatment of
acne vulgaris. J Invest Dermatol. 2000;115:183-192.
15. Fabbrocini G, Cacciapuoti S, De Vita V, Fardella N, Pastore F, Mon-
frecola G. The effect of aminolevulinic acid photodynamic therapy
on microcomedones and macrocomedones. Dermatology. 2009;219:
322-328.
16. Pollock B, et al. Topical aminolaevulinic acid-photodynamic therapy
for the treatment of acne vulgaris: a study of clinical efficacy and
mechanism of action. Br J Dermatol. 2004;151:616-622.
17. Ho€ rfelt C, Stenquist B, Larko
€ O, Faergemann J, Wennberg AM. Pho-
todynamic therapy for acne vulgaris: a pilot study of the dose-
response and mechanism of action. Acta Derm Venereol. 2007;
87:325-329.
18. Jeong E, Hong JW, Min JA, et al. Topical ALA-photodynamic
therapy for acne can induce apoptosis of sebocytes and down-
regulate their TLR-2 and TLR-4 expression. Ann Dermatol. 2011;23:
23-32.
19. Bourre L, Thibaut S, Briffaud A, Lajat Y, Patrice T. Potential efficacy
of a delta 5-aminolevulinic acid thermosetting gel formulation for
use in photodynamic therapy of lesions of the gastrointestinal tract.
Pharmacol Res. 2002;45:159-165.
20. Collaud S, Peng Q, Gurny R, Lange N. Thermosetting gel for the
delivery of 5-aminolevulinic acid esters to the cervix. J Pharm Sci.
2008;97:2680-2690.
21. Jeong B, Kim SW, Bae YH. Thermosensitive sol–gel reversible hydro-
gels. Adv Drug Deliv Rev. 2012;64:154-162.
22. Haslam JL, Higuchi T, Mlodozeniec AR. (1984). U.S. Patent
No. 4,474,753. Washington, DC: U.S. Patent and Trademark Office.
23. Doshi A, Zaheer A, Stiller MJ. A comparison of current acne grading
systems and proposal of a novel system. Int J Dermatol. 1997;36:
416-418.
24. Baldwin HE. Tricks for improving compliance with acne therapy. Der-
matol Ther. 2006;19:224-236.
25. Leyden JJ. A review of the use of combination therapies for the
treatment of acne vulgaris. J Am Acad Dermatol. 2003;49:S200-
S210.
26. de Lucas R, Moreno-Arias G, Perez-Lo  pez M, Vera-Casan ~o A,
Aladren S, Milani M. Adherence to drug treatments and adjuvant
barrier repair therapies are key factors for clinical improvement
in mild to moderate acne: the ACTUO observational prospective
multicenter cohort trial in 643 patients. BMC Dermatol. 2015;
15:17.
27. Layton A. The use of isotretinoin in acne. Dermato-endocrinology.
2009;1:162-169.
28. Kharkwal GB, Sharma SK, Huang YY, Dai T, Hamblin MR. Photody-
namic therapy for infections: clinical applications. Lasers Surg Med.
2011;43:755-767.
29. Wen X, Li Y, Hamblin MR. Photodynamic therapy in dermatology
beyond non-melanoma cancer: An update. Photodiagn Photodyn Ther.
2017;19:140-152.
30. Sakamoto FH, Lopes JD, Anderson RR. Photodynamic therapy for
acne vulgaris: a critical review from basics to clinical practice: part I.
Acne vulgaris: when and why consider photodynamic therapy? J Am
Acad Dermatol. 2010;63:183-193.
31. Sakamoto FH, Lopes JD, Anderson RR. Photodynamic therapy for
acne vulgaris: a critical review from basics to clinical practice: part I.
Acne vulgaris: when and why consider photodynamic therapy? J Am
Acad Dermatol. 2010;63:183-193.
32. Demidova TN, Hamblin MR. Photodynamic therapy targeted to
pathogens. Int J Immunopathol Pharmacol. 2004;17:245-254.
SERINI ET AL. | 7

33. Goldman MP, Atkin DH. ALA/PDT in the treatment of actinic ker-
atosis: spot versus confluent therapy. J Cosmet Laser Ther. How to cite this article: Serini SM, Cannizzaro MV, Dattola
2003;5:107-110.
A, et al. The efficacy and tolerability of 5-aminolevulinic acid
34. Braathen LR, Paredes BE, Saksela O, et al. Short incubation with
methyl aminolevulinate for photodynamic therapy of actinic ker-
5% thermosetting gel photodynamic therapy (PDT) in the
atoses. J Eur Acad Dermatol Venereol. 2009;23:550-555. treatment of mild-to-moderate acne vulgaris. A two-center,
35. Babilas P, Landthaler M, Szeimies RM. Photodynamic therapy in der- prospective assessor-blinded, proof-of-concept study. J
matology. Eur J Dermatol. 2006;16:340-348. Cosmet Dermatol. 2018;00:1–7. https://doi.org/10.1111/
36. Divaris DX, Kennedy J, Pottier RH. Phototoxic damage to sebaceous
jocd.12670
glands and hair follicles of mice after systemic administration of 5-
aminolevulinic acid correlates with localized protoporphyrin IX fluo-
rescence. Am J Pathol. 1990;136:891.