Evaluation of efficacy and safety of finasteride 1 mg in 3177 Japanese men with androgenetic alopecia

Before now, there has been no study of finasteride use exceeding 1 year in Japanese men with androgenetic alopecia (AGA) except the study subsequently conducted from the development phase. Since the launch of finasteride, no study in a larger population had been reported. Ethnic variation of the onset age, progressive nature and degree of hair loss of androgenetic alopecia are known. The therapeutic effect of oral finasteride (Propecia) was examined on androgenetic alopecia of Japanese men. The efficacy and safety of finasteride (1 mg tablet) was evaluated in Japanese men with AGA in the long term. The study enrolled 3177 men given finasteride 1 mg/day from January 2006 to June 2009 at our clinic. Efficacy was evaluated in 2561 men by the modified global photographic assessment; the photographs were assessed using the standardized 7-point rating scale. Safety data were assessed by interviews and laboratory tests in all men enrolled in the study. The overall effect of hair growth was seen in 2230 of 2561 men (87.1%), in whom hair greatly (11.1%), moderately (36.5%) and slightly (39.5%) increased. The response rate improved with increasing duration of treatment. Adverse reactions occurred in 0.7% (23/3177) of men; seven men discontinued treatment based on risk-benefit considerations. No specific safety problems associated with long-term use were observed. This study represents data collected at a single institution. Many patients did not receive follow-up examination. In Japanese men with AGA, oral finasteride used in the long-term study maintained progressive hair regrowth without recognized side-effect.     

Finasteride in the treatment of Japanese men with male pattern hair loss

Finasteride is a type 2 5 alpha-reductase inhibitor that inhibits conversion of testosterone to dihydrotestosterone, a key mediator of male pattern hair loss (androgenetic alopecia). The objective of this study was to identify the optimal dosage of finasteride and to evaluate its efficacy and safety in the treatment of Japanese men with male pattern hair loss. In this double- blind randomized study, 414 Japanese men with male pattern hair loss received finasteride 1 mg (n = 139), finasteride 0.2 mg (n = 137), or placebo (n = 38) once daily for 48 weeks. Efficacy was evaluated by global photographic assessment, patient self-assessment, and investigator assessment. All efficacy endpoints showed significant improvement with finasteride therapy by 12 weeks (p < 0.05 versus placebo). At 48 weeks, 58%, 54%, and 6% of men in the finasteride 1 mg, finasteride 0.2 mg, and placebo groups, respectively, had improved based on assessments of global photographs. All efficacy endpoints were numerically superior for the 1 mg dose over the 0.2 mg dose at 48 weeks. Finasteride treatment was generally well tolerated. Finasteride 1 mg\day slows hair loss and improves hair growth in Japanese men with male pattern hair loss.     

Long-term treatment with finasteride 1 mg decreases the likelihood of developing further visible hair loss in men with androgenetic alopecia (male pattern hair loss)

There are no reports on the effects of pharmacologic treatment on the likelihood of developing further visible hair loss in men with androgenetic alopecia (AGA). Our objectives were to examine whether finasteride 1 mg treatment decreases the likelihood of developing further visible hair loss in men with AGA. We conducted an analysis of global photographic assessment data from two Phase III trials in which 1553 men with AGA received finasteride 1 mg/day or placebo for up to 5 years. Finasteride 1 mg treatment led to a 93% decrease relative to placebo in the 5-year likelihood of developing further visible hair loss (95% CI: 89-97%; p < 0.001). We conclude that, in men with AGA, treatment with finasteride 1 mg/day over 5 years led to a marked and sustained decrease in the likelihood of developing further visible hair loss.     

Comparative efficacy of various treatment regimens for androgenetic alopecia in men

Our understanding of the aetiology of androgenetic alopecia (AGA) has substantially increased in recent years. As a result, several treatment modalities have been tried with promising results especially in early stages of AGA. However, as far as has been ascertained, there is no comprehensive study comparing the efficacy of these agents alone and in combination with each other. One hundered male patients with AGA of Hamilton grades II to IV were enrolled in an open, randomized, parallel-group study, designed to evaluate and compare the efficacy of oral finasteride (1 mg per day), topical 2% minoxidil solution and topical 2% ketoconazole shampoo alone and in combination. They were randomized into four groups. Group I (30 patients) was administered oral finasteride, Group II (36 patients) was given a combination of finasteride and topical minoxidil, Group III (24 patients) applied minoxidil alone and Group IV (10 patients) was administered finasteride with topical ketoconazole. Treatment efficacy was assessed on the basis of patient and physician assessment scores and global photographic review during the study period of one year. At the end of one year, hair growth was observed in all the groups with best results recorded with a combination of finasteride and minoxidil (Group II) followed by groups IV, I and III. Subjects receiving finasteride alone or in combination with minoxidil or ketoconazole showed statistically significant improvement (p<0.05) over minoxidil only recipients. No signifcant side-effects related to the drugs were observed. In conclusion, it is inferred that the therapeutic efficacy is enhanced by combining the two drugs acting on different aetiological aspects of AGA.     

Combined treatment with oral finasteride and topical minoxidil in male androgenetic alopecia: a randomized and comparative study in Chinese patients

Finasteride at 1 mg/day and 5% topical minoxidil are effective in male androgenetic alopecia (MAGA). However, studies describing their effects in Chinese individuals are scarce. 450 Chinese MAGA patients were randomly assigned to receive finasteride (n = 160), minoxidil (n = 130) and combined medication (n = 160) for 12 months. The patients returned to the clinic every 3 months for efficacy evaluation. And efficacy was evaluated in 428 men at treatment end, including 154, 122, and 152 in the finasteride, 5% minoxidil, and combination groups, respectively. All groups showed similar baseline characteristics, including age at enrollment, and duration and severity of alopecia (p > 0.05). At 12 months, 80.5, 59, and 94.1% men treated with finasteride, 5% minoxidil and the combination therapy showed improvement, respectively. Adverse reactions were rare (finasteride, 1.8%; minoxidil, 6.1%), and disappeared right after drug withdrawal. In conclusion, finasteride is superior to 5% minoxidil, while the combined medication showed the best efficacy.     

Intradermal injections with 0.5% minoxidil for the treatment of female androgenetic alopecia: A randomized,placebo‐controlled trial

Female androgenetic alopecia is one cause of alopecia in women, although the ideal treatment for this condition remains far from defined. The objective of this study was to evaluate the efficacy and safety of intradermal injections with 0.5% minoxidil for the management of female androgenetic alopecia in a randomized, placebo‐controlled trial. A total of 54 women diagnosed with female androgenetic alopecia were divided into two groups: one group received intradermal injections of 0.5% minoxidil, and the other received 0.9% saline. Biopsy, trichogram, Trichoscan (Tricholog GmbH, Freiburg, Germany), and self‐assessment findings were used to evaluate the outcomes of treatment with minoxidil. In the treated group, there was a significant increase in the terminal‐to‐vellus hair ratio (P < .001) and in the percentage of anagen hairs (P = .048) and an improvement in hair loss and volume (P = .021 and P = .028, respectively). These results show that intradermal injections with minoxidil were more effective than placebo (P < .001) in the treatment of female androgenetic alopecia with a good safety profile.     

非那雄胺对不同年龄组雄激素性脱发患者的疗效观察

目的评价非那雄胺1mg/d治疗不同年龄组雄激素性脱发(AGA)男性患者的疗效及安全性。方法选取117名符合Norwood/Hamilton分级Ⅲ～Ⅴ级及Ludwing分级Ⅰ～Ⅱ级的AGA患者,按年龄分为两组:I组(≤26岁)、II组(26岁),均每日口服非那雄胺1mg,连续12个月。结果Ⅰ组在治疗第3,6,9,12个月的有效率分别是为42.31%,65.38%,88.46%,96.15%;Ⅱ组分别为28.33%,46.67%,73.33%,80.00%。在治疗6个月、9个月和12个月时Ⅰ组和Ⅱ组的有效率差异均有统计学意义(P均0.05)。结论每日口服1mg非那雄胺能安全有效的治疗AGA,且疗效与年龄相关,≤26岁的患者疗效更佳。     

Evaluation of long‐term efficacy of finasteride in Korean men with androgenetic alopecia using the basic and specific classification system

Finasteride 1 mg is considered to be the standard treatment method for male androgenetic alopecia (AGA). However, there have only been a few studies investigating its long‐term efficacy. Moreover, its effect on various types of AGA remains unknown. In this study, the authors investigated the 5‐year efficacy of finasteride 1 mg in Korean men with AGA and analyzed the changes in hair growth according to the distribution of hair loss. The medical records of male AGA patients who were treated with oral finasteride for a period of at least 5 years at two university hospitals were retrospectively reviewed. Patients' photographs were evaluated using the basic and specific (BASP) classification and investigator's global assessment. Of the total 126 patients, 108 (85.7%) showed improvement after 5 years of treatment. According to the BASP classification, hair loss of the anterior hair line (basic type), vertex (V type), and frontal area (F type) was improved in 44.4%, 89.7% and 61.2% of patients, respectively. The V type showed a more rapid and steady improvement compared with the other types. Progression of alopecia after peak improvement was seen in 10.3% of cases of the V type, 16.2% of the F type and 0% of the basic type. In conclusion, finasteride 1 mg showed a sustainable effect for at least 5 years in Korean male AGA patients. The exact time points showing signs of first clinical improvement and sustainability were different depending on the type of alopecia.     

Topical fulvestrant solution has no effect on male and postmenopausal female androgenetic alopecia: results from two randomized, proof-of-concept studies

BACKGROUND: Androgenetic alopecia (pattern baldness) affects approximately half of all white-skinned men and women over the age of 40 years. Based on preclinical studies in mice in which topical fulvestrant (ICI182,780, an anti-oestrogen) caused telogen hair follicles to enter anagen, thereby causing hair growth, a topical formulation of fulvestrant was developed for the potential treatment of androgenetic alopecia. OBJECTIVES: To evaluate the efficacy of fulvestrant solution in stimulating hair growth in men and postmenopausal women with androgenetic alopecia in two randomized, phase II, minoxidil- and/or vehicle-controlled studies. METHODS: One hundred and two white-skinned men aged 18-50 years with Norwood/Hamilton grades III, IIIv, IV, V or Va androgenetic alopecia received topical fulvestrant 70 mg mL(-1) solution, vehicle or minoxidil 2% solution twice daily for 16 weeks. Seventy postmenopausal women with Ludwig grade 1 or 2 androgenetic alopecia received topical fulvestrant 70 mg mL(-1) solution or vehicle twice daily for 16 weeks. The endpoints in both studies were hair density, cumulative hair thickness and hair growth rate, measured by TrichoScan analysis of digital images. RESULTS: There were no statistically significant differences favouring fulvestrant over vehicle at study end (day 113) for any of the efficacy parameters in men or women. Statistically significant differences in favour of minoxidil over fulvestrant were seen from day 57 onwards for hair density, cumulative hair thickness and hair growth rate in men. CONCLUSIONS: These results indicate a lack of effect of topical fulvestrant in the treatment of subjects with androgenetic alopecia. The reasons for this lack of effect remain unclear.     

The effectiveness of combination therapies for androgenetic alopecia: A systematic review and meta‐analysis

Androgenetic alopecia (AGA) is the most common type of baldness affecting both men and women. Studies investigating combination therapies for AGA reported greater efficacy than monotherapy but without rigorous examination. The authors performed a meta‐analysis and systemic review to further verify the evidence. To evaluate the effectiveness of three common combination therapies of minoxidil with finasteride, low‐level laser light therapy (LLLT) or microneedling versus minoxidil monotherapy. We conducted a systematic review of randomized controlled trials (RCTs) of combination therapies consisting of topical minoxidil for AGA through April 2020. Quality assessment and data analysis were performed by Review Manager 5.3. Fifteen studies met the inclusion criteria involving a total of 1172 AGA patients. We conducted meta‐analysis for three groups of combined treatment separately, and all were superior to monotherapy in terms of global photographic assessment (P < .05). Combination of LLLT or microneedling with minoxidil also showed significant increase in hair count (P < .05) compared to monotherapy. The present study suggests that combination therapy could be an effective, safe and promising option for the treatment of AGA. However, more RCTs are needed to further investigate and confirm the efficacy of combined treatment.     

Value of hormonal levels in patients with male androgenetic alopecia treated with finasteride: better response in patients under 26 years old

BACKGROUND: Finasteride is a 5alpha-reductase inhibitor that has proved to be an effective treatment for men with androgenetic alopecia. OBJECTIVES: To investigate the hormonal influence of finasteride 1 mg daily on hormonal levels and hair growth in men of different ages and with different degrees of alopecia according to the Hamilton-Norwood scale. METHODS: Two hundred and seventy men aged 14-58 years with male androgenetic alopecia III-VI Hamilton-Norwood score (II-III Ebling score) were treated with finasteride 1 mg daily. Steroid hormone (free testosterone, 5alpha-dihydrotestosterone, dehydroepiandrosterone-sulphate, delta4-androstenedione, 17-hydroxyprogesterone), prostate-specific antigen (PSA) and sebum levels, and trichogram changes were determined at baseline, and at 6 and 12 months of treatment. RESULTS: According to significant hormonal statistical analysis, the patients were divided by age (up to or over 26 years). In the group of patients26 years. No variations in sebum levels were observed. CONCLUSIONS: High levels of 5alpha-dihydrotestosterone in patients相似文献   

Evaluation of sexual function with an international index of erectile function in subjects taking finasteride for androgenetic alopecia

OBJECTIVE: To evaluate variations in sexual and erectile function in subjects taking 1 mg of finasteride for androgenetic alopecia by administering the abridged 5-item version of the International Index of Erectile Function (IIEF-5) questionnaire before and during treatment. DESIGN: In a multicenter study, 186 patients with androgenetic alopecia were asked to complete the IIEF-5 regarding the domain of erectile function before (at baseline) and 4 to 6 months after beginning finasteride treatment. The test was self-administered. SETTING: The study was conducted in 7 institutional dermatology departments in Italy (Bologna, Rome, Genoa, Cagliari, Milan, Florence, and Bari). PATIENTS: A total of 186 patients with androgenetic alopecia were evaluated before and 4 to 6 months after the initiation of finasteride therapy (1 mg). All patients (age range, 19-43 years; mean age, 28.3 years) were followed up as outpatients. RESULTS: The score on each of the 5 domains of the IIEF-5 did not show any significant change after 4 to 6 months of treatment. CONCLUSIONS: Our results support the clinical impression that sexual side effects are actually much less common than reported in clinical trials. The sexual function of all patients remained stable during treatment with 1 mg of finasteride.     

Depression circumstantially related to the administration of finasteride for androgenetic alopecia

In this paper we report 19 patients (14 males, 5 females; mean age 28.16 years +/- 7.68 SD) out of a series of 23 (17 males, 5 females) who developed a mood disturbance (moderate to severe depression) during treatment with finasteride, 1 mg/day orally, for androgenetic alopecia (Hamilton subtypes III-V; Ludwig subtypes I-II). Depression, which significatively impaired sociofamilial relations, sleep and eating behaviour, was associated to marked anxiety in some cases, developed after 9-19 weeks of treatment with finasteride, and promptly resolved after suspension of the drug. Two patients accepted reintroduction of the drug, and depression relapsed within 2 weeks. Depression as an adverse effect of finasteride has been reported only once. Further studies are needed to confirm our circumstantial observations, which are based on a retrospective series of patients.     

Polymorphic CAG repeat numbers in the androgen receptor gene of female pattern hair loss patients

Female pattern hair loss (FPHL) is frequently referred to as female androgenetic alopecia (FAGA). However, the role of androgen in this type of hair loss remains uncertain. We previously reported greater therapeutic efficacy of finasteride in Japanese male androgenetic alopecia (MAGA) patients in cases where the CAG repeats of the androgen receptor (AR) gene were short. To examine the correlation between CAG repeat numbers and the therapeutic efficacy of finasteride in FPHL patients, the efficacy of finasteride (1 mg/day) was evaluated macroscopically. Because women have two X-chromosomes, the shorter and longer CAG repeat numbers were analyzed in 37 Japanese FPHL patients, then the correlation of these factors was statistically analyzed by anova. No statistical significance in terms of the differences in CAG repeat numbers was detected among the four groups classified on the basis of the efficacy of finasteride. From these results, it may be concluded that the efficacy of this medicine in each FPHL patient cannot be predicted by the CAG repeat numbers in the AR gene.     

Progression of hair loss in men with androgenetic alopecia (male pattern hair loss): long-term (5-year) controlled observational data in placebo-treated patients

Relatively little is known about the progression of androgenetic alopecia (AGA; male pattern hair loss) in untreated men. We evaluated the long-term (5-year) progression of AGA in men treated with placebo in a controlled clinical trial setting. We analyzed pooled data over 5 years from two replicate studies with finasteride 1 mg/day in men with predominantly vertex-pattern AGA. Each study consisted of an initial 1-year, randomized, double-blind, placebo-controlled base study and four consecutive, 1-year, double-blind, placebo-controlled extension studies. Change over time in scalp hair growth was evaluated by four predefined endpoints: scalp hair counts; assessment of standardized clinical photographs by an expert panel; investigator clinical assessment; and patient self-assessment. All four predefined endpoints demonstrated progressive scalp hair loss in men receiving placebo over the 5-year study period, with a loss of 239 hairs from baseline (26.3% decline in hair density) measured in the target area at 5 years (p < 0.001 vs. baseline). Similarly, visible progression of scalp hair loss was demonstrated by global photographic assessment, with 75% of placebo patients rated as worsened from baseline at 5 years. We found that scalp hair loss continued in a progressive manner over a 5-year period in placebo-treated men with AGA.     

Obesity and low-grade inflammation among young Finnish men with early-onset alopecia

BACKGROUND: Previous investigations have revealed an association of androgenetic alopecia (AGA), especially in younger subjects with severe early-onset AGA, with ischemic heart disease. OBJECTIVE: To examine the possible association between early-onset alopecia and low-grade inflammation measured by high-sensitivity C-reactive protein (hs-CRP) that has been recommended for the assessment of the cardiovascular disease (CVD) risk. METHODS: The study population consisted of young men (n = 727, aged 25-34 years) participating in a national survey. The grade of alopecia was assessed by a trained nurse using the Norwood/Hamilton Classification Scale. RESULTS: Men with moderate to extensive alopecia (17%) had a higher body mass index and larger waist, upper arm, hip and waist circumference than those with little to no alopecia (p < 0.05), and statistically insignificant differences were seen in the waist-to-hip circumference ratio (WHR), diastolic blood pressure and hs-CRP. With increasing hs-CRP, the mean WHR increased, but only among men with moderate to extensive alopecia (p = 0.043). CONCLUSION: Our findings show a relation between moderate to extensive alopecia and low-grade inflammation--a predictor of a future CVD--especially combined with central obesity, among men younger than 35 years.     

低剂量非那雄胺控制男性型秃发临床观察

目的通过随机双盲对照试验评估每日口服非那雄胺1mg治疗2年有效并满意后,减量为5mg/周及1mg隔1日口服治疗中国男性型秃发的疗效。方法选择非那雄胺治疗2年或2年以上的男性型秃发患者175例,随机分为非那雄胺减量治疗组88例和安慰剂对照组87例,分别口服非那雄胺(1~24周5mg/周,24~48周1mg隔日1次口服)或安慰剂48周。并由皮肤科医师在24~48周时对治疗前、后的头发进行显微照像并评价,同期患者也进行自我评价。结果治疗前、后头发显微照像分析认为,治疗24周时非那雄胺减量治疗组脱发率为48.86%,而安慰剂对照组为98.85%,差异有统计学意义(P<0.05)。治疗48周后非那雄胺减量治疗组的脱发率为73.86%,安慰剂对照组为100%,差异有统计学意义。患者在24周和48周时的自我评价的结果也与之相似。结论低剂量口服非那雄胺维持治疗对中国男性型秃发患者脱发有一定作用。     

Validation and clinical relevance of a novel scalp coverage scoring method

Background/aims: Distinctive patterns of defective scalp skin coverage or alopecia have been identified by clinicians but do not help measuring the dynamics of hair changes over time. Hence, we conceived the scalp coverage scoring (SCS) method that integrates cumulative changes of hair growth or loss. In this paper, we report the results of validation studies demonstrating that the SCS can be applied in real time in the clinic or on global photographs for evaluating the severity of androgenetic alopecia (AGA) of male subjects and for monitoring changes over time. Methods: Different panels totalling 38 different male subjects with AGA were classified according to a modified Norwood–Hamilton scale and were evaluated with the SCS system (real time or global photographs). The contrast‐enhanced phototrichogram method (CE‐PTG), a refined non‐invasive and validated analytical technique was used for calibration purposes. Results: The real time SCS was correlated with SCS on global photographs. The inter‐ and intra‐observer variation of SCS obtained on global photographs was less than 3%. The real time SCS was negatively correlated with the clinical staging of male pattern baldness according to the modified Norwood–Hamilton scale, confirming less scalp coverage in more severly affected subjects. In 12 male subjects with AGA, after SCS evaluation of the top of the head, a 1‐cm² central target site was explored with CE‐PTG. There was a significant correlation of real time SCS with the percentage of thick anagen hair (r = 0.53; P < 0.08) and with the density of thin hair (r = ?0.68; P < 0.02). Changes over time as documented on global photographs (18 subjects at baseline and after 12 and 60 months) were rated by a panel of independent experts (paired photographs) who were not blinded as to time. Randomised individual photographs were also examined one at a time for SCS. This procedure documents data obtained without control of baseline photographs and establishes blinding as to time. The changes calculated from SCS (after – baseline) were correlated (r = 0.9; P < 0.0001) with the rating of the panel of experts. Conclusions: When minimum technical precautions are taken prior to the scoring session, the main points of interest of the SCS method are:

• ? Non‐invasive quantitative and reproducible technique
• ? Measures dynamics of scalp hair growth and loss
• ? Easily applied in the hair clinic.

     

Scalp Dermatoscopic Findings in Androgenetic Alopecia and Their Relations with Disease Severity

Background

Clinicians are searching for new methods to diagnose and predict the course of androgenetic alopecia noninvasively.

Objective

Our aim is to evaluate trichoscopic findings and their relations with disease severity in androgenetic alopecia.

Methods

The videodermatoscopic findings of 143 female and 63 male patients with androgenetic alopecia were compared with each other, with those of healthy subjects (n=100), and with those of patients with other nonscarring alopecias (n=208). Mann-Whitney U-test, χ² analyses, and logistic regression analysis were used for statistical analysis.

Results

No statistically significant relation was found between trichoscopic findings and severity in male androgenetic alopecia (MAGA) on the basis of the modified Hamilton Norwood scale (among 7 degrees); however, multihair follicular unit and perifollicular pigmentation were related to low severity whereas white dots, honeycomb pattern pigmentation, and brown dots were related to high severity. On the other hand, according to the Ludwig classification, arborizing red lines were related to low severity and brown dots were related to high severity, whereas there was no difference in stages between the Ebling and Olsen classifications in female androgenetic alopecia (FAGA). In the characteristic trichoscopic findings in this study, perifollicular pigmentation was found as a normal feature of the scalp, whereas multihair follicular unit and honeycomb pigment pattern, which were previously considered as normal features, were observed to be related to androgenetic alopecia.

Conclusion

No relation was found between MAGA severity and trichoscopic findings, as well as between FAGA severity according to different disease severity classifications and trichoscopic findings.     

Guidelines for the diagnosis and treatment of male‐pattern and female‐pattern hair loss, 2017 version

Male‐pattern hair loss (MPHL, androgenetic alopecia) is a slowly progressive form of alopecia which begins after puberty. In 2010, we published the first Japanese edition of guidelines for the diagnosis and treatment of MPHL. It achieved the original goal of providing physicians and patients in Japan with evidence‐based information for choosing efficacious and safe therapy for MPHL. Subsequently, new therapeutic drugs and treatment methods have been developed, and women's perception of MPHL has undergone change and the term “female‐pattern hair loss (FPHL)” is becoming more common internationally. Thus, here we report a revised version of the 2010 guidelines aimed at both MPHL and FPHL. In these guidelines, finasteride 1 mg daily, dutasteride 0.5 mg daily and topical 5% minoxidil twice daily for MPHL, and topical 1% minoxidil twice daily for FPHL, are recommended as the first‐line treatments. Self‐hair transplantation, irradiation by light‐emitting diodes and low‐level lasers, and topical application of adenosine for MPHL are recommended, whereas prosthetic hair transplantation and oral administration of minoxidil should not be performed. Oral administration of finasteride or dutasteride are contraindicated for FPHL. In addition, we have evaluated the effectiveness of topical application of carpronium chloride, t‐flavanone, cytopurine, pentadecane and ketoconazole, and wearing a wig. Unapproved topical application of bimatoprost and latanoprost, and emerging hair regeneration treatments have also been addressed. We believe that the revised guidelines will improve further the diagnostic and treatment standards for MPHL add FPHL in Japan.