Onset Mechanism and Pharmaceutical Management of Dry Skin

Abstract

Dry skin is a common symptom of various conditions, and elderly individuals commonly exhibit this physiological symptom. Dry skin develops owing to sebum deficiency; however, the use of moisturizers can typically overcome this issue, particularly in patients in whom there are no other skin problems. If dry skin is left untreated, itching and eczema can occur, resulting in skin damage. Additionally, hemodialysis patients exhibit reduced barrier function and can experience pain associated with repeated needle insertion; the repeated use of lidocaine tape to manage the pain can cause further skin damage. To reduce the occurrence of dry skin, the skin is hydrated using moisturizers. Dry skin is also prominent in patients with varicose veins in the lower extremities, and many biochemical studies have shown that skin immunity is altered in patients with dry skin. Moreover, the incidences of dry skin and pruritus differ in male and female patients. Furthermore, in elderly patients, zinc deficiency is likely to cause dry skin, and zinc supplementation may maintain skin hydration. To date, few reports have described dry skin from a clinical point of view. In this review, research on dry skin is presented, and the findings of basic research studies are integrated.

1. INTRODUCTION

The skin is a major organ that is involved in contact with the external environment. Beginning with its surface, the skin is divided into the epidermis, dermis, and subcutaneous tissue. The outermost layer is the stratum corneum, which is covered by the sebum membrane; this tissue is in constant contact with the external environment. The stratum corneum is formed by corneocytes. These cells undergo various changes leading to the disappearance of cellular organelles, resulting in the mixing of ceramide with keratin strands and eventual shedding of corneocytes. During this destructive cycle, the epidermal thickness remains the same. The sebum membrane is formed by a mixture of moisture from sweat excreted by sweat glands and sebum excreted from sebaceous glands. Normal skin shows weak acidity (pH 4.5–6.0); thus, the sebum membrane prevents elevation of transepidermal water loss (TEWL) from the surface of the skin, thereby preventing bacterial invasion.¹⁾

Dry skin is a condition in which the capacitance of the skin is reduced owing to a decrease in skin barrier function and an increase in TEWL.²⁾ Dry skin also develops in specific diseases that are affected by aging and environmental factors, such as hemodialysis (HD). HD patients are unable to maintain body fluid homeostasis and must continuously undergo treatment to directly remove the toxic causes of uremia. Moreover, HD patients can develop complications from renal failure and often complain of dry skin. Indeed, HD patients must strictly limit water intake, and water removal by dialysis results in reduced water content in the skin compared with healthy adults, leading to lower skin capacitance.³⁾ Additionally, HD patients commonly wear lidocaine tape to reduce the pain associated with puncturing of the skin. The barrier function of the skin in these patients is often decreased owing to chronic stress under repeated skin insults. Accordingly, these patients commonly use moisturizers, such as heparinoids, for skin care.

In this review, the proper use of lidocaine tape in patients with dry skin is discussed. Dry skin in patients with varicose veins of the lower extremities and related symptoms, such as itching, are also described, as well as research on alleviation of dry skin in elderly individuals.⁴⁾

2. INFLUENCE OF PREMOISTURIZATION ON THE SKIN BARRIER FUNCTION OF LIDOCAINE TAPE IN HD PATIENTS

HD patients experience much physical and mental pain associated with the insertion of needles prior to dialysis. To alleviate this pain, tape-type lidocaine-containing local anesthetic patches are widely used in Japan.⁵⁾ This tape is typically applied to the needle insertion site for 30 min; however, some reports have indicated that 30 min is insufficient, and the tape is commonly applied for a longer time.^5,6) The absorption of lidocaine is modulated by permeation of the stratum corneum.⁷⁾ Thus, HD patients exhibit a variety of dermatological symptoms, such as pruritus, xerosis, pigmentation, and erythema.^8–12) These symptoms may affect transdermal lidocaine absorption, although the extent of this effect is still unclear (Fig. 1).

Fig. 1. Skin Condition of Patients Undergoing Hemodialysis

Patients undergoing hemodialysis have reduced skin barrier function. When the barrier function is reduced, the value of the transepidermal water loss (TEWL) increases and the capacitance decreases. Increasing the amount of water in the skin with a moisturizer increases the adhesive force and reduces dermatological issues.

In research from my laboratory, the current use of lidocaine tape was surveyed, and skin conditions in HD patients were evaluated.³⁾ Additionally, a method to enhance the absorption of lidocaine from the tape was assessed. Importantly, dry skin in HD patients may be caused not only by age but also by other factors specific to these patients.

Many methods have been investigated to enhance the transdermal delivery of lidocaine, including skin pretreatment by tape stripping or benzine, ultrasound, electroporation, and iontophoresis.^13–16) In my laboratory, application of absorbent cotton soaked in distilled water at 37 °C for 5 min was examined as a skin moisturizing method in HD patients (average age: 60.1 ± 13.9 years), and the effects of skin hydration on the anesthetic effects of lidocaine tape were determined. Briefly, the TEWL, electrical capacitance of the skin surface, and skin surface pH were measured (in that order) at the site where lidocaine tape was applied on the forearm. The patients remained in a room maintained at a temperature of 24–26 °C and humidity of 50–55% for 30 min. TEWL, which characterizes the skin water barrier function, was measured using a Tewameter TM 210 (Courage + Khazaka Electronic GmbH, Cologne, Germany). A corneometer CM 825 (Courage + Khazaka Electronic GmbH) was used to assess the electrical capacitance of the skin surface as an indicator of stratum corneum moisture, which is dependent on water content and the high dielectric constant of water relative to other skin components. The electrical capacitance was measured 5 s after removal of the cotton. The skin surface pH was measured with a skin-pH-meter PH905 (Courage + Khazaka Electronic GmbH). This clinical skin hydration method was based on basic research using porcine ear skin, which has major similarities to human skin.¹⁷⁾ Notably, the porcine skin results showed that the electrical capacitance of the skin surface increased significantly with skin hydration. Application of the skin hydration method for 30 min in HD patients was expected in to be at least as effective as longer applications. The lidocaine concentration in skin was found to increase with skin hydration, and a good correlation was observed between capacitance before the application of lidocaine tape and the lidocaine concentration in the skin.

Overall, this skin hydration method, which is simple and easy, only requires water application to the skin and is noninvasive from a clinical perspective, suggesting potential applications in the treatment of pain associated with needle insertion in HD patients. Further investigations are needed to better evaluate the anesthetic effects of lidocaine tape applied using this method.

This method is noninvasive and can be easily performed on patients. Furthermore, the analgesic effect is stable with lidocaine absorption by the skin. In addition, patients complain of skin itching at the time of application. Moisturizers are used because HD patients often present with dry skin. Although cotton has been used in previous studies for skin hydration, there are no studies on the effects of pretreatment with a moisturizer on lidocaine tape application. A previous study examined the effects of skin hydrated with heparinoid lotion on the use of lidocaine tape with HD.¹⁸⁾ In that study, the heparinoid lotion was applied on the skin and then dried rapidly, with any visual residue on the skin surface disappearing within 2 min. On the contrary, a significant increase in capacitance was observed and skin hydration was confirmed even with no visual residue on the skin surface. Skin hydration has been suggested to enhance the absorption of drugs by dry skin.¹⁸⁾ Residual ointment and lotion on the skin would reduce the contact area of lidocaine tape with the skin and reduce adhesiveness. It has been confirmed that the application of lidocaine tape to skin pretreated with heparinoid lotion has almost no effect on adhesiveness in both male and female patients with HD. In this study, adhesive strength was evaluated 2 min after the application of lidocaine tape. Lidocaine tape is known to have its lowest adhesive strength initially, which increases over time and eventually reaches its maximum strength.¹⁹⁾ Lidocaine tape is considered to have the highest risk of desquamation in the early stages of its application. Therefore, to evaluate the changes in adhesive strength with maximum sensitivity, we performed an evaluation in the initial stage of application, when the highest risk of tape peeling exists. It was confirmed that the amount of stripped striatum corneum by the tape was significantly reduced by pretreatment with heparinoid lotion. In particular, this phenomenon was significant in women. Thus, the reduction in the amount of stripped striatum corneum by heparinoid lotion lowered the risk of inducing skin irritation and improved the usability of lidocaine tape and cotton.

3. MECHANISM OF ITCH ONSET IN PATIENTS WITH VARICOSE VEINS

Varicose veins of the lower extremities are associated with various symptoms, including pain, swelling, and itching.^4,20–23) Among patients with varicose veins, 25.3% of women and 19.0% of men in the Edinburgh varicose vein study complained of pruritus, and the number of women complaining of pruritus increased significantly with age.²⁴⁾ However, the pathogenic mechanisms through which pruritus is associated with varicose veins of the lower extremities are unclear, and no curative treatment has been reported to date.

In research from my laboratory,^4,20) the mechanisms of pruritus in patients with varicose veins of the lower extremities were evaluated. Informed consent was obtained from patients who were diagnosed with varicose veins of the lower extremities at the Mie Heart Center and received sclerotherapy, and the amount of water in the stratum corneum, the TEWL, and itching before and after sclerotherapy were assessed. In addition, substance P, histamine, immunoglobulin (Ig) E, matrix metalloproteinase (MMP)-9, tryptase, IgA, adrenocorticotropic hormone (ACTH), and β-endorphin were measured as inflammatory mediators by collecting blood before and after sclerotherapy. For control patients, the amount of water in the stratum corneum and the TEWL were measured on the day when consent was obtained, and substance P, histamine, IgE, MMP-9, tryptase, ACTH, and β-endorphin levels in the blood were measured. The results showed that substance P, histamine, IgE, and tryptase, which are related to mast cell function, were significantly higher in the patients than in the healthy controls, suggesting involvement of the afferent nerves. These changes may have stimulated itching; indeed, when inflammation occurs at the site of varicose veins in the lower extremities, IgE is secreted from B cells, which binds to IgE high-affinity receptors on the surface of mast cells, promoting their degranulation (releasing histamine and tryptase).

These components then bind to receptors at nerve endings and send signals to the brain, triggering pruritus. In addition, binding of IgE to the IgE receptors on nerve terminals causes release of the neurotransmitter substance P, resulting in increased vascular permeability and histamine release from mast cells.²⁵⁾ Histamine then further stimulates sensory nerves, releasing substance P from the ends of C fibers and large amounts of histamine from surrounding mast cells.²⁰⁾ Pruritus in varicose veins of the lower extremities is induced and exacerbated by mutual amplification, promoting the action of histamine and substance P.

The onset of varicose veins differs in men and women.²⁴⁾ However, the relationship between the onset of pruritus and sex in patients with varicose veins is not clear. Patients with varicose veins are often under considerable stress owing to pain and itching.²⁶⁾ Moreover, stress is known to cause pruritus via β-endorphin and ACTH,²⁷⁾ and differences in stress sensitivity have been reported for men and women.^28,29) Therefore, to clarify sex differences in the mechanism of pruritus in patients with varicose veins of the lower extremities, β-endorphin and ACTH levels, which fluctuate with stress, were evaluated. The results showed that substance P, histamine, IgA, and IgE levels were high before sclerotherapy, but no significant differences were observed between men and women. Additionally, MMP-9 levels increased in both men and women compared with the levels in healthy controls before sclerotherapy, with no differences between men and women. In contrast, tryptase levels were clearly elevated in women, but not in men, with varicose veins compared with controls. In addition, ACTH levels were high in men before sclerotherapy and decreased after sclerotherapy, whereas no differences were observed before and after sclerotherapy in women. β-Endorphin levels were increased in both men and women before sclerotherapy, with higher levels in men than in women. Based on these findings, histamine and tryptase levels may play important roles in pruritus in women. In women, the female hormone progesterone induces the activation of immediate-type allergies. Because mast cells are involved in immediate-type allergic responses, these cells may show increased activation and therefore increased tryptase release in women.³⁰⁾ The results of this study showing significantly higher β-endorphin levels in men than in women may be related to the involvement of elevated β-endorphin in CD4+ T-cell functions.^31–33) Indeed, levels of CD4+ T cells in the serum were higher in men than in women, suggesting that this increase may have promoted β-endorphin production in men. ACTH has been reported to stimulate keratinocytes and increase histamine secretion.^34,35) Thus, increased ACTH levels due to varicose veins of the lower extremities may also have caused pruritus in men.

A strong link between skin disorders and zinc deficiency has been suggested.^36,37) Therefore, the relationship between pruritus in patients with varicose veins of the lower extremities and serum zinc was analyzed. Among patients who were diagnosed with varicose veins of the lower extremities at the Mie Heart Center and received sclerotherapy, the amount of water in the stratum corneum, the TEWL, and serum zinc levels before and after sclerotherapy were measured. For controls, the amount of water in the stratum corneum and the TEWL were measured on the day of obtaining informed consent, and serum zinc was measured by blood sampling. Notably, the water content of the stratum corneum was significantly lower in patients with pruritus than in patients without pruritus. Furthermore, water content in the stratum corneum was significantly lower in both groups than in healthy controls. Moreover, TEWL was significantly higher in patients with pruritus than in patients without pruritus, and the values were significantly higher in both groups than in healthy controls. Serum zinc was significantly lower in patients with pruritus than in healthy controls, but did not differ between patients without pruritus and healthy controls. Finally, there was a correlation between stratum corneum water content and serum zinc and an inverse correlation between TEWL and serum zinc among all patients. Zinc is known to suppress the degranulation of histamine from mast cells,³⁸⁾ and the decreased zinc results in higher histamine levels in patients with varicose veins than in healthy individuals. Overall, these findings suggest that mast cell-mediated inflammation is also a cause of pruritus in patients with varicose veins of the lower extremities and that the development of pruritus in these patients differs between men and women, with elevated tryptase causing pruritus in women and elevated β-endorphin causing pruritus in men. Furthermore, the findings showed that decreased serum zinc induced the pruritus associated with varicose veins of the lower extremities. In future studies, researchers should evaluate whether zinc supplementation may be an effective treatment for alleviating pruritus in patients with varicose veins of the lower extremities^4,20) (Fig. 2).

Fig. 2. The Pathway for Generation of Dry Skin Conditions in Patients with Varicose Veins

The pathway in males and females is depicted with solid and dotted lines, respectively, and strength of action is indicated with line thickness. Female patients with varicose veins in the lower extremities had significantly higher levels of tryptase, while the male patients had significantly higher levels of β-endorphin and adrenocorticotropic hormone (ACTH), suggesting a sex-related difference in the development of dry skin conditions. POMC: proopiomelanocortin; MMP-9: matrix metalloproteinase 9. (Color figure can be accessed in the online version.)

4. CHANGES IN TEWL IN ELDERLY INDIVIDUALS FOLLOWING ADMINISTRATION OF ZINC

Dry skin and chronic itching are common in the elderly. In the clinical setting, clinicians frequently encounter elderly individuals who have not received appropriate treatment, despite complaints of dry skin, itching, and infections as well as decreased QOL, such as sleep disorders and decreased concentration. Therefore, in my laboratory, the relationships between serum zinc concentrations and skin conditions (e.g., skin barrier function and dry skin) were examined in elderly individuals. Furthermore, the beneficial effects of oral zinc supplementation on skin conditions were assessed by administration of a zinc preparation to patients with low serum zinc levels and evaluation of their skin condition. The patients were 65 years of age or older, visited the Jose Clinic (Odai Town, Mie Prefecture, Japan) between October 2018 and February 2019, and had serum zinc concentrations lower than 80 µg/dL (low zinc group) based on the criteria of the Practice Guideline for Zinc Deficiency.³⁹⁾ The participants were administered zinc acetate hydrate (Nobelzin^® tablets) at 100 mg/d for 12 weeks from the start of the study, and TEWL, stratum corneum moisture content, serum zinc concentrations, and itching were evaluated every 4 weeks. The control patients had serum zinc concentrations greater than or equal to 80 µg/dL and were 65 years of age or older (normal zinc group; Fig. 3). There were nine patients in the study group (three men and six women, age: 78.89 ± 5.75 years) and nine patients in the control group (three men and six women, age: 80.11 ± 3.98 years). Before taking Nobelzin^®, TEWL was significantly higher and the serum zinc concentration was significantly lower in the low zinc group than in the normal zinc group. Additionally, the serum zinc concentration increased significantly 12 weeks after Nobelzin^® treatment, and there were significant differences between baselines values and those 8 weeks after treatment. TEWL decreased significantly between baseline and 12 weeks after Nobelzin^® treatment, and there was also a significant difference between the values at baseline and 8 weeks after treatment. There were no significant changes in the stratum corneum moisture content or itch scores during the observation period. An analysis of 45 samples (nine in the low zinc group with four time points and nine in the normal zinc group) showed a negative correlation between serum zinc concentrations and TEWL. Moreover, significant decreases in TEWL were observed as serum zinc levels increased after treatment in elderly individuals with low serum zinc levels, suggesting an improvement in skin barrier function. However, there were no significant changes in stratum corneum moisture content as serum zinc concentrations increased. This parameter is heavily affected by external conditions, such as temperature and humidity. Okada et al. reported that forearm stratum corneum moisture content was lower in winter than in summer.⁴⁰⁾ In the study from our laboratory, the study period was October to February, when temperature and humidity are lower. Therefore, although the indoor environment at the time of measurement was temperature and humidity controlled, the stratum corneum moisture content could have decreased. Accordingly, the decrease in TEWL may have contributed to maintenance of the stratum corneum moisture content, despite the environmental conditions. Moreover, oral zinc supplementation in elderly individuals with decreased serum zinc concentrations did not alter the severity of itch, but decreased TEWL and helped to maintain the moisture content of the stratum corneum. Thus, zinc supplementation can improve skin barrier function.⁴¹⁾

Fig. 3. Changes in TEWL Following Administration of Zinc to Elderly Individuals

The low zinc group was administered Nobelzin^® tablets for 12 weeks from the commencement of the study. Every 4 weeks, blood sampling was performed and the water content in the stratum corneum and TEWL were measured.

5. CONCLUSION

As the outermost organ, skin serves as a protective mechanism against physicochemical injury and sources of infection. Generally, young, well-moisturized skin is less susceptible to environmental effects, and itching and inflammation associated with the appearance of dry skin are less likely to occur. From research findings from my laboratory, dry skin is often caused by increased TEWL, decreased stratum corneum water content, decreased interkeratinocyte lipids and natural moisturizing factors, and decreased collagen. Moreover, the repair function of the skin tends to be delayed. In Japan, the aging population has increased, resulting in higher rates of skin disorders. In patients with dry skin, the efficacy and safety of transdermal preparations are enhanced by the application of moisturizers. However, the interactions between transdermal preparations and moisturizers are unclear. Further studies are needed to assess the timing of moisturizer application and the proper use of external preparations. The effects of daily diet and drugs on the skin should also be assessed.

The application of lidocaine-containing skin tape/patches is associated with skin damage and breakage. This problem has been evaluated in clinical practice, and researchers have shown that both in vivo and in vitro approaches, such as hydration and zinc supplementation, can prevent such skin disorders. However, the mechanisms cannot be easily verified in humans, and translational studies are still needed. Moreover, because the use of transdermal delivery systems has increased, reports of dermopathy have become more frequent, and greater skin damage is observed with the use of transdermal patches, particularly in patients with dry skin. Heparinoid treatment may alleviate these symptoms. Our experimental studies confirmed that dermopathy was elevated in patients who had transdermal patches applied, suggesting that inflammation should be carefully observed in patients with dry skin, such as elderly individuals. Furthermore, clinical research on the pre-application of moisturizing agents is needed to identify appropriate tape for transdermal delivery systems. Indeed, in studies in hairless mice, the use of moisturizers has been shown to increase blood concentrations of the treatment drug. However, the researchers concluded that skin care should be continued unless clinically problematic levels are observed.⁴²⁾

Itching due to dry skin has been observed in patients with varicose veins of the lower extremities, with distinct differences between men and women. However, no reports have investigated the relationships between dry skin and varicose veins of the lower extremities. Most studies of zinc supplementation have been performed in elderly individuals, and some of these reports have shown that zinc alleviates dry skin. Further work is needed to establish novel treatment strategies.

Organ inflammation, such as enteritis and arthritis, causes a decrease in skin barrier function. When applying external preparations to the skin, one should consider the relationship between the drugs and internal organs, and excess or deficiency of various factors inside and outside the body is related to skin barrier function. In future studies, researchers should expand their work to evaluate other conditions related to dry skin in order to further improve outcomes in these patients.

Acknowledgments

I would like to express my deep gratitude to Dr. Yasunori Morimoto of Josai University for assistance with this work. I would also like to thank the Master’s students in my laboratory who performed important research, as well as Dr. Yasushi Takai, Dr. Masataka Deguchi, Dr. Kenji Goto, and the Ph.D. students at Suzuka University of Medical Sciences. I also thank Dr. Satoshi Yokoyama and Dr. Keigo Nishida for cooperation with this work. Finally, I would like to express my thanks to Dr. Keiichi Hiramoto, who contributed to bridging clinical research and basic skin research.

Conflict of Interest

The author declares no conflict of interest.

Notes

This review of the author’s work was written by the author upon receiving the 44th Sato Memorial Domestic Award.

REFERENCES

• 1) Ya-Xian Z, Suetake T, Tagami H. Number of cell layers of the stratum corneum in normal skin—relationship to the anatomical location on the body, age, sex and physical parameters. Arch. Dermatol. Res., 291, 555–559 (1999).
• 2) Kobayashi H, Tagami H. Functional properties of the surface of the vermilion border of the lips are distinct from those of the facial skin. Br. J. Dermatol., 150, 563–567 (2004).
• 3) Ooi K, Sasaki H, Yoshizawa N, Sugawa T, Kimura S, Ueda H, Numajiri S, Kojima S, Katayama T, Mizutani Y, Morimoto Y. Influence of skin hydration on anesthetic effect of lidocaine tape in hemodialysis patients. Iryo Yakugaku, 34, 1011–1016 (2008).
• 4) Takai Y, Hiramoto K, Nishimura Y, Ooi K. Relationship between biochemical factors and skin symptoms in chronic venous disease. Arch. Dermatol. Res., 309, 253–258 (2017).
• 5) Miyake N, Okamoto M, Fukukawa T, Matsushita S, Sano M, Kurisu M, Iziri T, Tsutsumi H, Mitsuie T. Usefulness of lidocaine tape (Penles^®) for pain at time of puncture of blood access. Nihon Toseki Igakkai Zasshi, 29, 23–37 (1996).
• 6) Nakao M, Onji I. The optimum time interval for applying lidocaine containing adhesive tape is 6 to 8 hours for venipuncture pain relief. Masui, 46, 1368–1373 (1997).
• 7) Purdon CH, Azzi CG, Zhang J, Smith EW, Maibach HI. Penetration enhancement of transdermal delivery-current permutations and limitations. Crit. Rev. Ther. Drug Carrier Syst., 21, 97–132 (2004).
• 8) Yosipovitch G, Tur E, Morduchowicz G, Boner G. Skin surface pH, moisture, and pruritus in haemodialysis patients. Nephrol. Dial. Transplant., 8, 1129–1132 (1993).
• 9) Schwartz IF, Iaina A. Uraemic pruritus. Nephrol. Dial. Transplant., 14, 834–839 (1999).
• 10) Ostlere LS, Taylor C, Baillod R, Wright S. Relationship between pruritus, transepidermal water loss, and biochemical makers of renal itch in haemodialysis patients. Nephrol. Dial. Transplant., 9, 1302–1304 (1994).
• 11) Szepietowski JC, Sikora M, Kusztal M, Salomon J, Magott M, Szepietowski T. Uremic pruritus: a clinical study of maintenance hemodialysis patients. J. Dermatol., 29, 621–627 (2002).
• 12) Park TH, Park CH, Ha SK, Lee SH, Song KS, Lee HY, Han DS. Dry skin (xerosis) in patients undergoing maintenance haemodialysis: the role of decreased sweating oh the eccrine sweat gland. Nephrol. Dial. Transplant., 10, 2269–2273 (1995).
• 13) Kano T, Nakamura M, Hashiguchi A, Sadanaga M, Morioka T, Mishima M, Nakano M. Skin pretreatments for shortening onset of dermal patch anesthesia with 3% GA MHPh 2 Na–10% lidocaine gel mixture. Anesth. Analg., 75, 555–557 (1992).
• 14) Wallace MS, Ridgeway B, Jun E, Schulteis G, Rabussay D, Zhang L. Topical delivery of lidocaine in healthy volunteers by electroporation, electroincorporation, or iontophoresis: an evaluation of skin anesthesia. Reg. Anesth. Pain Med., 26, 229–238 (2001).
• 15) Tachibana K, Tachibana S. Use of ultrasound to enhance the local anesthetic effect of topically applied aqueous lidocaine. Anesthesiology, 78, 1091–1096 (1993).
• 16) Zempsky WT, Sullivan J, Paulson DM, Hoath SB. Evaluation of a low-dose lidocaine iontophoresis system for topical anesthesia in adults and children: a randomized, controlled trial. Clin. Ther., 26, 1110–1119 (2004).
• 17) Dick IP, Scott RC. Pig ear skin as an in vitro model for human skin permeability. J. Pharm. Pharmacol., 44, 640–645 (1992).
• 18) Björklund S, Engblom J, Thuresson K, Sparr E. Glycerol and urea can be used to increase skin permeability in reduced hydration condition. Eur. J. Pharm. Sci., 50, 638–645 (2013).
• 19) Maillard-Salin DG, Bécourt P, Couarraze G. A study of the adhesive-skin interface: correlation between adhesion and passage of a drug. Int. J. Pharm., 200, 121–126 (2000).
• 20) Takai Y, Hiramoto K, Nishimura Y, Ooi K. Sex differences of the inflammatory mediator level at the time of itch onset in patients with chronic venous disease. Yakugaku Zasshi, 138, 91–96 (2018).
• 21) Bartholomew JR, King T, Sahgal A, Vidimos AT. Varicose veins: newer, better treatments available. Cleve. Clin. J. Med., 72, 312–314, 319–321, 325–328 (2005).
• 22) Beebe-Dimmer JL, Pfeifer JR, Engle JS, Schottenfeld D. The epidemiology of chronic venous insufficiency and varicose veins. Ann. Epidemiol., 15, 175–184 (2005).
• 23) Bergan JJ, Schmid-Schonbein GW, Smith PDC, Nicolaides AN, Boisseau MR, Eklof B. Mechanisms of disease: chronic venous disease. N. Engl. J. Med., 355, 488–498 (2006).
• 24) Bradbury A, Evans C, Allan P, Lee A, Ruckley CV, Fowkes FG. What are the symptoms of varicose veins? Edinburgh vein study cross sectional population survey. BMJ, 318, 353–356 (1999).
• 25) Kinet JP. The high-affinity IgE receptor (Fc epsilon RI): from physiology to pathology. Annu. Rev. Immunol., 17, 931–972 (1999).
• 26) Snyder RJ. Venous leg ulcers in the elderly patient: associated stress, social support, and coping. Ostomy Wound Manage., 52, 58–66, 68 (2006).
• 27) Solomon S. POMC-derived peptides and their biological action. Ann. N. Y. Acad. Sci., 885, 22–40 (1999).
• 28) Hiramoto K, Homma T, Jikumaru M, Miyashita H, Sato EF, Inoue M. Fasting differentially modulates the immunological system: its mechanism and sex difference. J. Clin. Biochem. Nutr., 43, 75–81 (2008).
• 29) Urbach F, Forbes PD, Davies RE, Berger D. Cutaneous photobiology: past, present and future. J. Invest. Dermatol., 67, 209–224 (1976).
• 30) Zierau O, Zenclussen AC, Jensen F. Role of female sex hormones, estradiol and progesterone, in mast cell behavior. Front. Immunol., 3, 169 (2012).
• 31) Okuyama K, Hamanaka Y, Kawano T, Ohkawara Y, Takayanagi M, Kikuchi T, Ohno I. T cell subsets related with a sex difference in IL-5 production. Int. Arch. Allergy Immunol., 155 (Suppl. 1), 21–26 (2011).
• 32) Okuyama K, Kashimura T, Kawano T, Ohkawara Y, Takayanagi M, Kikuchi T, Ohno I. Higher sensitivity of male CD4+ T cells to suppressive effects of CD8+ T cells on IL-5 production compared to female CD4+ T cells. Int. Arch. Allergy Immunol., 158 (Suppl. 1), 35–41 (2012).
• 33) Verma-Gandhu M, Verdu EF, Bercik P, Blennerhassett PA, Al-Mutawaly N, Ghia JE, Collins SM. Visceral pain perception is determined by the duration of colitis and associated neuropeptide expression in the mouse. Gut, 56, 358–364 (2007).
• 34) Soumelis V, Reche PA, Kanzler H, Yuan W, Edward G, Homey B, Gilliet M, Ho S, Antonenko S, Lauerma A, Smith K, Gorman D, Zurawski S, Abrams J, Menon S, McClanahan T, de Waal-Malefyt Rd R, Bazan F, Kastelein RA, Liu YJ. Human epithelial cells trigger dendritic cell mediated allergic inflammation by producing TSLP. Nat. Immunol., 3, 673–680 (2002).
• 35) Hiramoto K, Yamate Y, Sato EF. The effects of ultraviolet eye irradiation on dextran sodium sulfate-induced ulcerative colitis in mice. Photochem. Photobiol., 92, 728–734 (2016).
• 36) Higurashi K, Iizuka N, Yoshimura H, Tanaka T, Nomoto S. Evaluation of colorimeteric method for zinc, using clinical chemistry analyzer. Biomedical Research on Trace Elements, 18, 380–385 (2007).
• 37) Ogawa Y, Kawamura T, Shimada S. Zinc and skin biology. Arch. Biochem. Biophys., 611, 113–119 (2016).
• 38) Chvapil M. Effect of zinc on cells and biomembranes. Med. Clin. North Am., 60, 799–812 (1976).
• 39) The Japanese Society of Clinical Nutrition. “Practice guideline for zinc deficiency.”: ‹http://jscn.gr.jp/pdf/aen2018.pdf›, accessed 8 September, 2019.
• 40) Okada R, Matukawa K, Kobayashi T, Miyakoshi Y. Seasonal changes in water content of the forearm skin (stratum corneum). Jpn. J. Biometeor., 52, 131–137 (2015).
• 41) Deguchi M, Jose H, Nishida K, Ooi K. Transepidermal water loss (TEWL)-decreasing effect by administration of zinc in the elderly people. Yakugaku Zasshi, 140, 313–318 (2020).
• 42) Murakami Y, Nagae H, Maehori N, Sekijima H, Ooi K. Combination of oxybutynin transdermal patch and heparinoid cream for long-term treatment of overactive bladder in elderly patients. Dermatology Aspects, 6, 1 (2018).