Atopik Dermatitin meyan kökü jeliyle tedavisi
Glycyrrhiza glabra L. cilt için dermatit, egzama, kaşıntı ve kistler de dahil olmak üzere bitkisel ilaç olarak kullanılmıştır. Topikal preparat olarak Meyan ekstresinin etkisi atopik dermatitde değerlendirildi. Bitki toplandı ve uygun bir çözücü ile süzme ile ekstre edildi. Glycyrrhizinic asite dayanarak titrimetri yöntemi kullanarak öz standartlaşdırıldı. Farklı topikal jeller farklı solvent kullanılarak formüle edilmiştir. Topikal hazırlıklar ayarlandıktan sonra iki haftadan fazla zamanda en iyi formulasyonlar çift-kör klinik çalışma taban jeliyle karşılaştırılmada atopik dermatitde öğrenildi. Jelleştirici ajan nihai formülasyon içinde en iyi sonuçlar gösterdiği gibi Propilen glikol öz ve Carbopol 940 için en iyi çözücü oldu. Glycyrrhizinic asit miktarının özü % 20.3 ve terkiplerine içinde % 19.6 olarak tespit edilmiştir. Yüzde iki meyan topikal jel eritem, ödem ve iki haftadan çok olan kaşıntı skorlarının azaltılmasında % 1 ‘den daha etkili oldu. Sonuçlar meyan özünün atopik dermatitin tedavisinde etkili bir ajan olarak kabul edile bileceğini gösterdi.
Giriş
Atopik dermatit atopik durumun kutanöz ifadesidir, ailenin asıtım durumundan, bahar nezlesi veya hastaların %70 kadarında dermatitin olmasıyla karakterize olunuyor. Hanifin yaptığı incelemede atopik dermatit davasıyla ilgili dört akım hipotez özetlemiştir: devirli fonksiyonel nükleotit bozukluğu, süper antijen rolü, IG-E aracılı alerji ve gida alerjenleri ve antijene karşı otoimmun. Topikal kortikosteroid kremler veya merhemler atopik dermatit akut fişeklerini kontrol eden tedavinin temelidir, onların geniş immünomodülatör etkileri nedenine esasen. Bu ve diğer tedaviler yan etkilere sahip oldukları için yeni tedavi yöntemlerini değerlendirmek gereklidir. Özellikle çeşitli otlar, Glycyrrhiza uralensis (Çinli bir meyan türü) karışımından oluşan geleneksel Çin ilaçları yaygın atopik dermatiti olan çocuklar için bir tedavi seçeneği sağladı. Doğu Asya’da deri hastalığı için bir elyaf bitki olan Çin meyan kökü (G. uralensis), steroid benzeri maddeler içerir, dahili olarak ele alındığında, veya topikal olarak uygulandığında, hızlı bir şekilde yardım sağlıyor. Glycyrrhiza glabra L. Avrasyada yereldir ve Avrupa’da (örnek, İspanya, İtalya, Fransa), Orta Doğu (örnek Suriye, İran, Türkiye, Irak), ve Asya’da yetiştiriliyor. Kullanılan kısımlar sonbaharda toplanan kurutulmuş köklerdir. G. glabra önemli miktarda liquiritigen ve liquiritin ve glycyrrhetinic asit ve glycyrrhisin gibi triterpenoids olan flavonlar içeriyor. Liquiritigenin, disodyum glycyrrhetinic asitin glycyrrhisin antienflamatuar etkinliğe sahip olduğu gösterilmiştir. Glycyrrhiza glabranın önemli bir anti-enflamatuar ve anti-allerjik etkisi vardır. Glycyrrhizin antikor oluşumu, stres tepkisi, ve inflamasyon kortizol adlı inhibisyonu pekiştiriyor. G. glabranın alkol ekstresi Staphylococcus aureus, Streptococcus mutans, Mycobacterium smegmatis’in ve Candida albicansa karşı in vitro anti-mikrobiyal aktivite göstermiştir. Antimikrobik etki çoğunluğu soflavenoid bileşenlerden dolayıdır. Bu çalışma atopik dermatit olan hastalarda meyan jelinin klinik etkinliği (% 1 ve% 2) karşılaştırmak için tasarlanmıştır.
Gereç ve yöntem
Gereçler
Aşağıdaki kimyasallar tedarikçilerinden alındığı gibi kullanılmıştır. Metil ve propil paraben, propilen glikol, PEG 200, PEG 300, PEG 400, izopropil alkol, gliserin, trietanolamin, metanol, aseton, etanol, NaOH, NH3, formalin (Merck), Carbopol 940 (BF Goodrich).
Bitkinin materyalları
Glycyrrhiza glabra L. kökleri 2001 yılında, baharda, İran’ın güneyinde, Şirazdan toplanmıştır. Kurutulmuş kökler tüm materyallerin kafes boyutu 0.5mm-den büyük olmadan geçe bilmesi için pudralandı.
Ekstraksiyon prosedürü
Toz kökler (600 g) bir gün için 1 litre metanol içinde eritildi ve bu adım filtre kağıdı ile filtrasyon yoluyla ardından iki kez tekrarlandı. Süzülen madde düşürülen basınç altında kuruyana kadar buharlaştırıldı ve (122 g,% 20.33) tartıldı.
Glycyrrhizic asitin tayini
Meyan kökü (2 g), 1 saat asetonun içinde % 3 HNO3 20 ml ile karıştırıldı ve daha sonra süzüldü ve 10 ml aseton ile yıkandı. Tortu 20 ml aseton ile geri akıtıldı tekrar filtre edildi ve bu işlem üç kez tekrarlandı. Bir araya getirilen ekstreler 100 ml aseton ile seyreltildi ve 40 ml Etanolla yıkandı, %30 NH3-ün 0,9 ml-i karışıma damla-damla ilave edildi. Amonyum glycyrrhizate süzüldü, aseton (50 ml toplam) ile 2-3 kez yıkandı ve 25 ml su içinde çözülmüş, 20 ml formalin ilave edildi ve 1 dakika sonra, karışım, 0.1 N NaOH ile titre edildi. Bu yöntem aynı zamanda meyan kökü preparatlarda Glycyrrhizic asit belirlenmesi için kullanılmıştır. Deney üç kez tekrarlandı.
Formülasyonların hazırlanması
PEG 200, 300, 400, izopropil alkol ve propilen glikol kurutulmuş ekstresi için ortak çözücü olarak kullanılmıştır ve propilen glikol en iyi levigator olarak seçilmiştir. Tablo I incelenen preparatların bileşenleri gösteriyor. Carbopol 940 korunmuş su (% 0.18 metil paraben ve propil paraben% 0.02) ve gece boyunca gliserin içinde dağıtıldı. Ekstrakt, propilen glikol içinde çözülmüş ve polimer dispersiyonu ilave edildi ve 10 dakika için 500 rpm’de bir çift kanatlı karıştırıcı (IKA-Werk, Almanya) ile karıştırıldı, ve 10 dakika boyunca pH 6.4 ‘e trietanolamin ile nötralize edildi ve daha sonra 300 rpm’de 10 dakikaya kadar karıştırıldı. Formülasyonlar 4, 25, ve 40 ‡ C iki hafta değerlendirilmenin fiziksel kararlılığını sağlamak için bekletildi. Klinik deneme için final formülasyonlar USP XXIV dayalı mikrobiyolojik olarak kontrol edildi.
Klinik çalışma ve istatistiksel analiz
Çalışma çift kör, randomize (basit rastgele örnekleme), prospektif, plasebo-kontrollü bir denemedir. Klinik araştırmanın birincil sonlanım noktası şiddetli ödem, kaşıntı ve eritemdir. 0.5 birimlerinin genel bir ortalama farkı varsayımı üzerinde ve 0.5 birimlerinin standart sapması 78 hastadan bir güç elde edildi.
Sonuç
Nihayet biz atopik dermatit yönetimi konusunda güncel yaklaşımları özetlemek istiyoruz. Tedavinin nihai amacı, hastanın günlük hayatlarında daha fazla sosyal faaliyetler için bir fırsat vermekti. Cilt bakımı, kaşıntı kontrolü ve arttırıcı faktörler dışlanması kontrolü tedavinin üç yönüdür ve bu mükemmel bir tedavi aracı için hastanın yanıtı dikkate alan topikal meyan hazırlıkların uygun kullanımı vardır.
The treatment of atopic dermatitis with licorice gel
Introduction
Atopic dermatitis is the cutaneous expression of the atopic
state, characterized by a family history of asthma, hay
fever, or dermatitis in up to 70% of patients.1 Hanifin
summarized four current hypotheses concerning the cause
of atopic dermatitis in his review: cyclic nucleotide
dysfunction, the role of superantigen, Ig-Emediated allergy
to airborne and food allergens, and autoimmunity to selfantigen.
2 Topical corticosteroid creams or ointments are
themainstay of therapy to control the acute flares of atopic
dermatitis, probably due to their broad immunomodulatory
effects.3,4 As these and other therapies have side effects
it is necessary to evaluate new therapeutic methods. A
traditional Chinese medication consisting of a mixture of
several herbs, especially Glycyrrhiza uralensis (a Chinese
species of licorice) has provided a therapeutic option for
children with extensive atopic dermatitis.5,6 Chinese
licorice root (G. Uralensis) which is a staple herb for skin
disease in east Asia, contains steroid-like substances,
which, when taken internally, or even applied topically,
rapidly provide relief.7
Glycyrrhiza glabra L. is native to Eurasia and
cultivated in Europe (e.g. Spain, Italy, France), the
Middle East (e.g. Syria, Iran, Turkey, Iraq), and Asia.
Those parts used are the dried roots collected in the
autumn.8 G. glabra contains substantial amounts of
flavones, such as liquiritigenin and liquiritin, and
triterpenoids, such as glycyrrhetinic acid and glycyrrhizin.
Liquiritigenin, disodium glycyrrhetinic acid and
glycyrrhizin have been shown to have antiinflammatory
activity.9–11 Glycyrrhiza glabra has significant
anti-inflammatory and anti-allergic activity.
Glycyrrhizin reinforces cortisol’s inhibition of antibody
formation, stress reaction, and inflammation. Alcohol
extract of G. glabra has displayed anti-microbial activity
in vitro against Staphylococcus aureus, Streptococcus
mutans, Mycobacterium smegmatis, and Candida albicans.
The majority of the antimicrobial effects are due to
soflavenoid components, with the saponins having a
lesser antibacterial effect.12 This study was designed to
compare the clinical efficacy of licorice gel (1% and 2%)
with that of placebo, in patients with atopic dermatitis.
M Saeedi1, K Morteza-
Semnani2 and M-R Ghoreishi3
Departments of 1Pharmaceutics and
2Medicinal Chemistry, Faculty of
Pharmacy, Mazandaran University of
Medical Sciences, Sari, Iran;
3Dermatologist, Sari, Iran
Glycyrrhiza glabra L. has been
used in herbal medicine for skin
eruptions, including dermatitis,
eczema, pruritus and cysts. The
effect of licorice extract as topical
preparation was evaluated on
atopic dermatitis. The plant was
collected and extracted by percolation
with suitable solvent.
The extract was standardized,
based on Glycyrrhizinic acid by
using a titrimetry method.
Different topical gels were formulated
by using different cosolvents.
After standardizing of
topical preparations, the best
formulations (1% and 2%) were
studied in a double–blind clinical
trial in comparison with base gel
on atopic dermatitis over two
weeks (30 patients in each
group). Propylene glycol was
the best co-solvent for the
extract and Carbopol 940 as
gelling agent showed the best
results in final formulations. The
quantity of glycyrrhizinic acid
was determined 20.3% in the
extract and 19.6% in the topical
preparation. Two percent licorice
topical gel was more effective
than 1% in reducing the scores
for erythema, oedema and itching
over two weeks (p,0.05).
The results showed that licorice
extract could be considered as
an effective agent for treatment
of atopic dermatitis. (J Dermatol
Treat (2003) 14: 153–157)
Received 20 September 2002
Accepted 3 June 2003
Keywords: Atopic dermatitis — Glycyrrhiza glabra — Oedema —
Erythema — Itching
Correspondence:
M. Saeedi, Faculty of Pharmacy, Taleghani Blvd., P.O.Box: 48175-861,
Sari, Iran; Tel/Faxz151-3243109. E-mail: saeedi_m_2001@yahoo.co.uk
Journal of Dermatological Treatment (2003) 14, 153–157
# 2003 Journal of Dermatological Treatment. All rights reserved. ISSN 0954-6634 153
Materials and methods
Materials
The following chemicals were used as received from the
suppliers. Methyl and propyl paraben, propylene glycol,
PEG 200, PEG 300, PEG 400, isopropyl alcohol,
glycerin, triethanolamine, methanol, acetone, ethanol,
NaOH, NH3, formalin (Merck), Carbopol 940 (BF
Goodrich).
Plant material
Glycyrrhiza glabra L. roots were collected from Shiraz, in
the south of Iran, in spring 2001. The dried roots were
powdered so that all the material could be passed
through a mesh size no larger than 0.5 mm.
Extraction procedure
Powdered roots (600 g) were macerated in 1 l of
methanol for one day, and the step was repeated
twice, following by filtration through filter paper. The
filtrate was evaporated to dryness under reduced
pressure and weighed (122 g, 20.33%).
Glycyrrhizic acid determination
The licorice extract (2 g) was stirred with 20 ml of 3%
HNO3 in acetone for 1 hour, then filtered and washed
with 10 ml of acetone. The residue was refluxed with
20 ml of acetone, filtered again, and this operation
repeated three times. The combined acetone extracts
were diluted to 100 ml, and washed down with 40 ml of
ethanol; 0.9 ml of 30% NH3 was added dropwise to the
mixture. Ammonium glycyrrhizate was filtered, washed
2–3 time with acetone (50ml total), and dissolved in
25 ml of water; 20 ml of formalin was added and after
1 min the mixture was titrated with 0.1 N NaOH in the
presence of phenolphthalein as indicator.13 This method
was also used for determination of glycyrrhizic acid in
licorice preparations. The assay was repeated three
times.
Preparation of the formulations
PEG 200, 300, 400, isopropyl alcohol and propylene
glycol were used as co-solvent for dried extract and
propylene glycol was chosen as the best levigator.
Table I shows the constituents of the investigated
preparations. Carbopol 940 was dispersed in preserved
water (methyl paraben 0.18% and propyl paraben
0.02%) and glycerin overnight. The extract was
dissolved in propylene glycol and was added to the
polymer dispersion and stirred with a double bladed
mixer (Ika-werk, Germany) at 500 rpm for 10 min, and
neutralized by triethanolamine to pH 6.4 and then
mixed at 300 rpm for 10 min. The formulations were
stored at 4, 25, and 40‡C to ensure physical stability
evaluation for two weeks. Final formulations for the
clinical trial were controlled microbiologically based on
USP XXIV.
Clinical trial and statistical analysis
The study was a randomized (simple-random sampling),
double blind, prospective, placebo-controlled trial. The
primary endpoint of the clinical trial is severity in
oedema, itching and erythema. On the assumption of an
overall mean difference of 0.5 units and a standard
deviation of 0.5 units, 78 patients (26 in each group)
were required to achieve a power of 95% to reject a null
hypothesis of equality, applying a two-sided test at the
5% significance level. With an estimated fraction of 35%
of the patients being not evaluable, a total of 108
patients, aged over 15 years, with clinically diagnosed
mild to moderate degrees of atopic dermatitis (1.
pruritus and scratching, 2. course marked by exacerbation
and remissions, 3. lesions typical of eczematous
dermatitis, 4. personal or family history of atopy, 5.
clinical course lasting longer than 6 weeks) were
recruited.1 Before enrollment to the study, written
informed consent was obtained from all patients or
the parents of those under the age of 18 years. Patients
receiving systemic or topical steroids, antibiotics, or
Formulation* Composition % (w/w)
Licorice
extract
Carbopol Propylene
glycol
Glycerin
F1 1 0.30 10 5
F2 1 0.30 15 5
F3 1 0.30 20 5
F4 1 0.40 15 5
F5 1 0.40 20 5
F6 1 0.50 10 5
F7 1 0.50 15 5
F8 1 0.50 20 –
F9 1 0.50 20 5
F10 1 0.75 10 5
F11 1 0.75 15 5
F12 1 0.75 20 5
F13 1 1.00 10 5
F14 1 1.00 15 5
F15 1 1.00 20 5
F16 2 0.25 20 5
F17 2 0.50 20 5
F18 2 0.75 20 5
F19 2 1.00 20 5
Placebo – 0.50 20 5
*Each formulation consists of preserved water (propyl paraben
0.02%w/w and methyl paraben 0.18% w/w) to 100 g. The
formulations was neutralized by triethanolamine to pH=6.8.
Table I
Formulations composition
154 M Saeedi et al The treatment of atopic dermatitis
other effective topical therapy within the previous 7
days, pregnant women, nursing mothers, and patients
with other skin disorders were excluded. Lesions
location was classified as head and neck, trunk,
hands, and feet.
The topical preparations (1% and 2% licorice gels and
placebo) were administered to patients, in three groups,
three times a day for two weeks. The overall clinical
response was assessed by the investigator based on
effect on oedema, itching, erythema and scaling,
according to the following 4-point scale: absent=0,
mild=1, moderate=2, and severe=3. Follow up of
patients ceased after two weeks. ANOVA, followed by
Student-Newman-Keuls test, was used to determine
significant differences between groups and p,0.05 was
considered significant.14
Results and discussion
Licorice contains as its major active ingredient the
triterpene glycoside glycyrrhizin (also known as glycyrrhizic
or glycyrrhizinic acid) in concentrations ranging
from 1% to 24%, depending on sources and methods of
assay. Glycyrrhizin on hydrolysis yields glycyrrhetinic
(or glycyrrhetic) acid and two molecules of glucoronic
acid.8 Thus the standardization of licorice extract and its
preparations were performed by determination of glycyrrhizinic
acid. From the glycyrrhizic acid determination
conducted according to the previously described
method, the quantity of glycyrrhizic acid obtained was
20.3±0.81% and 19.6±0.74% in licorice extract and
licorice gel respectively. All investigated formulations in
the clinical trial used the criteria of USP microbial
limitation.
On observing the clinical features of atopic dermatitis,
some of them showed resistance to topical steroids and
were even exacerbated by application of steroids, so it is
likely that long term topical use of steroids may
modulate the barrier-immunity function of the skin.
The present study compared the efficacy of up to two
weeks treatment with 1% and 2% licorice extract as a
herbal gel with placebo in patients with a clinical
diagnosis of atopic dermatitis.
A total of 108 patients were recruited in the present
study by a single investigator. 18 patients were
excluded from the efficacy analyses. Nine patients
were given systemic antibiotics, five patients were
pregnant, one patient was a nursing mother and
three patients were suffering from other skin disorders.
All of the 90 evaluable subjects complete two weeks
treatment. Table II shows patient characteristics in
several groups.
The assessment of the overall clinical responses,
relative to baseline, at the end of treatment after one
and two weeks is shown in Figure 1. Treatment with 1%
(F9) and 2% (F17) licorice gel resulted in a statistically
significant reduction in the scores for erythema after
two weeks (p,0.05). This effect was not observed for
1% extract gel after one week (pw0.05). The 2% licorice
gel showed more reduction in the scores for erythema
than 1% extract at the end of first and second weeks
(p,0.05). The licorice extract treatment was significantly
more effective than baseline in reducing the
scores for oedema and itching after one week (p,0.05)
and two weeks (p,0.01), and 2% licorice gel was more
effective than 1% extract at the end of first and second
weeks (p,0.05). Treatment with licorice extract was
not significantly effective in reducing the scores of
scaling (pw0.05). The effect of 1% and 2% licorice gel
in reducing in reducing the scores for erythema, oedema
and itching were significantly more than placebo after
one and two weeks (p,0.01).
Baseline evaluation showed that treatment groups
were well balanced in respect of number per group, age
and sex distribution, previous eczema treatment and
severity of signs and symptoms of eczema.
At the end of the treatments, the reduction of
erythema scores was 35.02% for 1% licorice extract
and 60.76% for 2% licorice gel. The reduction of
oedema scores was 56.64% and 83.76% for 1% and 2%
licorice gel treatment after two weeks respectively. At
the end of the treatments, the reduction of itching
scores was 44.1% and 72.53% for 1% and 2% licorice
gel respectively. A study carried out in 1994 reinforced
the excellent reputation of Glycyrrhiza glabra in atopic
dermatitis. Thirty-seven children were given a Chinese
herbal medicine containing licorice (and some other
plants) orally. After one year, 18 of the children had
experienced at least a 90% reduction in their symptoms.
6 Another study showed that topical steroids
exacerbated the dermatitis in about one third of the
patients15 but no side effects were observed in treatment
with licorice topical gel.
Licorice extract
(1%)
Licorice extract
(2%)
Placebo
Age
Mean 32.7 34.1 35.3
Range 16–51 16–49 17–53
Sex
Male 13 12 10
Female 17 18 20
Duration of eczema (years)
Mean 3.8 3.5 3.6
Range 0.01–25 0.01–21 0.01–25
Area of eczema
Head and neck 8 9 7
Trunk 3 2 2
Hands 18 19 19
Feet 1 – 2
Table II
The comparison of patient characteristics
M Saeedi et al The treatment of atopic dermatitis 155
Conclusion
Finally we would like to summarize the current approach
with regard to the management of atopic dermatitis. The
final goal of the treatment is to give patients the
opportunity for improved social activities in their daily
life. Skin care, control of pruritus and exclusion of the
exacerbating factors are three facets of the therapy and the
appropriate use of topical licorice preparations in considering
the patients’ response to this excellent therapeutic tool.
The use of 2% licorice extract gives satisfactory effects in
treatment of atopic dermatitis.
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