Treatment of the Chronic Itch of Atopic Dermatitis Using Standard Drugs and Kampo Medicines

Abstract

Atopic dermatitis is a common skin disease accompanied by intense itching. Relapsing eczema is caused by immune imbalances and skin-barrier disruption. The immunopathy and barrier dysfunction are closely related to the onset of itching and subsequent scratching, and intractable dermatitis is amplified by the itch-scratch cycle. The standard therapy for atopic dermatitis is topical corticosteroids and immunosuppressants to lessen the inflammation, along with moisturizing agents to improve the physiologic skin dysfunction. Corticosteroids are the primary treatment for the inflammation in atopic dermatitis. Some clinical trials demonstrated a tendency for the alleviation of pruritus with long-term treatment. Tacrolimus results in instant burning and itching in the short term, but they resolve a few days after the beginning of use and then are relieved. Substance P is a neuropeptide released from sensory nerve fibers and a neurotransmitter of pain and itching. Basic experimental reports indicated that the antipruritic effect of tacrolimus is probably dependent on depleting substance P, followed by transient induction. Oral administration of antihistamines and antiallergics is used as adjunctive pharmacotherapy for pruritus. It is known that second-generation antihistamines are less sedative or nonsedative drugs compared with the first generation, and the drugs have additional efficacy in blocking some chemical mediators. Japanese traditional Kampo medicines are also used for the treatment of atopic dermatitis. This paper discusses the efficacy of representative Kampo medicines in the treatment of inflammation and itching based on murine atopic dermatitis models. Information on the mechanism of action of Kampo medicines will result in more choice of pharmacotherapeutic agents for complex diseases such as atopic dermatitis.

1. INTRODUCTION

Persistent itching is one of the most unpleasant symptoms of atopic dermatitis. Atopic dermatitis is defined as a chronic, relapsing, eczematous skin disease characterized by pruritus and inflammation and accompanied by cutaneous physiological dysfunction in the guidelines of the Japanese Dermatological Association.¹⁾ Generally, homeostasis in the skin is maintained by systematic keratinocyte differentiation from the stratum basal to stratum corneum and numerous structural proteins in the layer, whereas abnormalities of cell differentiation and lack of proteins related to skin moisturizing cause atopic skin. Because some atopic dermatitis patients have gene mutants of filaggrin,^2,3) which is a proteins related to the skin moisturizing function,⁴⁾ the dysfunction of the epidermis defense system due to loss of moisture retention aggravates inflammation and pruritus through outside allergic or nonallergic stimuli. The stimuli evoke a destructive scratching action, so that severe physiologic dysfunction is enhanced.⁵⁾ Therefore, the strategy of therapy for atopic dermatitis is breaking the vicious itch-scratch cycle.

Currently, numerous traditional Japanese Kampo medicines are used to treat atopic dermatitis as supplemental or alternative agents.^6,7) We attempted to clarify the efficacy of Kampo medicines in the treatment of atopic dermatitis in basic experiments because they could potentially expand the choice of pharmacotherapy for patients. This review describes pharmacotherapies for persistent itching in chronic eczema such as atopic dermatitis using standard drugs and Kampo medicines.

2. THERAPIES FOR ATOPIC DERMATITIS IN GUIDELINES

In the guidelines for the treatment of atopic dermatitis of the Japanese Society of Allergology, the standard therapies are the removal of causative and exacerbating factors, skin care, and pharmacotherapy.⁸⁾ Representative causative and exacerbating factors are food, clothing, detergents, mental stress, etc. In infants, atopic dermatitis is sometimes complicated by food allergies, which are high risk factors for the appearance atopic dermatitis.⁹⁾

Correction of skin dysfunction is important in the treatment of atopic dermatitis. The function of moisture retention deteriorates due to abnormality of the epidermal structure in atopic skin. Dry skin in atopic dermatitis lowers the threshold of itching and results in susceptibility to infection. Therefore, improving dry skin and skin-barrier functions prevents the onset of itching, recurrence of inflammation, and persistent itching. It was reported that a urea-containing moisturizer improves the skin-barrier function in atopic dermatitis patients.¹⁰⁾ In that study, treatment with a moisture cream improved transepidermal water loss and reduced skin susceptibility to reagent irritants.

Pharmacotherapy for atopic dermatitis is based on the concept that it is an inflammatory cutaneous disease. Therefore, topical corticosteroids are applied to control the inflammation of atopic dermatitis. Corticosteroids are the most effective antiinflammatory agents available for the treatment of many chronic inflammatory and immune diseases. Corticosteroids activate several antiinflammatory factors and suppress proinflammatory factors. Corticosteroids bind to glucocorticoid receptor α (GRα) in the cytoplasm of cells. The activated ligand-binding GRα is released from chaperone heat shock protein-90 and others and rapidly translocates to the nucleus. Within the nucleus, GRα binds as a homodimer to glucocorticoid response elements (GREs) in the promoter regions of target genes and regulates the expression of antiinflammatory factor, an inhibitor of nuclear factor (NF)-κB.¹¹⁾ Additionally, ligand-activated GRα can modulate proinflammatory factors such as activator protein-1 and NF-κB independent of binding to GREs.¹²⁾ Corticosteroids inhibit GATA-binding protein 3 functions, and the transcription of Th2 cytokines such as interleukin (IL)-4 and IL-5 via GRα and mitogen-activated protein kinase activity.¹³⁾ It is thought that corticosteroids are not valid for the treatment of itching. Our laboratory found that corticosteroids fail to inhibit the immunologic release of chemical mediators such as histamine, leukotriene, and prostaglandin D₂ from human cultured mast cells.¹⁴⁾ However, topical treatment with steroidal (hydrocortisone) cream lessened the severity of atopic dermatitis excoriation compared with placebo in a double-blind, randomized, clinical study.¹⁵⁾ A recent meta-analysis has demonstrated that the use of corticosteroids significantly reduced the pruritus associated with atopic dermatitis compared with vehicle alone.¹⁶⁾ Corticosteroids may suppress itching with long-term treatment by regulating inflammatory cytokines, chemokines, and adhesion molecules. However, they can also cause adverse effects in adult atopic dermatitis patients with long-term treatment.¹⁷⁾

The topical immunosuppressant tacrolimus ointment induces and maintains remission of atopic dermatitis. Tacrolimus ointment can also be applied to the face or lesion sites, where topical steroids are not recommended. Tacrolimus couples to FK506-binding protein 12, followed by blocking the dephosphorylation of nuclear factor of activated T cells,¹⁸⁾ and then inhibits the transcription of IL-2, which is necessary for the growth, proliferation, and differentiation of lymphocytes. In a randomized, blinded trial of efficacy of tacrolimus ointment compared with a corticosteroid (hydrocortisone acetate) ointment in children with atopic dermatitis, the former significantly improved elements in the eczema severity index such as erythema, papulation, excoriations, lichenification, and itching in comparison with the latter.¹⁹⁾ In that trial, a few patients experienced skin burning after the first few days of treatment. In a similar trial in adult atopic dermatitis by the same group, tacrolimus had the same effects on atopic dermatitis as a corticosteroid,²⁰⁾ but transient local burning and itching occurred.²¹⁾ Those results indicate that the effectiveness of tacrolimus is approximately equivalent to that of topical corticosteroids. The itching involved in treatment with tacrolimus vanishes a few days after beginning use, and long-term use relieves itching. In our basic experiment with a murine atopic dermatitis model in which inflammatory eczema and persistent scratching were induced by repeated painting with hapten, a chemical inducer of contact eczema, topical treatment with tacrolimus suppressed the scratching behavior.²²⁾ Because the scratching behavior of mice was suppressed by the opioid μ-antagonist naloxone, the actions were evoked by itching.²³⁾ The scratching induced by repeated painting with hapten was inhibited by the topical application of tacrolimus, but not by topical dexamethasone.²³⁾ In the mice to which topical tacrolimus was applied, substance P could not be detected in the treated skin, whereas it was found in dexamethasone-treated skin.²⁴⁾ Substance P is a neuropeptide that is released from sensory nerve fibers to cause or exacerbate inflammation and it stimulates mast cells to release allergic mediators such as histamine. Additionally, oral administration of tacrolimus in murine atopic dermatitis models alleviated the mast cell degranulation that induces scratching behavior²⁵⁾ and passive cutaneous anaphylaxis accompanied by scratching,²²⁾ and therefore tacrolimus may affect mast cell-related mediators and factors.

Antihistamines and antiallergics are representative systemic drugs for relieving itching. The major pharmacologic effects of antihistamines are ascribed to H₁-receptor antagonism. The binding of histamine to the H₁ receptor exacerbates the vascular permeability of capillaries and causes itching. Generally, antihistamines (first-generation antihistamines such as diphenhydramine and chlorpheniramine) have effects on the instant itching caused by insect bites and acute urticaria, but not on persistent itching from tinea, scabies, psoriasis, and atopic dermatitis.²⁶⁾ Antiallergics (second-generation antihistamines such as azelastine, olopatadine, and fexofenadine) are less sedative or nonsedative agents compared with the first-generation agents. Moreover, they are used to treat allergy because they block leukotriene and prostaglandin release from mast cells.²⁷⁾ It was reported that second-generation antihistamines had greater efficacy in the histamine iontophoresis-induced wheal-and-flare response and caused less psychomotor dysfunction in a randomized double-blind, placebo-controlled study in healthy volunteers.²⁸⁾ In a double-blind, placebo-controlled trial in pruritus associated with atopic dermatitis, fexofenadine significantly decreased the severity of pruritus compared with placebo.²⁹⁾ In the Japanese Guidelines for the Management of Atopic Dermatitis, antihistamines are referred to as adjunctive therapy for each process of atopic dermatitis.¹⁾

3. KAMPO MEDICINES

The Guidelines for the Management of Atopic Dermatitis mention that herbal medicines should be used as adjunctive therapy. Kampo medicines are composed of herbal, animal, and mineral crude drugs and prepared according to formulas given in the Chinese and Japanese classical literature. Current Kampo formulas developed uniquely from the Chinese originals and are prescribed for specific diagnoses based on Oriental medicine. The conceptual diagnoses are grounded on numerous empirical case studies.

One crude drug composing Kampo medicine contains only small amounts of multiple active constituents. The numerous constituents act in a complicated but harmonic manner in a Kampo formula. Consequently, some Kampo medicines are used as total modulators for maintaining homeostasis, while others are used for acute conditions, e.g., kakkonto containing ephedrine and glycyrrhizin is prescribed for the common cold. Interestingly, kakkonto is used to treat stiff shoulders because of a similar condition in the Kampo philosophy.

Kampo medicines are prescribed based on both the physiological and mental condition of the patient. The condition is categorized by multiple parameters depending on the degree of infirmity and progression or stage. In some cases, the condition is indicated by the most suitable crude herbal component, such as “Cinnamomi Cortex Symptom, Ephedrae Herba Symptom, Ginseng Radix Symptom, and Bupleuri Radix Symptom.” We classified major Kampo formulas used for atopic dermatitis into three types according to the level of strength (Fig. 1). The following paragraphs discuss juzentaihoto, hochuekkito, shofusan, orengedokuto, and yokukansan. The standard components of these Kampo medicines are shown in Table 1.

Fig. 1. Simple Classification of Specific Diagnoses Based on Oriental Philosophy

Kampo medicines are indicated for three conditions. The condition of “overabundance” refers to excessive activities. The condition of “insufficiency” means lacking vitality. The condition of “moderateness” is a medium between overabundance and insufficiency. The Kampo medicines in boldface type are mentioned in this review.

Table 1. Formulations and Compositions of the Kampo Medicines Juzentaihoto, Hochuekkito, Orengedokuto, Shofusan, and Yokukansan

Kampo medicine	Component
Juzentaihoto	Astragali Radix
	Cinnamomi Cortex
	Rehmanniae Radix
	Paeoniae Radix
	Cnidii Rhizoma
	Atractylodis Lanceae Rhizoma
	Angelicae Radix
	Ginseng Radix
	Poria
	Glycyrrhizae Radix
Hochuekkito	Astragali Radix
	Atractylodis Lanceae Rhizoma
	Ginseng Radix
	Angelicae Radix
	Bupleruli Radix
	Zizyphi Fructus
	Aurantii Nobilis Pericarpium
	Glycyrrhizae Radix
	Cimicifugae Rhizoma
	Zingiberis Rhizoma
Orengedokuto	Scutellariae Radix
	Coptidis Rhizoma
	Gardeniae Fructus
	Phellodendri Cortex
Shofusan	Gypsum Fibrosum
	Rehmanniae Radix
	Angelicae Radix
	Bardanae Fructus
	Atractylodis Lanceae Rhizoma
	Saposhnikoviae Radix
	Akebiae Caulis
	Anemarrhenae Rhizoma
	Glycyrrhizae Radix
	Sophorae Radix
	Schizonepetae Spica
	Sesami Semen
	Cicadae Periostracum
Yokukansan	Atractylodis Lanceae Rhizoma
	Poria
	Cinidii Rhizoma
	Uncariae Uncus et Ramulus
	Angelicae Radix
	Bupleruli Radix
	Glycyrrhizae Radix

Juzentaihoto and hochuekkito are invigorating medicines prescribed to improve chronic fatigue and regulate immune imbalance. Juzentaihoto replenishes hematopoietic cells containing leukocytes and ameliorates circulation of blood. Juzentaihoto upregulates natural-killer (NK) activity,³⁰⁾ and therefore it is prescribed for cancer patients to reduce the side effects and complications of chemotherapy. Hochuekkito supports digestion and absorption, so that it activates the immune system. It was reported that hochuekkito activates immunocompetent cells in Peyer’s patches and epithelial cells in the intestinal immune system³¹⁾ and then enhances the virus-specific antibody response by the systemic immune system.³²⁾

Juzentaihoto and hochuekkito moderate the immune imbalance not only in cancer but also in allergy. Persistent allergy is caused by long-term immune disruption. We developed murine models of atopic dermatitis and then characterized the effects of Kampo medicines in the models. We attempted to evaluate juzentaihoto, hochuekkito, shofusan, and orengedokuto in a murine model of atopic dermatitis, in which the ears of mice were painted with mite antigen. The Kampo medicines inhibited dermatitis and corrected the Th1/Th2 balance skewed to Th2.³³⁾ In a clinical study, concomitant hochuekkito significantly reduced the dose of topical corticosteroids and tacrolimus needed without aggravating dermatitis.³⁴⁾

Orengedokuto and yokukansan are used for eczema exacerbated by physical and emotional stress. Atopic dermatitis can also be exacerbated by physical irritation and social stress. It was reported that chronic itching and pruritus were ameliorated by treatment with yokukansan in chronic urticaria (not atopic dermatitis) patients.³⁵⁾ In murine studies, yokukansan ameliorates the development of atopic dermatitis-like lesions and epidermal barrier dysfunction of moisture retention, which were evoked by the stress of social isolation through individual rearing, in addition to decreasing the occurrence of scratching behavior in the mice.^36,37)

Shofusan is used clinically to treat secretory eczema with persistent itching. In the murine atopic dermatitis model of hapten treatment, long-lasting scratching behavior was induced in an immunoglobulin E (IgE)-dependent manner³⁸⁾ but not induced in mast cell-deficient mice.³⁹⁾ Accordingly, we believe that the intense, persistent scratching is induced by constant degranulation of mast cells. We demonstrated that the persistent scratching was suppressed quickly by a single oral administration of shofusan and could be resolved after several doses.⁴⁰⁾ Shofusan also had a marked effect on the development of scratching in the atopic dermatitis murine model.⁴⁰⁾ These murine data support the classical indications for shofusan administration.

Animal models are unable to express all symptoms of a disease. However, we can analyze in detail one or more elements of a pathologic condition using histologic, immunologic, and serologic approaches. Target genes and proteins causing a condition can be elucidated comprehensively. It is expected that experimental approaches will confirm the effects of Kampo medicines on complex symptoms such as the persistent itching in atopic dermatitis.

4. CONCLUSION

Atopic dermatitis is a troublesome syndrome involving immune, environmental, and genetic factors. Immune imbalance, barrier dysfunction, and intense itching are closely related, and therefore the therapeutic strategy is disconnecting and breaking the interrelationships. Itching in particular lowers the quality of life of atopic dermatitis patients. The improvement of itching is therefore the most important issue in atopic dermatitis.

It is critical to establish a simple, basic experimental model to clarify the complicated relationships among itching and causative factors in atopic dermatitis, such as the interactions between immune cells and nerve factors. In the search for agents to treat those key factors in this intractable, chronic, complex disease, Kampo medicines appear to hold potential.

REFERENCES

• 1)  Saeki H, Furue M, Furukawa F, Hide M, Ohtsuki M, Katayama I, Sasaki R, Suto H, Takehara K, Committee for Guidelines for the Management of Atopic Dermatitis of Japanese Dermatological Association. Guidelines for management of atopic dermatitis. J. Dermatol., 36, 563–577 (2009).
• 2)  Palmer CN, Irvine AD, Terron-Kwiatkowski A, Zhao Y, Liao H, Lee SP, Goudie DR, Sandilands A, Campbell LE, Smith FJ, O’Regan GM, Watson RM, Cecil JE, Bale SJ, Compton JG, DiGiovanna JJ, Fleckman P, Lewis-Jones S, Arseculeratne G, Sergeant A, Munro CS, El Houate B, McElreavey K, Halkjaer LB, Bisgaard H, Mukhopadhyay S, McLean WH. Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis. Nat. Genet., 38, 441–446 (2006).
• 3)  Marenholz I, Nickel R, Rüschendorf F, Schulz F, Esparza-Gordillo J, Kerscher T, Grüber C, Lau S, Worm M, Keil T, Kurek M, Zaluga E, Wahn U, Lee YA. Filaggrin loss-of-function mutations predispose to phenotypes involved in the atopic march. J. Allergy Clin. Immunol., 118, 866–871 (2006).
• 4)  Kamata Y, Taniguchi A, Yamamoto M, Nomura J, Ishihara K, Takahara H, Hibino T, Takeda A. Neutral cysteine protease bleomycin hydrolase is essential for the breakdown of deiminated filaggrin into amino acids. J. Biol. Chem., 284, 12829–12836 (2009).
• 5)  Wahlgren CF. Itch and atopic dermatitis: an overview. J. Dermatol., 26, 770–779 (1999).
• 6)  Kobayashi H, Takahashi K, Mizuno N, Kutsuna H, Ishii M. An alternative approach to atopic dermatitis: Part I-Case-series presentation. Evid. Based Complement. Alternat. Med., 1, 49–62 (2004).
• 7)  Kobayashi H, Takahashi K, Mizuno N, Kutsuna H, Ishii M. An alternative approach to atopic dermatitis: Part II-Summary of cases and discussion. Evid. Based Complement. Alternat. Med., 1, 145–155 (2004).
• 8)  Katayama I, Kohno Y, Akiyama K, Ikezawa Z, Kondo N, Tamaki K, Kouro O; Japanese Society of Allergology. Japanese guideline for atopic dermatitis. Allergol. Int., 60, 205–220 (2011).
• 9)  Kijima A, Murota H, Takahashi A, Arase N, Yang L, Nishioka M, Yamaoka T, Kitaba S, Yamauchi-Takihara K, Katayama I. Prevalence and impact of past history of food allergy in atopic dermatitis. Allergol. Int., 62, 105–112 (2013).
• 10)  Lodén M, Andersson AC, Lindberg M. Improvement in skin barrier function in patients with atopic dermatitis after treatment with a moisturizing cream (Canoderm). Br. J. Dermatol., 140, 264–267 (1999).
• 11)  Nicolaides NC, Galata Z, Kino T, Chrousos GP, Charmandari E. The human glucocorticoid receptor: molecular basis of biologic function. Steroids, 75, 1–12 (2010).
• 12)  Jonat C, Rahmsdorf HJ, Park KK, Cato AC, Gebel S, Ponta H, Herrlich P. Antitumor promotion and antiinflammation: Down-modulation of AP-1 (Fos/Jun) activity by glucocorticoid hormone. Cell, 62, 1189–1204 (1990).
• 13)  Maneechotesuwan K, Yao X, Ito K, Jazrawi E, Usmani OS, Adcock IM, Barnes PJ. Suppression of GATA-3 nuclear import and phosphorylation: a novel mechanism of corticosteroid action in allergic disease. PLoS Med., 6, e1000076 (2009).
• 14)  Akabane H, Murata M, Kubota M, Takashima E, Tanaka H, Inagaki N, Horiba M, Nagai H. Effects of salmeterol xinafoate and fluticasone propionate on immunological activation of human cultured mast cells. Allergol. Int., 55, 387–393 (2006).
• 15)  Sears HW, Bailer JW, Yeadon A. Efficacy and safety of hydrocortisone buteprate 0.1% cream in patients with atopic dermatitis. Clin. Ther., 19, 710–719 (1997).
• 16)  Sher LG, Chang J, Patel IB, Balkrishnan R, Fleischer AB Jr. Relieving the pruritus of atopic dermatitis: a meta-analysis. Acta Derm. Venereol., 92, 455–461 (2012).
• 17)  Furue M, Terao H, Rikihisa W, Urabe K, Kinukawa N, Nose Y, Koga T. Clinical dose and adverse effects of topical steroids in daily management of atopic dermatitis. Br. J. Dermatol., 148, 128–133 (2003).
• 18)  Fruman DA, Klee CB, Bierer BE, Burakoff SJ. Calcineurin phosphatase activity in T lymphocytes is inhibited by FK 506 and cyclosporin A. Proc. Natl. Acad. Sci. U.S.A., 89, 3686–3690 (1992).
• 19)  Reitamo S, Van Leent EJ, Ho V, Harper J, Ruzicka T, Kalimo K, Cambazard F, Rustin M, Taïeb A, Gratton D, Sauder D, Sharpe G, Smith C, Jünger M, de Prost Y, European/Canadian Tacrolimus Ointment Study Group. Efficacy and safety of tacrolimus ointment compared with that of hydrocortisone acetate ointment in children with atopic dermatitis. J. Allergy Clin. Immunol., 109, 539–546 (2002).
• 20)  Reitamo S, Rustin M, Ruzicka T, Cambazard F, Kalimo K, Friedmann PS, Schoepf E, Lahfa M, Diepgen TL, Judodihardjo H, Wollenberg A, Berth-Jones J, Bieber T, European Tacrolimus Ointment Study Group. Efficacy and safety of tacrolimus ointment compared with that of hydrocortisone butyrate ointment in adult patients with atopic dermatitis. J. Allergy Clin. Immunol., 109, 547–555 (2002).
• 21)  Reitamo S, Wollenberg A, Schöpf E, Perrot JL, Marks R, Ruzicka T, Christophers E, Kapp A, Lahfa M, Rubins A, Jablonska S, Rustin M, The European Tacrolimus Ointment Study Group. Safety and efficacy of 1 year of tacrolimus ointment monotherapy in adults with atopic dermatitis. Arch. Dermatol., 136, 999–1006 (2000).
• 22)  Yamashita H, Ito T, Kato H, Asai S, Tanaka H, Nagai H, Inagaki N. Comparison of the efficacy of tacrolimus and cyclosporine A in a murine model of dinitrofluorobenzene-induced atopic dermatitis. Eur. J. Pharmacol., 645, 171–176 (2010).
• 23)  Inagaki N, Shiraishi N, Igeta K, Itoh T, Chikumoto T, Nagao M, Kim JF, Nagai H. Inhibition of scratching behavior associated with allergic dermatitis in mice by tacrolimus, but not by dexamethasone. Eur. J. Pharmacol., 546, 189–196 (2006).
• 24)  Inagaki N, Shiraishi N, Igeta K, Nagao M, Kim JF, Chikumoto T, Itoh T, Katoh H, Tanaka H, Nagai H. Depletion of substance P, a mechanism for inhibition of mouse scratching behavior by tacrolimus. Eur. J. Pharmacol., 626, 283–289 (2010).
• 25)  Yamashita H, Makino T, Mizukami H, Nose M. Pharmacological characterization of a chronic pruritus model induced by multiple application of 2,4,6-trinitrochlorobenzene in NC mice. Eur. J. Pharmacol., 563, 233–239 (2007).
• 26)  Klein PA, Clark RA. An evidence-based review of the efficacy of antihistamines in relieving pruritus in atopic dermatitis. Arch. Dermatol., 135, 1522–1525 (1999).
• 27)  Shichijo M, Inagaki N, Nakai N, Kimata M, Nakahata T, Serizawa I, Iikura Y, Saito H, Nagai H. The effects of anti-asthma drugs on mediator release from cultured human mast cells. Clin. Exp. Allergy, 28, 1228–1236 (1998).
• 28)  Kamei H, Isaji A, Noda Y, Ishikawa K, Senzaki K, Yamada K, Sugiura K, Tomita Y, Nabeshima T. Effects of single therapeutic doses of promethazine, fexofenadine and olopatadine on psychomotor function and histamine-induced wheal- and flare-responses: a randomized double-blind, placebo-controlled study in healthy volunteers. Arch. Dermatol. Res., 304, 263–272 (2012).
• 29)  Kawashima M, Tango T, Noguchi T, Inagi M, Nakagawa H, Harada S. Addition of fexofenadine to a topical corticosteroid reduces the pruritus associated with atopic dermatitis in a 1-week randomized, multicentre, double-blind, placebo-controlled, parallel-group study. Br. J. Dermatol., 148, 1212–1221 (2003).
• 30)  Kamiyama H, Takano S, Ishikawa E, Tsuboi K, Matsumura A. Anti-angiogenic and immunomodulatory effect of the herbal medicine “Juzen-taiho-to” on malignant glioma. Biol. Pharm. Bull., 28, 2111–2116 (2005).
• 31)  Kiyohara H, Nonaka K, Sekiya M, Matsumoto T, Nagai T, Tabuchi Y, Yamada H. Polysaccharide-containing macromolecules in a Kampo (traditional Japanese herbal) medicine, hochuekkito: Dual active ingredients for modulation of immune functions on intestinal Peyer’s patches and epithelial cells. Evid. Based Complement. Alternat. Med., 2011, 1-B (2011).
• 32)  Kiyohara H, Nagai T, Munakata K, Nonaka K, Hanawa T, Kim SJ, Yamada H. Stimulating effect of Japanese herbal (Kampo) medicine, hochuekkito on upper respiratory mucosal immune system. Evid. Based Complement. Alternat. Med., 3, 459–467 (2006).
• 33)  Gao XK, Fuseda K, Shibata T, Tanaka H, Inagaki N, Nagai H. Kampo medicines for mite antigen-induced allergic dermatitis in NC/Nga mice. Evid. Based Complement. Alternat. Med., 2, 191–199 (2005).
• 34)  Kobayashi H, Ishii M, Takeuchi S, Tanaka Y, Shintani T, Yamatodani A, Kusunoki T, Furue M. Efficacy and safety of a traditional herbal medicine, hochu-ekki-to in the long-term management of kikyo (delicate constitution) patients with atopic dermatitis: A 6-month, multicenter, double-blind, randomized, placebo-controlled study. Evid. Based Complement. Alternat. Med., 7, 367–373 (2010).
• 35)  Kato S, Kato TA, Nishie H, Nishima S, Iwanaga T, Monji A, Nakano M, Takeshita H, Furue M. Successful treatment of chronic urticaria with a Japanese herbal medicine, yokukansan. J. Dermatol., 37, 1066–1067 (2010).
• 36)  Jiang J, Yamaguchi T, Funakushi N, Kuhara T, Fan PS, Ueki R, Suto H, Kase Y, Ikeda S, Ogawa H. Oral administration of Yokukansan inhibits the development of atopic dermatitis-like lesions in isolated NC/Nga mice. J. Dermatol. Sci., 56, 37–42 (2009).
• 37)  Funakushi N, Yamaguchi T, Jiang J, Imamura S, Kuhara T, Suto H, Ueki R, Kase Y, Kobayashi H, Ogawa H, Ikeda S. Ameliorating effect of Yokukansan on the development of atopic dermatitis-like lesions and scratching behavior in socially isolated NC/Nga mice. Arch. Dermatol. Res., 303, 659–667 (2011).
• 38)  Yamashita H, Tasaki D, Makino T, Matsuoka K, Nose M, Inagaki N, Mizukami H. The role of IgE and repeated challenge in the induction of persistent increases in scratching behavior in a mouse model of allergic dermatitis. Eur. J. Pharmacol., 605, 153–157 (2009).
• 39)  Yamashita H, Michibata Y, Mizukami H, Ogihara Y, Morita A, Nose M. Dermal mast cells play a central role in the incidence of scratching behavior in mice induced by multiple application of the hapten, 2,4,6-trinitrochlorobenzene. Exp. Dermatol., 14, 438–444 (2005).
• 40)  Yamashita H. Assessment of relief from pruritus due to Kampo medicines by using murine models of atopic dermatitis. J. Trad. Med., 30, in press (2013).