Pharmacology and Therapeutics
Tachyphylaxis to Topical Steroid Measured
by Histamine-induced Wheal Suppression
G. SINCH, M.D., AND P. K. SINCH, M.D.
INTERNATIONAL jOURNAL OF DERMATOLOCY June
1986 Vol. 25 pp.324-326.
From the Department of Dermato-Venereology,
Institute of Medical Sciences, Banaras Hindu University, Varanasi, India
Address for correspondence: Gurmohan Singh,
M.D., New D/7 (Near-Petrol Pump), Banaras Hindu University, Varanasi-221 005,
India.
ABSTRACT; Ten healthy volunteers were
studied to find out whether tachyphyiaxis occurs on repeated application of
topical steroids. The Singh and Singh modification of the Reddy and Singh
(1976) technique was used. Fluocinolone acetonide cream (O.1%) under occlusion
was applied daily for 14 days on the flexor aspect of the forearms. The wheal
was induced by pricking with histamine acid phosphate solution and the volume
of the wheal produced was calculated. The test was repeated on the same sites
on alternate days for 14 days. The maximum wheal suppression, which gradually
diminished, was observed on the 8th day. By the 14th day, there was practically
total tolerance to topical steroid, which showed minimal suppression of
histamine wheal formation. This confirms the occurrence of the phenomenon of
tachyphylaxis by different experimental techniques.
The role of topical steroids in the
management of noninfective inflammatory and allergic dermatoses is well
established. Soon after the success of hydrocortisone as a topical remedy in
these disorders, a number of potent, synthetic, topical steroids were
synthesized. In clinical practice, patients sometimes complain about the
reduced effectiveness of steroids on repeated and continuous applications. The
occurrence of acute tolerance to repeatedly administered or topically applied
drug is known as tachyphylaxis. This concept is relatively new as far as
topical steroids are concerned. It was first reported by du-Vivier and
Stoughton1) in 1975 by using the McKenzie and Stoughton2) technique. The Reddy
and Singh technique3) of assessing the potency of topical steroids was
considered to be closer to clinical practice and to match more sophisticated
methods.4) We have, however, improvised the technique by measuring the volume
of the wheal, which is a more sensitive indicator5) of histamine response. This
technique has been used to study the efficacy of repeatedly applied steroid
under occlusion.
Methods
Ten healthy volunteers aged 15 to 30 years were selected for the study.
None of them had used systemic or topical steroids or antihistaminies for at
least 56 days prior to the study.
After cleaning the forearms with 70% alcohol, two sites, 50 mm apart
were selected on each forearm, avoiding any prominent vein. The wheal was
induced by pricking with histamine acid phosphate solution (0.15%). Reddy and
Singh's3) technique, modified by Singh and Singh,5) was used to measure the
height of the wheal with a spherometer and the volume of wheal was calculated
by using the formulaπr2h (r denotes
radius and h denotes height).
The measured amounts (O.5 ml) of fluocinolone acetonide cream (0.1%) on
one forearm and bland cream on the other were applied with tuberculine
syringes. The sites were occluded with polythene, which was kept in place by an
elastic crepe bandage. The fresh, occlusive dressings were applied daily after
cleaning with 70% alcohol. Subjects were instructed to keep the dressings dry.
The histamine wheal test was repeated on days 2, 4, 6, 8, 10, 12, and 14 of the
experiment.
Results
In the present study, the suppression of the histamine-induced wheal volume was observed from the second day of the experiment. The volume of the wheal decreased gradually and reached its minimum on day 8 (Table 1). After day 8, there was a steep increase in the volume of wheal, reaching about 80% of the control volume on day 14. Repeated applications of fluocinolone acetonide under occlusion resulted in its reduced efficacy after the 8th day; efficacy became minimal in 14 days (Fig.1).
Discussion
Tachyphylaxis to some internally administered drugs (ie, catecholamine)
is a known phenomenon; it is defined as acute tolerance that develops rapidly
after administration of only a few doses of a drug.
du-Vivier and Stoughton1) were the first to describe this phenomenon for
topical steroids with regard to their vasoconstrictor effect on human skin.
They showed that the vasoconstriction produced by a potent topical steroid
diminishes rapidly with subsequent applications. In their experiment,
fluocinonide showed maximum vasoconstriction in about 2 days and was sharply
diminished on repeated applications, reaching minimum vasoconstriction in 3 to
4 days. After stopping the application for the subsequent 5 days, the capacity
of normal skin to respond to topical steroid by the vasoconstrictor effect
returns to the pretreatment level.1)
Barry and Woodford6) observed that the blanching effect first produced
increases in 3 days, then diminishes significantly during the subsequent 5 days
of repeated applications. In addition, they showed that only 2 days of rest was
enough to bring back the normal blanching response.
The present study was focused at yet another effect of topical steroids,
ie, suppression of local histamine response, which has been used by Reddy and
Singh3) and later modified by Singh and Singh5) as a technique for bioassay of
topical steroids. This steroid effect may more closely predict the clinical
response in inflammatory dermatoses. Even with daily occlusive dressings of a
fluocinolone acetonide (0.1%) cream, the suppression of the volume of the wheal
produced by histamine prick was increased gradually, reaching its maximum
between days 4 and 8. The effect then suddenly decreased and the drug became
practically ineffective in suppressing the wheal formation in response to
histamine pricks on day 14 of continuous steroid application.
These observations support the earlier reports that acute tolerance to
various effects of topical steroids can occur on their repeated application to
normal skin. We have observed that the effect of occlusion with fluocinolone
acetonide cream on normal skin increases for the first 4 days and then remains
stable for another 4 days, after which time tolerance develops. Maximum
tolerance is observed after another 6 days of continuous treatment.
As
our experiments are on normal skin, it may be postulated that the time taken
for the above effects may vary with the status of the skin in clinical
practice. In cases where stratum corneum, in particular, and the epidermis, in
general, are thickened (as in lichen simplex chronicus), it may take longer. In
acute inflammatory dermatoses, all of these effects may be observed in a
shorter time period.
These findings must be translated to clinical therapeutic practice to
attain the maximum advantage of various topical steroid application to
different dermatoses. Further studies, however, need to be done to determine
whether these experimental findings predict the clinical response.
Drug Name
fluocinolone acetonide cream: Fluonid,
Synalar
References
1. du-Vivier A, Stoughton RB. Tachyphylaxis
to the action of topically appiied corticosteroids. Arch Dermatol.
1975;111:581-583.
2. McKenzie AW, Stoughton RB. Methods for comparing percutaneous absorption
of steroids. Arch Dermatol. 1962;86:608-610.
3. Reddy BSN. Singh G. A new model for
human bioassay of topical corticosteroids. Br J Dermatol. 1976;94:191-193.
4. Ive A, Comaish S. Potency and efficacy
of topical steroids. In:Rock A, Savin J, eds. Recent advances in Dermatology.
Edinburgh: Churchill Livingstone, 1980:292.
5. Singh PK, Singh G. An improvised model
for bioassay of topical corticosteroids. Indian J Dermatol Venereol Leprol.
1985 (in press). '
6. Barry BW, Woodford R. Vasoconstrictor
activities and bioavailabilities of seven proprietary corticosteroid creams
assessed using a nonoccluded multiple dosage regimen: clinical implication. Br
J Dermatol. 1977;95:555-560.
付記
米国では（英語論文であるので、世界的にと読み替えてもいい）1970年代中頃には既に、ステロイドの連日外用でその効果の減弱する事が広く認められています。このことを示す論文がこの二編です。
1) du Vivier A, Stoughton RB: Tachyphylaxis to the action of topically applied corticosteroids. Arch Dermatol 111: 581-583, 1975
2) Singh G, Singh PK: Tachyphylaxis to topical steroid measured by histamine-induced wheal suppression. Intern J Dermatol 25: 324-326, 1986
1) 外用ステロイドの作用に対する効果減弱反応
2) ヒスタミンで誘発される膨疹が抑制される事によって分かる外用ステロイドに対する効果減弱反応
１）では、日に2-3回外用すると3-4日で血管収縮効果がほぼ消失し、3-4日の無外用で血管収縮効果が元に戻る事を示し、
２）では、毎日ステロイドを外用していると、人工的に作る蕁麻疹を抑える作用が8日目に最高に達するがその後減弱し、14日目には蕁麻疹発生を全く抑制しなくなるということを示している。
このように、外用ステロイドの連続投与では直ぐに効果が無くなる事が実験的に証明されている。
日本のアトピー性皮膚炎患者は医師に、ステロイドの外用効果が無くなる事を訴えるが医師にはなかなか認めてもらえないでいる。前述二論文のなかの「はじめに」に当たる部分に共通して次の事が述べられている。「初めは劇的に効くが、持続的に使用しているとその効果は減弱するというしばしば聞かれる患者の訴え」や「臨床現場では、患者は時々、ステロイドの効果が反復持続外用によって減弱すると訴える」と。このことは、持続外用によってステロイドには効果減弱反応が起こるということが1970年代中頃の米国では広く認められていることを意味している。これの反映がPhysician's Desk Reference の中にある「小児には3週間以上の長期使用の効果と安全性は確認されていない」という言葉となっているのであろう。
しかるに日本皮膚科学界の中枢部の人間にはこのことがなかなか認識できない。何らかの理由でこのことに目をつぶっているのであろう。多くの患者が「ステロイドが効かない」あるいは「皮膚が薄くなったり痒くなったりするのは外用治療の副作用と思う」ために民間療法に走り、多くの無駄金を使わされているというのに。そして、患者が民間療法に走るのは脱ステロイドという「非科学的な」治療方法を宣伝する一部の「悪い」医師がいるためであると宣伝している。患者の訴えをよく聞かなければならないという彼らの言葉をどのように考えればいいのであろうか。アトピー性皮膚炎に対するステロイド外用に対する問題提起が激烈であったことで事の本質を見失うようでは科学者としては問題である。彼らの猛省を促す必要がある。
ステロイド依存症と効果減弱反応とはよく似ているが違うものであろう。前者は、ステロイド無しには皮膚全体の普通の代謝ができない状態であり、後者は皮膚の特定の反応が減弱しているだけであると考えられる。従って、おそらく境界ははっきりしないであろうが、後者は前者の入り口に存在する状態であろう。