Topical nicotinamide in acne

43 Pages·2013·5.51 MB·Italian

Volume 3 - Number 2/2012
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WORK IN PROGRESS LAVORI IN CORSO
As it can be seen in this issue of the European Stefano Veraldi Come si può vedere in questo numero dello
Journal of Acne, the Italian Acne Clubgains European Journal of Acne, l’Italian Acne
“kudos” for the adherence of new Italian colleagues: Club aumenta di prestigio, grazie all’adesione
Iwish to thank them for their support. dinuovicolleghi, che desidero qui ringraziare.
The importance of the international editorial board, Grande è anche l’importanza del nuovo board
with several prestigious dermatologists, is great. editoriale internazionale, con vari prestigiosi
Someof them are coming from extra-european dermatologi, anche extra-europei (mi domando:
countries (Iwonder if it is now time to name our nonèarrivato il momento di chiamare il giornale
journal as International Journal of Acne). International Journal of Acne?).
The activity of the Italian Acne Boardkeeps up: L’attività dell’Italian Acne Boardcontinua: è pronto
aCDon oral isotretinoin is ready; a new book on un CD sull’isotretinoina orale; tra breve sarà
seborrhoeic dermatitis will be published very soon. pubblicato un nuovo libro sulla dermatite seborroica e
Furthermore, we are evaluating the possibility saranno messi in cantiere un nuovo libro sulla
ofwriting novel books on cosmetology cosmetologia dell’acne e uno sulla rosacea.
ofacneandrosacea.
Dulcis in fundo, anche se è un po’ prematuro,
Lastly, I have some interesting news: in 2013, cisaranno grandissime novità per quanto riguarda
theAcne Daywill be held in Milan (the sooner, l’Acne Daydel 2013: sarà organizzato a Milano e,
thebetter). In consideration of the attendance of inconsiderazione della partecipazione di numerosi
several international dermatologists, it will be dermatologi stranieri, si chiamerà
namedInternational Acne and Rosacea Days. InternationalAcneand Rosacea Days.
Il lavoro, quindi, continua…
Volume 3, Number 2/2012
Editorial Board Content
Topical nicotinamide in acne: a critical review pag 21
Stefano Veraldi, Giuseppe Micali, Mauro Barbareschi, Aurora Tedeschi, Rossana Schianchi
Editor
Spa water for acne therapy pag 27
Stefano Veraldi Milano Silvia Alberti Violetti
Co-Editor Epidemiologia dell’acne: oltre i dati europei pag 31
Gabriella Fabbrocini, Maria Carmela Annunziata, Nevena Skroza, Vincenzo Bettoli,
Mauro Barbareschi Milano Nayera Moftah, May el-Samahy, Zrinka Bucvic Mokos, Mauro Barbareschi,
Stefano Veraldi, Giuseppe Micali, Francesco Bruno, Giuseppe Monfrecola
Scientific Board
Acne e fotoprotezione pag 37
Vincenzo Bettoli Ferrara Giuseppe Monfrecola, Rosanna Izzo
Stefano Calvieri Roma
Strategie per migliorare l’aderenza terapeutica nell’acne pag 43
Gabriella Fabbrocini Napoli
Gabriella Fabbrocini, Luigia Panariello, Valerio De Vita,
Giuseppe Micali Catania
Dario Bianca, Maria Chiara Mauriello, Giuseppe Monfrecola
Giuseppe Monfrecola Napoli
Follicular biopsy (FB) can be useful for monitoring therapeuthic
Nevena Skroza Roma
compliance in acne patients pag 49
Annarosa Virgili Ferrara
Gennaro Ilardi, Gabriella Fabbrocini, Nevena Skroza, Sara Cacciapuoti,
Managing Editor Ersilia Tolino, Claudio Marasca, Giuseppe Monfrecola
Counseling: adherence to therapy and quality of life pag 54
Antonio Di Maio Milano
Gabriella Fabbrocini, Caterina Mazzella, Rosanna Izzo, Giuseppe Monfrecola
Cosmetics and acne: a primer pag 57
Aurora Tedeschi, Laura Guzzardi, Giuseppe Micali
Italian Acne Club
Mario Bellosta (Pavia), Enzo Berardesca (Roma), Carlo Bertana (Roma), Alessandro Borghi (Ferrara), Francesco Bruno (Palermo), Maria Pia De Padova (Bologna),
Paolo Fabbri (Firenze), Mario Maniscalco (Sciacca), Carlo Pelfini (Pavia), Mauro Picardo (Roma), Maria Concetta Potenza (Roma), Marco Romanelli (Pisa),
AlfredoRossi(Roma), Rossana Schianchi (Milano), Patrizio Sedona (Venezia), Riccarda Serri (Milano), Aurora Tedeschi (Catania),
Antonella Tosti (Bologna/Miami), Matteo Tretti Clementoni (Milano)
International Editorial Board
Zrinka Bukvic Mokos (Zagreb, Croatia), Tam El Ouazzani(Casablanca, Morocco), May El Samahy(Cairo, Egypt), Uwe Gieler(Giessen, Germany),
Maite Gutierrez Salmerón(Granada),Marius-Anton Ionescu(Paris, France),Monika Kapinska Mrowiecka(Cracow, Poland),Nayera Moftah (Cairo, Egypt),
Nopadon Noppakun(Bangkok, Thailand),Gerd Plewig(Munich, Germany), Miquel Ribera Pibernat (Barcelona),Robert Allen Schwartz(Newark, Usa),
Jacek Szepietowski(Breslau, Poland), Shyam Verma (Ladodra, India)
Editorial Staff
Direttore Responsabile: Pietro Cazzola Consulenza grafica: Piero Merlini
Direttore Generale: Armando Mazzù Impaginazione: Stefania Cacciaglia
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European Journal of Acne and Related Diseases
Volume 3, n. 2, 2012
Stefano Veraldi1, Giuseppe Micali2, Mauro Barbareschi1, Aurora Tedeschi2,
Rossana Schianchi3
1 Department of Anaesthesiology, Intensive Care and Dermatological Sciences, University of Milan, I.R.C.C.S. Foundation, Cà Granda
Ospedale Maggiore Policlinico, Milan, Italy; 2 Department of Surgical and Medical Sciences, Dermatology Section, University of
Catania, Italy; 3 European Institute of Dermatology, Milan, Italy
Topical nicotinamide in acne: a critical review
S
UMMARY
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cases of contact dermatitis were published so far. Finally, topical nicotinamide can be used in association
Furthermore, topical nicotinamide lacks of photoaller- with other topical anti-acne drugs.
Key words: Acne, topical nicotinamide.
Introduction
Nicotinamide (also known as niacina - sidered a safe compound. In fact, it is considered
mide) is a water-soluble amide of nicotinic acid by the Food and Drug Administration (FDA) as
(also known as niacin). They are similarly effective 'Generally Recognized as Safe' (GRAS)5.
because they can be converted into each other. Several acute toxicity studies evaluated the safety of
Other synonyms are vitamin B3 and vitamin pella- nicotinamide in animal models. In mice, the LD
50
gra preventing (vitamin PP). for both subcutaneous and intraperitoneal injections
Nicotinamide is a component of two very impor- of nicotinamide is approximately 2 g/kg5.
tant enzymes involved in hydrogen transfer: nicoti- In rats, the LD for oral administration is 2.5-3.5
50
namide adenine dinucleotide (NAD, coenzyme I) g/kg 5; LD for nicotinamide injected subcuta-
50
and nicotinamide adenine dinucleotide phosphate neously is 1.68 g/kg5. Long term studies in male
(NADP, coenzyme II)1, 2. These two codehydroge- Sprague-Dawley rats, using daily dosages of up to
nases supply hydrogen to the respiratory chain for 600 mg/kg of nicotinamide injected intraperi-
oxidation and energy production3. toneally for five weeks, had only minimal effects,
resulting in a decrease in food intake and less
weight gain in a dose-dependent manner 5, 6. In all
Toxicology instances, these dosages far exceed the dosages of
nicotinamide used clinically. Nicotinamide was
Nicotinamide is present in all living cells. shown to have oncopreventive effects and no car-
It is consumed in the diet: it is contained mainly in cinogenic or cocarcinogenic effects5, 7, 8.
the liver (5-25 mg of nicotinamide/100 g), beef, Data on mutagenicity of nicotinamide are negative:
kidney and fish (2-15 mg/100 g), and mushrooms several studies demonstrated that many mutagens
(3-5 mg/ 100 g)4. Nicotinamide is therefore con- act by reducing intracellular levels of nicotinamide
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European Journal of Acne and Related Diseases
Volume 3, n. 2, 2012
in target cells5. It was observed an increase in DNA Nicotinamide inhibits the synthesis of poly-
repair after treatment of mouse lymphocytes with adenosinediphosphate-ribose-polymerase-1
0.5-10 nmol/l solutions of nicotinamide5. (PARP-1), a nuclear enzyme contributing to DNA
Studies on the reproductive effects of nicotinamide repair, which, if overactivated, causes cell necro-
were carried out in several species. The drug has sis3. PARP enhances nuclear factor-kB (NF-kB)-
not been shown to be teratogenic. Contrariwise, it mediated transcription, which plays a central role
has protective effects in some animal models9. in the expression of cytokines, adhesion molecules
Several studies were conducted to evaluate the irri- and inflammatory mediators3.
tation and sensitization potential of 4% nicoti- Nicotinamide inhibits the expression of intercellu-
namide gel. In repeated insult patch tests, using a lar adhesion molecule-1 (ICAM-1) and major his-
modified Draize-Shelanski-Jordan protocol, 227 tocompatibility complex-II (MHC-II), and the syn-
subjects were exposed to the drug for six weeks. thesis of interleukins (ILs) 1 and 12, tumor necro-
The results of this study demonstrated that 4% sis factor (TNF)-(cid:0)and macrophage migration inhi-
nicotinamide gel was neither irritanting nor sensi- bition factor (MIF) 3, 19. MIF inhibition may be
tizer5. Furthermore, phototoxicity and photoaller- responsible for the steroid-sparing effect of nicoti-
gy studies were performed in 25 patients. These namide, as MIF is upregulated by corticosteroids3.
studies showed no evidence of phototoxicity or Propionibacterium (P.) acnes is implicated in the
photoallergy5. inflammatory phase of acne. It has been shown that
it activates IL-8 synthesis by interacting with Toll-
like receptor (TLR)-2 on the surface of ker-
Pharmacokinetics atinocytes. Some authors demonstrated that nicoti-
namide downregulates IL-8 gene expression at
In vitro studies on percutaneous absorp- transcriptional and post-transcriptional levels and
tion of topically applied nicotinamide were per- IL-8 protein synthesis in a dose-dependent manner,
formed10, 11. Total absorption, expressed as per- through phosphorylation of the mitogen-activated
cent of applied dosage, was 11.1 ± 6.2 in vivo11. protein kinase (MAPK) and TLR-2 degradation. In
Following oral administration, peak plasma con- addition, nicotinamide decreases the half-life of
centrations are achieved at 1-3 hours, with peak IL-8 mRNA by affecting its stability16, 20.
concentrations of 0.08-1.1 μmol/ml for doses of 1- Furthermore, nicotinamide acts as an electron
6 g, respectively12. scavenger3, 5, 15.
The drug is metabolized by intestinal bacteria and Finally, topical nicotinamide has a stabilizing
the liver and is excreted in the urine13, 14. effect on epidermal barrier function [reduction in
transepidermal water loss (TEWL) and improve-
ment in the moisture content of the horny layer]21.
Mechanisms of action
Nicotinamide leads to an increase in protein syn-
thesis (e.g. keratin, filaggrin and involucrin)21, has
The clinical activity of nicotinamide may a stimulating effect on ceramide synthesis 21,
result from the presence of a pyridine ring in the speeds up the differentiation of keratinocytes, and
chemical structure5. raises intracellular NADP levels1.
Several theories were proposed for the mechanism The activity of nicotinamide on sebum excretion
of action of topical nicotinamide in acne. rate (SER) was studied by Draelos et al.22. A total
Nicotinamide acts in acne as anti-inflammatory of 100 Japanese subjects were enrolled in a double-
agent. It inhibits neutrophil chemotaxis3, 5, 15, 16 and blind, placebo-controlled study. Fifty subjects
synthesis of phosphodiesterase (PDE): the resultant applied a 2% nicotinamide moisturizer on the face
increase in cyclic AMP (cAMP) induces the inhibi- for 4 weeks and 50 subjects applied a placebo mois-
tion of release of proteases from leukocytes and the turizer for 4 weeks. SER measurements were taken
inhibition of lymphocyte transformation3, 5, 17, 18. at baseline, week 2 and week 4. The group treated
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European Journal of Acne and Related Diseases
Volume 3, n. 2, 2012
with nicotinamide demonstrated significantly low- controlled studies which were carried out in United
ered SER after 2 and 4 weeks of application22. Kingdom. A total of 969 patients with mild to
A commercially available product of 4% nicoti- moderate inflammatory acne of the face were treat-
namide oil-free cream contains an anti-bacterial ed twice daily for 8-12 weeks with 4% nicoti-
adhesive (ABA) substance: the latter is sucrose namide gel (= 486 patients) or placebo (= 483
stearate. This substance inhibits the adhesion of P. patients): 709 patients were considered evaluable
acneson cytoplasmic membrane of corneocytes of at the end of the study (356 patients in the nicoti-
the infra-infundibulum. Seven volunteers of both namide group and 353 in the vehicle group). Three
genders with acne applied once a day on one fore- clinical criteria of evaluation were used: acne
arm, for three days, a gel containing sucrose severity rating, physician’s global evaluation and
stearate; the other forearm was considered as con- papule/pustule count. Acne severity rating:
trol. Corneocytes were isolated from the two fore- patients treated with nicotinamide experienced
arms of each volunteer and incubated with P. greater improvement over baseline at final visit
acnes. Bacterial adhesion to corneocytes was quan- compared with vehicle (p = 0.013). Patients under
tified by flow-cytofluorimetry: fluorescence inten- 21 years of age showed significant improvement
sity of corneocytes-bacteria complex was mea- (p = 0.009) with nicotinamide use compared with
sured. ABA inhibited the adhesion of 50% P. acnes vehicle, whereas there was no difference between
in three patients and of 82 to 97% in four patients nicotinamide and vehicle in the over 21 age group
23. of patients. Physician’s global evaluation: a signif-
icantly greater improvement at final visit in the
group of patients treated with nicotinamide com-
Clinical studies pared with the group treated with the vehicle (p =
0.016) was observed. A significant clinical
The first clinical study on the activity and improvement was observed with nicotinamide
tolerability of topical nicotinamide in acne was treatment in the pre-21 year age group only (p =
published in 1995 by Shalita et al. 15. In this dou- 0.024). Papule/pustule count: in the group of
ble-blind study, 4% nicotinamide gel was com- patients treated with nicotinamide, papule/pustule
pared to 1% clindamycin gel in the treatment of count fell from 29.43 ± 0.77 at baseline to 15.40 ±
moderate inflammatory acne. Seventy-six patients 0.70 at final visit, compared with 29.34 ± 0.78 to
were randomly assigned to apply either nicoti- 16.07 ± 0.69 in the vehicle group, e.g. a non signif-
namide (n = 38) or clindamycin (n = 38), twice icant (p = 0.16) difference between the two groups.
daily for eight weeks. Efficacy was evaluated at The high vehicle response observed in these
weeks 4 and 8 using Physician's Global Evaluation, patients was most likely a consequence of the
Acne Lesion Counts and Acne Severity Rating. hydro-alcoholic gel vehicle, which exerted some
After eight weeks, both treatments induced compa- therapeutic effect. Side effects were limited to
rable (P = 0.19) beneficial results in the Physician's local erythema and dryness24.
Global Evaluation: 82% of the patients treated with In 2003, two Indian studies were published25,26. In
nicotinamide and 68% treated with clindamycin the study by Dos et al. 25, eighty patients with
improved. Both treatments induced statistically moderate acne were enrolled for the comparative
similar reduction in acne lesions (papules and pus- evaluation of 1% clindamycin phosphate (40
tules: -60% nicotinamide versus -43% clindamycin: patients) versus 1% clindamycin phosphate and
P = 0.168), and acne severity (-52% nicotinamide 4% nicotinamide gel (40 patients). This study did
group versus -38% clindamycin group: P = 0.161). not show any added advantage of clindamycin in
These results demonstrated that nicotinamide is of combination with nicotinamide over clindamycin
comparable efficacy to clindamycin15. alone 25.
Griffiths24, in 1995, published the results of three In the trial by Sardesai et al. 26, a total of 75
multicentre, randomized, double-blind, vehicle- patients with inflammatory acne were divided into
23
European Journal of Acne and Related Diseases
Volume 3, n. 2, 2012
three groups. Group A was treated with 4% nicoti- association nicotinamide-adapalene is more effec-
namide and 1% clindamycin, group B was treated tive than the association adapalene-moisturizer: it
with 1% clindamycin and group C, which was con- is possible that nicotinamide and adapalene pos-
sidered to have resistance to local antibiotics due sess a synergistic effect 28.
to no response to treatment, was treated with the A multicentre, double-blind, randomized study was
combination. At the end of eight weeks, the results conducted by clinical and biophysical non-invasive
were compared. It was concluded that addition of measurements to evaluate the efficacy and tolerabil-
nicotinamide was of not much value in treating ity of a 4% nicotinamide-phospholipidic (linoleic
inflammatory acne26. acid rich-phosphatidylcholine) emulsion versus 1%
Weltert et al.27 carried out a double-blind clinical topical clindamycin phosphate, both applied once
trial in which 4% nicotinamide gel was compared daily for 12 weeks. The nicotinamide-phospholi-
to 4% erythromycin gel. Two groups of 80 patients pidic association resulted slightly superior to clin-
each with moderate inflammatory acne of the face damycin for all parameters studied (better compli-
were treated for eight weeks. The efficacy was ance and global clinical improvement)30.
evaluated by means of retention and inflammatory Finally, a multicentre, prospective, non-random-
lesion count and clinical score of seborrhoea. ized, open, parallel-group study will be soon pub-
Nicotinamide and erythromycin led to equivalent lished31. Patients with mild to moderate acne, who
regression of inflammatory lesions: this was visi- were treated with a topical retinoid for at least one
ble from the first month of treatment. Seborrhoea month and had developed skin irritation, were
score presented a more significant decrease in the assigned to one of the two following treatments:
group treated with nicotinamide27. 0.2% myrtacine + 4% vitamin PP (n = 116) or a
An Italian, multicentre, controlled, sponsor-free simple emollient cream (n = 48). Myrtacine is an
study, carried out by the Italian Acne Board ethanolic extract obtained from myrtle leaves. It
(IAB)28, demonstrated that 4% nicotinamide oil- showed several pharmacological properties in
free cream, applied twice daily for 12 weeks, vitro: it inhibits keratinocyte proliferation, inhibits
induced a significant clinical improvement (≥50% the growth of P. acnes, decreases the synthesis of
from baseline) in 21 out of 64 patients (32.8%) pro-inflammatory mediators via the cyclo-oxige-
with mild to moderate acne. When nicotinamide nase and lipo-oxigenase pathways, and decreases
(applied once daily for 12 weeks) was associated lipase activity. Both treatments were administered
with 0.1% adapalene gel (applied once daily for 12 twice daily. Study endpoints were: improvement in
weeks), 54 out of 106 patients (50.9%) improved. signs and symptoms of retinoid dermatitis, global
This group of patients was compared with another efficacy, reduction in acne severity, overall clinical
group of 78 patients who were treated with adapa- outcome, patient satisfaction and tolerability. At
lene (1 application/day for 12 weeks) and a mois- day28, the association myrtacine—vitamin PP sig-
turizer (1 application/day for 12 weeks). A signifi- nificantly decreased signs (erythema, dryness/scal-
cant clinical improvement was observed in 32 out ing and oedema) and symptoms (itching, stinging
of 78 patients (41%). Acne severity and treatment and burning sensation) of retinoid dermatitis
efficacy were evaluated by means of the Global (p < 0.01) compared with the simple emollient
Acne Grading System (GAGS)29. Results of these cream. In addition, the association myrtacine—vit-
three studies may be summarized as follows: a) amin PP decreased acne severity in a significantly
one-third of patients significantly improved with greater proportion of patients (p = 0.023) and was
nicotinamide alone. This improvement was some- associated with a better clinical outcome (global
times (approximately in 15% of patients) slow (up improvement: p < 0.001) compared with the sim-
to three weeks). b) Tolerability was excellent. ple emollient cream. The association myrtacine—
Topical nicotinamide lacks of photoallergic or vitamin PP was also associated with greater patient
phototoxic potential: therefore, it can be used in satisfaction and was better tolerated than the sim-
complete safety also in the summertime. c) The ple emollient cream.
24
European Journal of Acne and Related Diseases
Volume 3, n. 2, 2012
Conclusions
Results of clinical studies published so far photoallergic or phototoxic potential: therefore, it
on the treatment of acne with topical nicotinamide can be used in complete safety also in the summer-
may be summarized as follows: a) nicotinamide time. When associated with 0.2% myrtacine, it is
can be considered as an effective drug for the treat- effective for prevention and treatment of retinoid
ment of mild to moderate inflammatory acne; b) dermatitis; c) topical nicotinamide can be used in
tolerability is excellent: no cases of contact der- association with other topical anti-acne drugs,
matitis due to topical nicotinamide were published although, to our knowledge, it was associated so far
so far. Furthermore, topical nicotinamide lacks of only with adapalene and phosphatidylcholine.
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European Journal of Acne and Related Diseases
Volume 3, n. 2, 2012
Silvia Alberti Violetti
Department of Pathophysiology and Transplantation, Università degli Studi di Milano - Fondazione IRCCS Ca' Granda - Ospedale
Maggiore Policlinico, Milan - Italy
SPA water for acne therapy
S
UMMARY
oletti
berti Vi aSnpda tthheerrampayl, musuind gh masi nbeereanl swpirdienlgy fsauclftourrsic.-rich one, influences some its etiopathogenetic
Al
Silvia museendt ionf d“ecrlmasastioclaolg”y maesd iccoinmep lteo- sIino nIsta/yleya, rb),a lins eaostthoenriasphyin fgolyr paacinde b(yu sthuea llpyu btwlice lvhee asleths-,
treat a lot of skin diseases. but in literature there are no data that support a role of
Acne is one of these, because of spa water, particularly this spa therapy in acne.
Key words: Balneotherapy, acne, acne therapy.
Dear Sir,
Spa therapy, based on the use of mineral bonds contained in keratins, shedding the corneo-
spring and thermal mud, has been widely used in cytes accumulated in sebaceous follicles2; further-
medicine. In dermatology, from the studies by Von more, in sebaceous glands, sulfur can decrease dif-
Hebra and Duhring about keratolytic effect of spa ferentiation of sebocytes and sebum excretion 3.
waters, balneotherapy has been considered as com- Sulfur waters also possess antibacterial and anti-
plement of “classical” medicine to treat a lot of fungal properties, due to pentathionic acid pro-
diseases, especially psoriasis and atopic dermati- duced by interaction between sulfur and oxygen
tis1. Acne is another disease of the skin that could radicals in the deeper layers of the epidermis 5.
improve by means of spa waters. In Italy, bal- Furthermore, not only sulfuric waters, but also
neotherapy for acne (usually twelve sessions/year), other mineral waters, induce vasodilation, an anal-
is astonishingly paid by the public health, despite gesic influence on pain receptors, and inhibition of
of its dramatic situation according the economical the immune response5, 6.
point of view. These data leaded to think that sulfuric waters were
I performed a systematic review in Pubmed, the best ones for acne therapy; however, Karatsi7
EMBASE and Cochrane Library on balneotherapy suggested that it isn’t know if only a single element
in the treatment of acne. Literature reports that bal- or component of a spa source makes more effective
neotherapy, especially using sulfuric-rich spa one mineral water than another one, but probably it
water, influences some etiopathogenetic factors of is due to combination of multiple elements.
acne, through a keratolytic effect and reduction of I found no randomized controlled trials about the
sebum production: sulfur can break disulfide treatment of acne with balneotherapy. In addition,
27