Abstract
We conducted a 16-week double-blind randomized controlled single-center trial to evaluate the safety and efficacy of dermal rice bran supercritical CO2 extract (RB-SCE) in the treatment of androgenic alopecia. Fifty alopecia patients were randomly assigned to the experimental and placebo groups. The experimental group received a dermal application of 0.5% RB-SCE (8 mL/d) to the head skin for 16 weeks while the control group received a dermal application of placebo. Changes in hair count, diameter, and density were evaluated with a Folliscope®. Patient satisfaction was evaluated via questionnaire and clinical photographs were rated by dermatologists. The results showed that RB-SCE significantly increased hair density and hair diameter in male subjects. Patient satisfaction and the evaluation of photographs by dermatologists also confirmed the effectiveness of RB-SCE in the treatment of alopecia. No adverse reactions related to RB-SCE were reported. Therefore, RB-SCE shows promise for use in functional cosmetics and pharmaceuticals.
A daily loss of about 50–60 scalp hairs is considered normal, but a loss exceeding approximately 100 hairs will result in alopecia. Alopecia has been estimated to affect between 0.2 and 2% of the world’s population.1–3) Although medically viewed as a relatively minor dermatological condition, alopecia may have a significant negative impact on quality of life based on the psychological and symbolic importance of hair.
The demand for drugs that alter hair growth and appearance has spawned a multi-billion dollar industry. To date, only two alopecia treatments, minoxidil and finasteride, have been approved by the U.S. Food and Drug Administration. Topical minoxidil solution (Rogaine for Men and Women; Pharmacia Corp., Peapack, NJ, U.S.A.) has been shown to stimulate new hair growth and to help prevent further hair loss in affected areas in both men and women with alopecia,4,5) although the specific mechanism of action remains unclear. Finasteride (Propecia; Merck Co., Rahway, NJ, U.S.A.) is a synthetic azo-steroid that is a potent and highly selective non-competitive antagonist of 5α-reductase type 2. It binds irreversibly to the enzyme and inhibits the conversion of testosterone to dihydrotestosterone.6)
Generally, minoxidil is well tolerated for long-term daily use. Side effects of minoxidil are uncommon, but contact dermatitis,7) skin irritation,8,9) dizziness, and tachycardia9) have been reported. Finasteride is also generally well tolerated, with few adverse effects reported over 5 years. In finasteride-treated patients, 1.9% reported loss of libido and 1.4% reported erectile dysfunction in the first year. The placebo-treated group reported the same events with frequencies of 1.3 and 0.6%, respectively. These events appeared to resolve on cessation of the treatment and, in some cases, during continued treatment.10) Both drugs were discovered as the result of serendipity rather than rational hair drug design. Thus, to develop more precise therapies for alopecia, the mechanisms of hair growth-promoting effects as well as new drugs and natural hair growth enhancers require exploration.
In previous research, rice bran supercritical CO2 extract (RB-SCE) was found to be a potent inducer of hair growth in mice11) via 5-alpha-reductase inhibition.12) In addition, the toxicological safety of RB-SCE was investigated using the 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay in RAW264.7 cells. Further safety evaluations included single oral dose toxicity in rats,13) an acute dermal and ocular irritation test,14) a single dose and 4-week repeated dose dermal toxicity study,15) and a genotoxicity assessment.16) Thus, RB-SCE is thought to be safe. Despite its therapeutic potential and safety, no reports have described a clinical study of RB-SCE for alopecia.
Therefore, in the present study, we evaluated the safety of RB-SCE and its effects on markers of hair growth in alopecia. We expect that the results of this open-label trial can provide basic clinical information regarding changes in biochemical markers after RB-SCE treatment.
MATERIALS AND METHODS
Test MaterialRB-SCE (rice bran, Oryza sativa L. var. japonica) was prepared in a semi-continuous flow-type apparatus with a 3-L extractor.11) Test tonic products with or without RB-SCE were prepared and kindly supplied by Kolmar Korea (Sinjeong-ri, Yeongi-gun, Chungcheongnam-do, Korea). The studied formulations (Table 1) were prepared in a PRIMIX RM homomixer (PRIMIX Co., Ltd., Japan) at 3000 rpm within 10 min and supplemented with 0.5% (w/w) RB-SCE. A placebo formulation was prepared without RB-SCE.
Table 1. Formulation of the Test Tonic Product Containing RB-SCE
| INCI | Percentage of components (w/w) |
|---|
| Water (aqua), demineralized | as 100% |
| Glycerin | 1.0 |
| Hydroxyethyl cellulose | 0.5 |
| Tetrasodium EDTA | 0.03 |
| C12–14 Pareth-12 | 2.0 |
| Hyaluronic acid | 0.5 |
| Alcohol | 15.0 |
| RB-SCE | 0.5 |
| PEG-40 castor oil | 2.0 |
| Triethanolamine | 0.3 |
INCI=International Nomenclature of Cosmetic Ingredients; RB-SCE=rice bran supercritical CO2 extract.
The study design and a flow chart of study subjects are shown in Fig. 1. We enrolled 50 patients who were diagnosed with alopecia according to the criteria for the diagnosis of alopecia in Korean patients. Informed consent was obtained from all study participants. To assess the degree of hair loss, we used the Hamilton–Norwood classification for men and the Ludwig classification for women. This was a double-blind randomized controlled clinical trial. The patient group comprised a total of 50 subjects including 22 women and 28 men. They were enrolled in either the RB-SCE group or the placebo group by the table of random numbers. They were randomized 1 : 1 to either RB-SCE or placebo treatment (25 patients each; Table 2). The RB-SCE group received a dermal application of a test tonic product containing 0.5% RB-SCE to bald scalp skin and the placebo group received a dermal application of a test tonic product that contained no RB-SCE. At the baseline visit, subjects were given a plastic bottle containing a 16-week supply of their assigned test tonic (with or without RB-SCE). They were instructed to treat the scalp with 4 mL of solution once or twice a day at approximately 12-h intervals (total daily dose of 8 mL).
Table 2. Age and Sex Distribution of Alopecia Areata Patients
| Enrollment | Completion |
|---|
| N | Age (years) | N | Age (years) |
|---|
| RB-SCE treated group | Male | 12 | 39.0±8.6 | 9 | 41.0±9.2 |
| Female | 13 | 42.6±12.8 | 12 | 42.2±13.3 |
| Sub-total | 25 | — | 21 | — |
| Mean | — | 40.1±11.0 | — | 41.7±11.5 |
| Placebo group | Male | 16 | 41.9±8.2 | 13 | 41.3±6.6 |
| Female | 9 | 50.0±15.7 | 9 | 50.0±15.7 |
| Sub-total | 25 | — | 22 | — |
| Mean | — | 44.8±11.9 | — | 44.9±11.8 |
| Sum (male/female) | Total | 50 (28/22) | — | 43 (22/21) | — |
| Range | | 25–68 | | 28–68 |
| Mean | — | 42.0±11.37 | — | 43.3±11.58 |
RB-SCE=Test tonic containing RB-SCE; Placebo=Test tonic with no RB-SCE. The patient group comprised a total of 50 subjects including 22 women and 28 men. Of these, 43 subjects (12 men and 11 women) completed the study visits and intervention. Six men and one woman were excluded from the efficacy analysis due to poor compliance (<80%).
Scalp photography and phototrichography (Folliscope 2.5; LeadM Co., Seoul, Korea) were performed at baseline (0 week) and after 8 and 16 weeks of treatment. The study protocol was approved by the institutional review board (IRB) of the Korea University Ansan Hospital (IRB No. AS13141). All procedures were conducted in accordance with the ethics standards of the Declaration of Helsinki and Good Clinical Practice Guidelines.
To ensure compliance and monitor adverse effects, subjects underwent diagnostic tests conducted by a dermatologist after 8 and 16 weeks. To assess treatment compliance, subjects were asked to bring in their solution bottle at the end of the study and the remaining test tonic volume was measured by research staff. Restricted food and drugs during the study period included any hair growth-promoting agents, alopecia treatments, prostatic disease treatments, hormone products, and skin and hair health supplements.
For all site visits, subjects were asked to visit at the same time in the morning. Physical examinations including vital sign and hair measurements were performed at baseline and after 8 and 16 weeks. The patient questionnaire assessment and skin tolerance and safety evaluations by clinical observation were also performed after 8 and 16 weeks of treatment.
Inclusion CriteriaThe study inclusion criteria were as follows: age greater than 18 years; a diagnosis of alopecia more than 2 weeks prior to the study; treatment requirement; and agreement to participate in this clinical trial after receipt of an explanation of the objectives, methods, and efficacy of the study drug.
Exclusion CriteriaThe study exclusion criteria were as follows: treatment with other products or medications within 2 weeks before study initiation; allergy to any component of RB-SCE; medication for another disease; pregnancy or breastfeeding; enrollment in another clinical study within 3 months of this study; inability to understand the objectives and methods of this clinical trial; and inappropriateness for study participation as deemed by the clinician.
PhototrichographyHair measurement was performed via phototrichography according to the methods of Oh and Son17) using a computerized hand-held USB camera (Folliscope 2.5) at baseline and after 8 and 16 weeks. Briefly, the primary site of scalp baldness was tattooed and examined for hair density (number of hairs per square centimeter) and hair diameter (micrometer). Hair density per square centimeter was determined manually under 50-fold magnification. Hair diameter was measured under 100-fold magnification.
Expert Panel Assessment of Global PhotographsStandardized global photographs of the primary site of scalp baldness were obtained at baseline, 8 weeks, and 16 weeks. The patient’s head was placed in a stereotactic device to maintain consistency of patient positioning and photographic distance.18) Subjects were instructed to maintain their hairstyle throughout the study and to avoid dyeing their hair or using any hair enhancement procedures.
Global photographs were reviewed in a blinded manner by an expert panel of three dermatologists (Jae Beom Park, Sung Kyu Jung, and Sang Wook Son) at the end of the trial using a 7-point scale.19) Assessments included the percentage of scalp affected by alopecia and a scoring of hair regrowth from −3 to +3 using a 7-point scale as follows: greatly, moderately, or slightly decreased; no change; slightly, moderately, or greatly increased.
Patient Questionnaire AssessmentAfter 8 and 16 weeks of treatment, each subject was asked to perform a self-assessment of personal hair growth and scalp appearance. The self-assessment questionnaire parameters included size of the vertex spot, hair loss on top of the scalp, bitemporal recession, hair shedding, hair quality, and overall satisfaction.20) Patient satisfaction was assessed using the 3-point rating scale (improved, no change, or worse) most commonly used in alopecia-related research.17)
Skin Tolerance and Safety EvaluationsProduct safety was assessed by a dermatologist’s clinical observation as well as subject feedback. Adverse effects were recorded using WHO Adverse Reaction Terminology and evaluated for a causal relationship to the treatment. The objective signs were erythema, edema, scaling, and papule. The subjective signs included itching, prickling, burning, stinging, stiffness, tightness, burning of the eyes, weeping, etc. The frequency, duration, and intensity of each symptom and a possible or probable relationship with the test samples were investigated.
Statistical AnalysisAll statistical analyses were performed using SPSS software (version 12.0; SPSS Inc., Chicago, IL, U.S.A.). A paired t-test was used to evaluate statistically significant differences in hair density, hair diameter, and expert panel assessment. Student’s t-test was used to evaluate increases in hair density and hair diameter. The chi-square test was used to evaluate statistically significant between-group differences in the questionnaire analysis. Statistical significance was accepted at p-values less than 0.05.
RESULTS
Characterization of PatientsThis study took place between February 2014 and July 2014. Of the 61 people who were screened for study inclusion, 50 subjects (28 men and 22 women) participated. Seven subjects (6 men and 1 woman) withdrew after the baseline visit for personal reasons, and 43 subjects (22 men and 21 women) completed the study (Table 2). Patient ages ranged from 28 to 68 years (mean, 43.3±11.6 years). Mean ages were 41.7 years in the RB-SCE group and 44.9 years in the placebo group.
Hair DensityAt baseline, the average number of hairs in male subjects in the RB-SCE group was 93.50 strands/cm2. After RB-SCE treatment, hair density increased to 96.56 and 103.22 strands/cm2 at 8 and 16 weeks, respectively. The hair density of the RB-SCE group was not significantly increased after 8 weeks but was significantly increased after 16 weeks. In the placebo group, hair density increased from 88.19 strands/cm2 at baseline to 88.00 and 90.89 strands/cm2 at 8 and 16 weeks, respectively. The hair density of the placebo group was not significantly increased after 8 and 16 weeks (Table 3). The average increase in the number of hairs was 3.06 and 9.72 strands/cm2 in the RB-SCE group and only −0.19 and 2.69 strands/cm2 in the placebo group at 8 and 16 weeks, respectively. The increase in hair density did not significantly differ between the RB-SCE and placebo groups at 8 weeks but did significantly differ at 16 weeks (Table 3, p=0.410 and p=0.034).
Table 3. Hair Density at 0, 8 and 16 Weeks after Treatment in Male and Female Subjects
| Hair density (strand/cm2) | Pairwise comparison p value | Changes of hair density (strand/cm2) |
|---|
| 0 wk | 8 wk | 16 wk | 0 wk vs. 8 wk | 8 wk vs. 16 wk | 0 wk vs. 16 wk | ΔX1 | ΔX2 | ΔX3 |
|---|
| Male | RB-SCE | 93.50±11.8 | 96.56±11.2 | 103.22±10.1 | 0.106 | 0.000 | 0.000 | 3.06±5.04 | 6.67±3.35 | 9.72±4.62 |
| Placebo | 88.19±23.4 | 88.00±14.8 | 90.89±17.5 | 0.949 | 0.055 | 0.269 | −0.19±10.7 | 2.89±4.90 | 2.69±8.37 |
| p | | | | | | | 0.410 | 0.059 | 0.034 |
| Female | RB-SCE | 81.96±13.6 | 89.38±8.4 | 95.59±8.4 | 0.024 | 0.005 | 0.006 | 7.42±9.82 | 6.21±6.10 | 13.63±13.87 |
| Placebo | 70.56±11.1 | 76.67±7.3 | 80.94±10.0 | 0.089 | 0.126 | 0.039 | 6.11±9.47 | 4.28±7.51 | 10.39±12.66 |
| p | | | | | | | 0.280 | 0.148 | 0.198 |
RB-SCE=Test tonic with RB-SCE; Placebo=Test tonic without RB-SCE. ΔX1=hair density after 8 wk−hair density at 0 wk; ΔX2=hair density after 16 wk−hair density after 8 wk; ΔX3=hair diameter after 16 wk−hair diameter at 0 wk.
In female subjects, the average number of hairs in the RB-SCE group was 81.96 strands/cm2 at baseline. After RB-SCE treatment, hair density significantly increased to 89.38 and 95.59 strands/cm2 at 8 and 16 weeks, respectively. In the placebo group, hair density increased from 70.56 strands/cm2 at baseline to 76.67 and 80.94 strands/cm2 at 8 and 16 weeks, respectively. The hair density of the placebo group was not significantly increased after 8 weeks but was significantly increased after 16 weeks (Table 3). The average increase in the number of hairs was 7.42 and 13.63 strands/cm2 in the RB-SCE group and only 6.11 and 10.39 strands/cm2 in the placebo group at 8 and 16 weeks, respectively. The increase in hair density did not significantly differ between the RB-SCE and placebo groups at 8 and 16 weeks (Table 3, p=0.280 and p=0.198).
Hair DiameterThe average hair diameter in male subjects in the RB-SCE group was 57 µm at baseline, increasing to 66 and 75 µm after 8 and 16 weeks of treatment, respectively. In the RB-SCE group, hair diameter was significantly increased after 8 and 16 weeks. In the placebo group, hair diameter also increased from 59 µm at baseline to 66 and 69 µm after 8 and 16 weeks, respectively. In the placebo group, hair diameter was not significantly increased after 8 weeks but was significantly increased at 16 weeks (Table 4). The change in diameter did not differ significantly between the RB-SCE and placebo groups at 8 weeks (8.6 vs. 6.8, p=0.711). However, the change in hair diameter from 8 to 16 weeks in the RB-SCE group was 3.1-fold higher than that in the placebo group (8.8 vs. 2.8, p=0.001), and the change from baseline to 16 weeks in the RB-SCE group was 1.8-fold higher (17.3 vs. 9.7, p=0.127) (Table 4).
Table 4. Hair Diameter at Baseline and 8 and 16 Weeks after Treatment in Male and Female Subjects
| Hair diameter (µm) | p | Increase of hair diameter (µm) |
|---|
| 0 wk | 8 wk | 16 wk | 0 wk vs. 8 wk | 8 wk vs. 16 wk | 0 wk vs. 16 wk | ΔX1 | ΔX2 | ΔX3 |
|---|
| Male | RB-SCE | 57±18 | 66±14 | 75±16 | 0.013 | 0.000 | 0.001 | 8.6±8.1 | 8.8±3.6 | 17.3±10.2 |
| Placebo | 59±17 | 66±16 | 69±16 | 0.059 | 0.012 | 0.011 | 6.8±11.8 | 2.8±3.5 | 9.7±11.6 |
| p | | | | | | | 0.711 | 0.001 | 0.127 |
| Female | RB-SCE | 72±15 | 80±11 | 89±14 | 0.027 | 0.001 | 0.001 | 8.0±10.9 | 8.6±6.8 | 16.6±13.3 |
| Placebo | 62±14 | 73±10 | 74±11 | 0.046 | 0.672 | 0.027 | 11.0±13.9 | 0.5±3.4 | 11.5±12.8 |
| p | | | | | | | 0.586 | 0.004 | 0.389 |
RB-SCE=Test tonic with RB-SCE; Placebo=Test tonic without RB-SCE. ΔX1=hair diameter after 8 wk−hair diameter at 0 wk; ΔX2=hair diameter after 16 wk−hair diameter after 8 wk; ΔX3=hair diameter after 16 wk−hair diameter at 0 wk.
The average hair diameter in female subjects in the RB-SCE group was 72 µm at baseline, increasing to 80 and 89 µm after 8 and 16 weeks of treatment, respectively. In the RB-SCE group, hair diameter was significantly increased after 8 and 16 weeks. In the placebo group, hair diameter also increased from 62 µm at baseline to 73 and 74 µm after 8 and 16 weeks, respectively. In the placebo group, hair diameter was not significantly increased after 8 weeks but was significantly increased at 16 weeks (Table 4). The change in diameter did not differ significantly between the RB-SCE and placebo groups at 8 weeks (8.6 vs. 11.0, p=0.586). However, the change in hair diameter from 8 to 16 weeks in the RB-SCE group was 21.5-fold higher than that in the placebo group (8.6 vs. 0.5, p=0.004), and the change from baseline to 16 weeks in the RB-SCE group was 1.4-fold higher (16.6 vs. 11.5, p=0.389) (Table 4).
Expert Panel Assessment of Global PhotographsGlobal photographs were reviewed in a blinded manner by expert panels composed of three dermatologists using a 7-point scale (Fig. 2). After 16 weeks of treatment, the experts observed improved hair growth in the RB-SCE group (score=0.89±0.601, p=0.002), while no improvement in hair growth was observed in male subjects in the placebo group (0.08±0.862, p=0.753). At 8 weeks of treatment, the average score was 0.67 in the RB-SCE group and 0.00 in the placebo group, and the difference was not statistically significant (p=0.061). However, at 16 weeks of treatment, the average score in the RB-SCE group (0.89±0.601) was clearly higher than that in the placebo group (0.08±0.862) (p=0.024) (Table 5).
Table 5. Expert Panel Assessment of Global Photographs (7-Point Scale) in Male and Female Subjects
| Expert panel assessment (score value) | p* |
|---|
| 0 wk | 8 wk | 16 wk |
|---|
| Male | RB-SCE | 0 | 0.67±0.707 | 0.89±0.601 | 0.002 |
| Placebo | 0 | 0.00±0.817 | 0.08±0.862 | 0.753 |
| p | | 0.061 | 0.024 | |
| Female | RB-SCE | 0 | 0.67±0.779 | 1.25±0.452 | 0.000 |
| Placebo | 0 | 0.56±0.527 | 1.11±0.601 | 0.013 |
| p | | 0.717 | 0.552 | |
RB-SCE=Test tonic with RB-SCE; Placebo=Test tonic without RB-SCE. * p=expert panel assessment value after 16 wk−expert panel assessment value at 0 wk.
After 16 weeks of treatment, the experts observed improved hair growth in female subjects in both the RB-SCE group (score=1.25±0.452, p=0.000) and the placebo group (1.11±0.601, p=0.013). At 8 weeks of treatment, the average score was 0.67 in the RB-SCE group and 0.56 in the placebo group, and the difference was not statistically significant (p=0.717). At 16 weeks of treatment, the average score in the RB-SCE group (1.25±0.452) and in the placebo group (1.11±0.601) and the difference were not statistically significant (p=0.552) (Table 5).
Analysis of Subject Self-questionnairesThe bitemporal recession and hair shedding of male subjects in the RB-SCE group were significantly higher than those in the placebo group at 16 weeks based on the chi-square test for uniformity of groups (p=0.003, p=0.011, respectively; Table 6). No statistically significant between-group differences in all titles in the questionnaire analysis were observed in female subjects (Table 7). The overall satisfaction of all added male and female subjects in the RB-SCE treatment group was higher at 16 weeks than at 8 weeks (p=0.033, data not shown). In addition, the overall satisfaction of the RB-SCE group was significantly higher than that of the placebo group at 16 weeks (p=0.005).
Table 6. Questionnaire Analysis Results in Male Subjects
| | RB-SCE (%) | Placebo (%) | p Value |
|---|
| 8 wk | 16 wk | 8 wk | 16 wk | 8 wk/16 wk | RB-SCE/Placebo |
|---|
| Size of vertex spot | Improved | 44.4 | 44.4 | 15.4 | 23.1 | | |
| No change | 55.6 | 55.6 | 84.6 | 76.9 | 1 | 0.290 |
| Worse | 0.0 | 0.0 | 0.0 | 0.0 | | |
| Hair loss on top of scalp | Improved | 44.4 | 66.7 | 23.1 | 46.2 | | |
| No change | 55.6 | 33.3 | 76.9 | 53.8 | 0.343 | 0.342 |
| Worse | 0.0 | 0.0 | 0.0 | 0.0 | | |
| Bitemporal recession | Improved | 44.4 | 77.8 | 15.4 | 15.4 | | |
| No change | 55.6 | 22.2 | 84.6 | 84.6 | 0.147 | 1 |
| Worse | 0.0 | 0.0 | 0.0 | 0.0 | | |
| Hair shedding | Improved | 66.7 | 77.8 | 23.1 | 23.1 | | |
| No change | 33.3 | 22.2 | 69.2 | 76.9 | 0.391 | 0.011 |
| Worse | 0.0 | 0.0 | 7.7 | 0.0 | | |
| Hair quality | Improved | 33.3 | 55.6 | 15.4 | 30.8 | | |
| No change | 66.7 | 44.4 | 76.9 | 69.2 | 0.271 | 0.245 |
| Worse | 0.0 | 0.0 | 7.7 | 0.0 | | |
| Overall satisfaction | Improved | 55.6 | 77.8 | 38.5 | 38.5 | | |
| No change | 44.4 | 22.2 | 61.5 | 61.5 | 0.371 | 0.069 |
| Worse | 0.0 | 0.0 | 0.0 | 0.0 | | |
The chi-square test was used to evaluate statistically significant between-group differences in the questionnaire analysis. RB-SCE=Test tonic with RB-SCE; Placebo=Test tonic without RB-SCE.
Table 7. Questionnaire Analysis Results in Female Subjects
| | RB-SCE (%) | Placebo (%) | p Value |
|---|
| 8 wk | 16 wk | 8 wk | 16 wk | 8 wk/16 wk | RB-SCE/Placebo |
|---|
| Size of vertex spot | Improved | 33.3 | 33.3 | 55.6 | 44.4 | | |
| No change | 66.7 | 66.7 | 44.4 | 55.6 | 1 | 0.604 |
| Worse | 0.0 | 0.0 | 0.0 | 0.0 | | |
| Hair loss on top of scalp | Improved | 41.7 | 33.3 | 44.4 | 66.7 | | |
| No change | 58.3 | 66.7 | 55.6 | 33.3 | 0.673 | 0.130 |
| Worse | 0.0 | 0.0 | 0.0 | 0.0 | | |
| Bitemporal recession | Improved | 25.0 | 16.7 | 55.6 | 44.4 | | |
| No change | 75.0 | 83.3 | 44.4 | 55.6 | 0.615 | 0.163 |
| Worse | 0.0 | 0.0 | 0.0 | 0.0 | | |
| Hair shedding | Improved | 41.7 | 58.3 | 66.7 | 66.7 | | |
| No change | 50.0 | 33.3 | 33.3 | 22.2 | 0.693 | — |
| Worse | 8.3 | 8.3 | 0.0 | 11.1 | | |
| Hair quality | Improved | 25.0 | 58.3 | 66.7 | 55.6 | | |
| No change | 75.0 | 41.7 | 33.3 | 44.4 | 0.098 | 0.899 |
| Worse | 0.0 | 0.0 | 0.0 | 0.0 | | |
| Overall satisfaction | Improved | 50.0 | 83.3 | 55.6 | 66.7 | | |
| No change | 50.0 | 16.7 | 44.4 | 33.3 | 0.083 | 0.375 |
| Worse | 0.0 | 0.0 | 0.0 | 0.0 | | |
The chi-square test was used to evaluate statistically significant between-group differences in the questionnaire analysis. RB-SCE=Test tonic with RB-SCE; Placebo=Test tonic without RB-SCE. —: not determined.
On the basis of both subject reports and clinical observation by the investigators, no adverse reactions such as itching, prickling, burning, stinging, stiffness, tightness, burning of the eyes, weeping, erythema, edema, scaling, papule, or any other RB-SCE-related reaction were noted in all 43 subjects both at 8 and 16 weeks of treatment utilization.
DISCUSSION
Alopecia is a common form of hair loss in both men and women, affecting approximately 0.2 to 2% of the world’s population.1–3,21) Although topical minoxidil and oral finasteride are available for the treatment of alopecia, these medicines have sometimes been reported to have adverse effects.7–10) In our previous study, RB-SCE showed hair growth-promoting potential similar to that of 3% minoxidil, as evidenced by findings of hair follicles induced in the anagen stage, and a significant increase in the number of hair follicles in C57BL/6 mice.11) However, there have been no clinical studies of RB-SCE. We therefore performed this clinical study to confirm the ability of RB-SCE to improve hair loss in 43 patients treated with or without RB-SCE.
Clinical research on topical alopecia treatments included clinical studies of procyanidin B-222) and minoxidil.4,23) After 48 weeks of male pattern hair loss treatment, the parameter known as non-vellus hair count (mean change from baseline) in the 5% minoxidil, 2% minoxidil, and placebo groups measured 18.6, 12.7, and 3.9 strands/cm2, respectively.4) The change from baseline in the non-vellus hair count was significantly superior with 5% topical minoxidil compared to 2% topical minoxidil and placebo. After 48 weeks of female pattern hair loss treatment, the non-vellus hair count (mean change from baseline) in the 5% minoxidil, 2% minoxidil, and placebo groups measured 24.5, 20.7, and 9.4 strands/cm2, respectively.23) As in the male patients, 5% topical minoxidil was significantly superior to 2% topical minoxidil and placebo in the female patients. To investigate the effects of topical procyanidin B-2 (1%), which is purified from apples, on the scalp and hair, a placebo controlled clinical trial was performed in male pattern baldness.22) After 16 weeks, a significantly greater increase in the total number of hairs in the designated scalp area (1.0 cm2) was observed in subjects receiving procyanidin B-2 than in those receiving placebo (procyanidin B-2, 14.68 strands/cm2; placebo, −10.16 strands/cm2). In our study, the non-vellus hair counts (mean change from week 0) were 9.72 and 2.69 strands/cm2 in male subjects in the RB-SCE and placebo groups, respectively, showing a statistically significant difference between the groups (p=0.034; Table 3). In female subjects, the hair counts were 13.63 and 10.39 strands/cm2 in the RB-SCE and placebo groups, respectively. However, there was no statistically significant difference between the groups (p=0.198; Table 3). Although study duration, race, gender, drug administration protocol, and other factors differ between our study and the prior studies, the increase in hair count in the 0.5% RB-SCE group after 16 weeks in our study (9.72 strands/cm2 in male subjects) is similar to or slightly lower than that reported for 2% minoxidil after 48 weeks of treatment in men (12.7 strands/cm2)4) or for 1% procyanidin B-2 after 16 weeks of treatment in men (14.68 strands/cm2).22)
In terms of hair diameter, it was reported that 78.9% of subjects treated with 1% procyanidin B-2 showed an increased mean hair diameter, whereas only 30.0% in the placebo group showed any increase. The change in hair diameter after 16 weeks was 2.68 and −1.08 µm, respectively, in the 1% procyanidin B-2 and placebo groups. The increased ratio (8.04%) of hairs measuring more than 40 µm in diameter after 16 weeks of procyanidin B-2 treatment was significantly higher than that in controls (−4.32%). In our study, the hair diameter (mean change from week 8) after 16 weeks was 8.8 µm (from 66 to 75 µm) and 2.8 µm (from 66 to 69 µm) in male subjects with RB-SCE and placebo, respectively, showing a significant increase (p=0.001; Table 4). The hair diameter (mean change from week 8) after 16 weeks was 8.6 µm (from 80 to 89 µm) and 0.5 µm (from 73 to 74 µm) in female subjects with RB-SCE and placebo, respectively, showing a significant increase (p=0.004; Table 4). The increase in hair diameter in the RB-SCE group after 16 weeks (17.3 and 16.6 µm in male and female subjects, respectively) was higher than that reported for 1% procyanidin B-2 after 16 weeks (8.04 µm).
Regarding the expert panel assessment of global photographs in male subjects, at 16 weeks of treatment, the average score in the RB-SCE group (0.89±0.601) was clearly higher than that in the placebo group (0.08±0.862), and the difference was statistically significant (p=0.024) (Table 5). In female subjects at 16 weeks of treatment, the average score in the RB-SCE group (1.25±0.452) and in the placebo group (1.11±0.601) and the difference were not statistically significant (p=0.552) (Table 5).
Self-questionnaires have been reported useful for the evaluation of new potential hair growth-promoting candidates or medicines.4,17,23) In the study of Olsen et al. in male patients,4) patient questionnaire hair growth composite scores at week 48 (efficacy-evaluable population) for 5% minoxidil, 2% minoxidil, and placebo were 60.4, 56.8, and 50.7, respectively. In the study of Lucky et al. in female patients,23) patient questionnaire hair growth composite scores at week 48 (efficacy-evaluable population) for 5% minoxidil, 2% minoxidil, and placebo were 64.5, 60.5, and 56.4, respectively. In our study, the population with improvement in bitemporal recession and hair shedding in the RB-SCE group of male subjects was significantly larger than that in the placebo group at 16 weeks based on the chi-square test for uniformity of groups (p=0.003, p=0.011, respectively; Table 6), but it otherwise was not in female subjects (Table 7). Although comparison with previous results is difficult because of the use of different questionnaire items,4,23) we confirmed that 2 items in questionnaire analysis results in the RB-SCE group were significantly increased compared to those in the placebo group after 16 weeks, especially in male subjects.
Overall, the significant differences in hair density, hair diameter, and expert panel assessment of global photographs were shown in male subjects after 16 weeks of treatment with RB-SCE. In addition, the significant differences between the RB-SCE and placebo groups after 16 weeks showed in hair density, expert panel assessment of global photographs, and questionnaire analysis in male subjects. In female subjects after 16 weeks of treatment with RB-SCE, the significant differences in hair density, hair diameter, and expert panel assessment of global photographs were shown but not significantly different from those of the placebo group.
In a previous study,11) to examine the hair growth-promoting activity of RB-SCE, we selected linoleic acid (LA), oryzanol (OZ), policosanol (PS), and tocotrienol (TT) as the main components of RB-SCE. In particular, the unsaturated fatty acids such as γ-LA, LA, and oleic acid as well as RB-SCE have been shown to have anti-hair loss activity by inhibiting the 5-α-reductase enzyme in androgen-responsive organs.12,24) In this study, RB-SCE had a significant hair growth-promoting effect in male subjects but not in female subjects, meaning that RB-SCE may have an effect in androgen-dependent hair loss. Recently, female patients with alopecia were reported to be divided by androgen-dependent female pattern hair loss (FPHL) and androgen-independent FPHL according to the serum androgen levels of the female patients.25,26) The analyses of blood chemistry tests including hormonal levels for female patients are needed in further study.
Previous researchers have confirmed the toxicological safety of RB-SCE in RAW264.7 cells. Additional safety evaluations included single oral dose toxicity in rats,13) an acute dermal and ocular irritation test,14) a single dose and 4-week repeated dose dermal toxicity study,15) and a genotoxicity assessment.16) As urinalysis, hematological tests, clinical biochemistry tests, necropsies, and histopathological examinations were performed in male and female rats after 4-week repeated-dose dermal administration of RB-SCE, no liver or kidney damage was observed.15) In addition, in this study, no specific side effects such as irritant contact dermatitis, allergic contact dermatitis, itching, pricking, burning, erythema, oozing, vesicles, skin rashes, and so on were observed in patients receiving RB-SCE. Therefore, RB-SCE is thought to be safe for topical application in humans.
However, the limitations of this study are the single-center study design, small number of subjects, and lack of blood chemistry research including hormonal levels, extensive interviews with patients about hormonal effects detected by sexual dysfunction (e.g., loss of libido), and confirmation of the absence of liver or kidney damage. Further studies, including multicenter studies with longer treatment periods, larger sample-size patient populations, blood chemistry research, and extensive patient interviews, are needed to confirm the present results.
RB-SCE is a mixture of fatty acids and oily materials and not a purified compound. Nevertheless, the increase in hair density and diameter as well as patient satisfaction with 0.5% RB-SCE after 16 weeks were similar to or slightly lower than those reported for 2% minoxidil after 48 weeks or 1% procyanidin B-2 after 16 weeks. Therefore, RB-SCE appears to have considerable hair growth-promoting potential.
CONCLUSION
In conclusion, these results suggest that treatment with RB-SCE can improve hair regrowth in human androgen-dependent alopecia without side effects at a moderate dose. Therefore, RB-SCE is a potentially promising source of functional cosmetics and pharmaceuticals developed to treat male pattern and androgen-dependent female pattern hair loss.
Acknowledgment
This work was supported by a Grant (No. 311014-03) from the Ministry for Food, Agriculture, Forestry and Fisheries, Republic of Korea.
Conflict of Interest
The authors declare no conflict of interest.
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