Oral administration of Jumihaidokuto inhibits UVB-induced skin damage and prostaglandin E2 production in HR-1 hairless mice.

This study was conducted to investigate whether and how Jumihaidokuto (JHT), a traditional Chinese medicine, prevents UVB-induced skin damage in male HR-1 hairless mice. JHT has been traditionally prescribed for patients presenting skin disorders with redness and swelling, and, in Japan, it is approved for prescription to patients with acute and/or purulent skin disorders, hives, acute eczema, and athlete's foot. Considering the traditional use of JHT, we hypothesized that oral administration of JHT might emerge as an effective strategy to prevent UVB-induced skin damage, such as edema and erythema. Here, we pretreated mice with JHT (1000 mg/kg, p.o.) for 3 weeks and then administered a single dose of UVB irradiation (250 mJ/cm2) on the dorsal skin. UVB irradiation increased the erythema index and transepidermal water loss (TEWL) and decreased the skin water content in the epidermis at 72 h post-irradiation. JHT treatment inhibited the increase of TEWL and the loss of water content in the epidermis, but not the elevation of the erythema index. Moreover, administration of JHT suppressed UVB-induced epidermal hyperplasia by blocking the proliferation of keratinocytes and also inhibited irradiation-triggered reduction of collagen fibers and infiltration of immune cells into the dermis. Lastly, administration of JHT suppressed UVB-induced production of proinflammatory mediators, such as prostaglandin E2 and interleukin-1ß. These results suggest that JHT prevents UVB-induced skin damage and that the underlying mechanism involves the inhibition of proinflammatory mediators.

[Mechanism of Inhibitory Effects of Cherry Bark-containing Jumihaidokuto on Benzoyl Peroxide Induced Erythema in Hairless Mice].

Benzoyl peroxide (BPO) has been widely used to treat acne vulgaris. Skin flaking, erythema and skin irritation have been observed as side effects of BPO in the treatment of this disorder. In a clinical study, cherry bark-containing jumihaidokuto significantly reduced the erythema induced by BPO application. However, its mechanism of action has not been clarified. In the present study, an application of 10% BPO caused erythema and an increase in interleukin (IL)-1α in the skin of hairless mice, and these changes were significantly suppressed by cherry bark-containing jumihaidokuto at 600 mg/kg. In addition, using a three-dimensional cultured human epidermis model (LabCyte EPI-MODEL), cherry bark-containing jumihaidokuto extract at 250 or 500 µg/mL significantly suppressed IL-1α mRNA expression induced by the application of 0.2 mM BPO. Therefore, cherry bark-containing jumihaidokuto may have suppressed BPO-induced erythema by inhibiting the increase in the IL-1α level in the skin.

Experience in Using Jumihaidokuto and Orengedokuto for Skin Disorders Caused by Molecular Target Drugs / 日本東洋医学雑誌

In some molecular targeted therapies, skin disorders including acne-like rashes or maculopapular rashes frequently appear, which are often clinically problematic. In Kampo medicine, it has been reported that the combination of jumihaidokuto and orengedokuto (hereinafter called JHT + OGT) is effective for acne. In this study, we report the experiences of JHT + OGT for the treatment of rashes caused by molecular targeted therapies. We extracted patients from June 2013 to June 2017 who took molecular targeted therapies and the treatment with JHT + OGT for skin rashes. The primary endpoint was severity of rashes before and after treatment by JHT + OGT (judged by CTCAE v4.0). In 22 patients (14 males and 8 females), the rashes after treatment with JHT + OGT significantly improved compared with those before treatment (from the median grade of 2 to 1 [p = 0.011]), with 14 cases of improvement, 6 cases of no change, and 2 cases of deterioration. It was suggested that JHT + OGT for skin rashes caused by molecular targeted therapies could be one of the treatment options.

Impact of Jumihaidokuto (Shi-Wei-Bai-Du-Tang) on Treatment of Chronic Spontaneous Urticaria: A Randomized Controlled Study.

OBJECTIVE: To study the effect of Jumihaidokuto (Shi-Wei-Bai-Du-Tang, ) in the management of chronic spontaneous urticaria. METHODS: A randomized two-arm, parallel group study was conducted to compare the effect of Jumihaidokuto (6 g daily) with a control for 8 weeks. Concomitant therapy (e.g., antihistamines) was continued. Twenty-one subjects with severe chronic urticaria were enrolled in this study. The primary treatment outcome was the severity score proposed by the Japanese Dermatological Association. Secondary outcomes were quality of life (Skindex-16), itch intensity (Visual Analogue Scale), and patients' subjective disability due to wheal or itch. After the subjects were randomly assigned to groups by block randomization, 10 received Jumihaidokuto, and 11 did not. All subjects had already taken antihistamines. RESULTS: Improvement was significant when comparing the severity score of the Jumihaidokuto group with that of the control group (P<0.01). Skindex-16 values for both groups gradually decreased in the same fashion. CONCLUSION: Concomitant use of Jumihaidokuto with antihistamine was more effective than antihistamine alone in the management of chronic idiopathic urticaria. (Trial Registration No. UMIN000007251).

Impact of Jumihaidokuto (Shi-Wei-Bai-Du-Tang) on Treatment of Chronic Spontaneous Urticaria: A Randomized Controlled Study / 中国结合医学杂志

OBJECTIVE@#To study the effect of Jumihaidokuto (Shi-Wei-Bai-Du-Tang, ) in the management of chronic spontaneous urticaria.@*METHODS@#A randomized two-arm, parallel group study was conducted to compare the effect of Jumihaidokuto (6 g daily) with a control for 8 weeks. Concomitant therapy (e.g., antihistamines) was continued. Twenty-one subjects with severe chronic urticaria were enrolled in this study. The primary treatment outcome was the severity score proposed by the Japanese Dermatological Association. Secondary outcomes were quality of life (Skindex-16), itch intensity (Visual Analogue Scale), and patients' subjective disability due to wheal or itch. After the subjects were randomly assigned to groups by block randomization, 10 received Jumihaidokuto, and 11 did not. All subjects had already taken antihistamines.@*RESULTS@#Improvement was significant when comparing the severity score of the Jumihaidokuto group with that of the control group (P<0.01). Skindex-16 values for both groups gradually decreased in the same fashion.@*CONCLUSION@#Concomitant use of Jumihaidokuto with antihistamine was more effective than antihistamine alone in the management of chronic idiopathic urticaria. (Trial Registration No. UMIN000007251).

Inhibition of Human Kallikrein 5 Protease by Triterpenoids from Natural Sources.

Stratum corneum tryptic enzyme kallikrein 5 (KLK5) is a serine protease that is involved in the cell renewal and maintenance of the skin barrier function. The excessive activation of KLK5 causes an exacerbation of dermatoses, such as rosacea and atopic dermatitis. Some triterpenoids are reported to suppress the serine proteases. We aimed to investigate whether bioactive triterpenoids modulate the KLK5 protease. Nineteen triterpenoids occurring in medicinal crude drugs were evaluated using an enzymatic assay to measure the anti-KLK5 activity. The KLK5-dependent cathelicidin peptide LL-37 production in human keratinocytes was examined using immunoprecipitation and Western blotting. Screening assays for evaluating the anti-KLK5 activity revealed that ursolic acid, oleanolic acid, saikosaponin b1, tumulosic acid and pachymic acid suppressed the KLK5 protease activity, although critical molecular moieties contributing to anti-KLK5 activity were unclarified. Ursolic acid and tumulosic acid suppressed the proteolytic processing of LL-37 in keratinocytes at ≤10 µM; no cytotoxicity was observed. Both triterpenoids were detected in the plasma of rats administered orally with triterpenoid-rich crude drug Jumihaidokuto. Our study reveals that triterpenoids, such as ursolic acid and tumulosic acid, modulate the KLK5 protease activity and cathelicidin peptide production. Triterpenoids may affect the skin barrier function via the regulation of proteases.

Jumihaidokuto effectively inhibits colon inflammation and apoptosis in mice with acute colitis.

Jumihaidokuto, a Japanese kampo medicine, is prescribed in Japan for its anti-inflammatory activity. Here we have examined its beneficial effects against acute colitis induced by dextran sulfate sodium (DSS) in mice. We have used C57BL/6 female mice, divided into two groups and received 3% DSS in drinking water during the experimental period (8days). Treatment group mice received 1g/kg/day dose of Jumihaidokuto orally whereas DSS control group received equal volume of distilled water. Normal control group mice received plain drinking water. Jumihaidokuto treatment attenuated the colitis symptoms along with suppression of various inflammatory marker proteins such as IL-1ß, IL-2Rα, IL-4, CTGF and RAGE. It has also down-regulated the oxidative stress and apoptotic signaling in the colons of mice with colitis. The present study has confirmed the beneficial effects of Jumihaidokuto on DSS induced acute colitis in mice and suggests that it can be a potential agent for the treatment of colitis.

Plasma Pharmacokinetics of Polyphenols in a Traditional Japanese Medicine, Jumihaidokuto, Which Suppresses Propionibacterium acnes-Induced Dermatitis in Rats.

Most orally administered polyphenols are metabolized, with very little absorbed as aglycones and/or unchanged forms. Metabolic and pharmacokinetic studies are therefore necessary to understand the pharmacological mechanisms of polyphenols. Jumihaidokuto (JHT), a traditional Japanese medicine, has been used for treatment of skin diseases including inflammatory acne. Because JHT contains various types of bioactive polyphenols, our aim was to clarify the metabolism and pharmacokinetics of the polyphenols in JHT and identify active metabolites contributing to its antidermatitis effects. Orally administered JHT inhibited the increase in ear thickness in rats induced by intradermal injection of Propionibacterium acnes. Quantification by LC-MS/MS indicated that JHT contains various types of flavonoids and is also rich in hydrolysable tannins, such as 1,2,3,4,6-penta-O-galloyl glucose. Pharmacokinetic and antioxidant analyses showed that some flavonoid conjugates, such as genistein 7-O-glucuronide and liquiritigenin 7-O-glucuronide, appeared in rat plasma and had an activity to inhibit hydrogen peroxide-dependent oxidation. Furthermore, 4-O-methylgallic acid, a metabolite of Gallic acid, appeared in rat plasma and inhibited the nitric oxide reaction. JHT has numerous polyphenols; it inhibited dermatitis probably via the antioxidant effect of its metabolites. Our study is beneficial for understanding in vivo actions of orally administered polyphenol drugs.

One Case of Wells' Syndrome Successfully Treated with Kampo Medicines / 日本東洋医学雑誌

Wells' syndrome (eosinophilic cellulitis), whose etiology is idiopathic, is clinically characterized by solitary or multiple cellulitis-like eruptions which occur on the extremities and trunk. Corticosteroids are usually used for palliative treatment, but relapses are often observed. We observed an 8 year-old patient with Wells' syndrome successfully treated with Kampo medicines. In 2001, skin eruptions appeared on his extremities. In 2002, a histopathologic examination determined his disease to be Wells' syndrome, and corticosteroids were subsequently used for treatment. In January 2007, his skin eruptions worsened, and he first visited our outpatient clinic in May. After oral administration with keigairengyoto, his skin eruptions were slightly improved, but afterwards, they again worsened. In June, jumihaidokuto was administered instead of the former prescription, and the skin conditions had begun to improve. Because dry skin appeared in November, keigairengyoto was again added. With these treatments, his skin eruptions stably improved. In previous reports, Kampo medicines had not been used for the treatment of Wells' syndrome. This case, however, suggests that Kampo medicines are a candidate for the treatment of Wells' syndrome.

5 Cases of Seborrheic Dermatitis Successfully Treated with Kampo Medicine / 日本東洋医学雑誌

We successfully treated 5 patients with seborrheic dermatitis using Kampo medicine. Three of these patients presented with facial the lesions which had persisted for 1 to 2 years despite their having received treatment with steroid ointments or ketokonazol lotions. We treated these patients with jumihaidokuto and they recovered significantly within a few months. The two remaining patients presented with scalp lesions, which had persisted for10and 25 years respectively. We treated them with a combined formulation of keigairengyoto, makyoyokukanto and yokukansankachimpihange, and they improved remarkably after 2 and 8 months respectively.

A Case Report of Mycosis Fungoides Successfully Treated with Traditional Herbal Medicine in Addition to Western Medicine / 日本東洋医学雑誌

We report a case of a 40-year-old male with mycosis fungoides who was successfully treated with traditional herbal (Kampo) medicine in addition to Western medicine-including electron beam therapy and local injections of IFN-γ. In December 1991, he noticed erythema on his upper extremities, and the eruptions gradually worsened. In July 1997, various-sized skin tumors appeared on his trunk. He was diagnosed as being at the tumor stage of mycosis fungoides on the basis of a histological examination.<br>In September1997, he was referred to our department and was treated with Jumi-haidoku-to, Takuri-shodoku-in, Naitaku-san, Kyuki-kyogai-to, etc., for his skin lesions. When he felt thirst and heat from the irradiation, he was given Byakko-ka-ninjin-to. He also received Ohgi-kenchu-to for diarrhea and general malaise. He is currently receiving IFN-γ and immunotherapy at the department of dermatology, and his condition is good. Careful follow-up will be necessary. It is thought that the traditional herbal medicines are useful for the treatment of mycosis fungoides.

Experiences in the Use of Shiun-ko for Verruca Vulgaris / 日本東洋医学雑誌

Twenty-seven cases with verruca vulgaris were examined in which the treatment consisted of oral administration of biscoclaurin alkaloids and Kampo medicine (Jumi-haidoku-to) with Siun-ko ointment. Seven of these cases were cured within one month-12 cases were cured within three months; and 8 cases required more than 3 months for a cure to be effected. However, there were no regressions or ineffective cases. Histopathological features of 5 cases examined after two or four weeks usage of Siun-ko ointment showed swelling of keratinocytes with formation of lacunae or fissures. This combination is thought to be an effective and useful treatment.

A Clinical Study of the Efficacy of Several Kampo Formulas in the Treatment of Acne Vulgaris / 日本東洋医学雑誌

Patients with acne vulgaris which could not be sufficiently controlled with antibiotics (tetracycline), or who had been receiving treatment for a prolonged period were selected for treatment with Kampo medicine. Patients in whom joint use of Kampo resulted in a decrease in blemishes, patients who were able to reduce the amount of antibiotics required or stop antibiotics altogether and patients who improved with Kampo alone were grouped according to the Kampo formula being taken. The formulas Seijobofu-to, Jumihaidoku-to and Keishibuuryo-gan proved to be effective. The patients in these groups were found to have certain characteristics in common. In particular, almost all of the cases with adult acne (25 years of age or older) had the symptoms of cold hands and feet, stiff shoulders, menorrhalgia, worsening of the condition before the menstrual period and other symptoms associated with Stagnated Blood. Formulas known as ‘agents for expelling Stagnated Blood’ (Kuoketsuzai), particularly Keishibukuryo-gan, were found to be effective.