The Open Dermatology Journal




ISSN: 1874-3722 ― Volume 12, 2018
REVIEW ARTICLE

Reexamination of Treatment of Seborrheic Keratosis Given Availability of New Prescription Therapy With Hydrogen Peroxide



Korina Gaishauser1, *, Craig G. Burkhart2
1 The University of Toledo College of Medicine, 2534 W. Village, OH 43614, Toledo, United States
2 Medical University of Ohio, University of Toledo College of Medicine, Ohio University College of Osteopathic Medicine, Columbus, United States

Abstract

Seborrheic Keratoses (SKs) are one of the most common dermatologic lesions seen by dermatologists. They are biologically benign and do not usually require removal for medical reasons; however, many patients choose removal due to cosmetic preferences. Currently, cryotherapy (liquid nitrogen spray) is the most common mode of removal [1]. Although patients often desire an effective topical treatment, few have been developed that rival the effects of cryotherapy. This article aims to review current available topical treatments, with a particular focus on both the benefits and potential pitfalls of a novel treatment, concentrated Hydrogen Peroxide (H2O2).

Keywords: SK, Hydrogen peroxide, Cryotherapy, Dermatologic lesions, Topical treatments, Epidermal tumor.


Article Information


Identifiers and Pagination:

Year: 2018
Volume: 12
First Page: 86
Last Page: 89
Publisher Id: TODJ-12-86
DOI: 10.2174/1874372201812010086

Article History:

Received Date: 10/7/2018
Revision Received Date: 2/9/2018
Acceptance Date: 15/9/2018
Electronic publication date: 17/10/2018
Collection year: 2018

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© 2018 Gaishauser and Burkhart.

open-access license: This is an open access article distributed under the terms of the Creative Commons Attribution 4.0 International Public License (CC-BY 4.0), a copy of which is available at: (https://creativecommons.org/licenses/by/4.0/legalcode). This license permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


* Address correspondence to this author at the The University of Toledo College of Medicine, 2534 W. Village, OH 43614, Toledo, United States, Tel: 330-421-2393; E-mail: korina.gaishauser@rockets.utoledo.edu




1. INTRODUCTION

Seborrheic Keratosis (SK) is one of the most common benign epidermal tumors seen by dermatologists. SKs affect men and women equally, and usually arise in patients over the age of 50 years old [1Jackson JM, Alexis A, Berman B, Berson DS, Taylor S, Weiss JS. Current understanding of seborrheic keratosis: Prevalence, etiology, clinical presentation, diagnosis, and management. J Drugs Dermatol 2015; 14(10): 1119-25.[PMID: 26461823] , 2Roh NK, Hahn HJ, Lee YW, Choe YB, Ahn KJ. Clinical and histopathological investigation of seborrheic keratosis. Ann Dermatol 2016; 28(2): 152. Mar 31]. SKs are composed of an accumulation of senescent epidermal cells that have been arrested in the G1 phase of the cell cycle. Apoptosis of these cells is inhibited by p16 (a cyclin-dependent kinase inhibitor) which is overexpressed in all SK lesions [3Nakamura S, Nishioka K. Enhanced expression of p16 in seborrhoeic keratosis; A lesion of accumulated senescent epidermal cells in G1 arrest. Br J Dermatol 2003; 149(3): 560-5.[http://dx.doi.org/10.1046/j.1365-2133.2003.05589.x] [PMID: 14510989] ]. They typically present as well demarcated, slightly elevated patches or plaques that range in color from flesh-toned to gray, brown, or black [1Jackson JM, Alexis A, Berman B, Berson DS, Taylor S, Weiss JS. Current understanding of seborrheic keratosis: Prevalence, etiology, clinical presentation, diagnosis, and management. J Drugs Dermatol 2015; 14(10): 1119-25.[PMID: 26461823] , 2Roh NK, Hahn HJ, Lee YW, Choe YB, Ahn KJ. Clinical and histopathological investigation of seborrheic keratosis. Ann Dermatol 2016; 28(2): 152. Mar 31].

Variation in this presentation does exist, and may suggest a variety of benign or malignant lesions, or inflammatory eruptions. According to a 2014 United States Survey involving 594 practicing, board-certified dermatologists, 43% of patients with SKs decide to undergo removal of the lesions. Upon consideration for removal, it is suggested that the lesions are first categorized as of either cosmetic or medical concern [4Ranasinghe GC, Friedman AJ. Managing seborrheic keratoses: Evolving strategies for optimizing patient outcomes. J Drugs Dermatol 2017; 16(11): 1064-8.[PMID: 29141054] ]. Biologically benign, removal of SKs is not warranted unless histological confirmation indicates otherwise, or the lesions become pruritic, erythematic, or otherwise an irritant to the patient. Of notable concern is Leser-Trélat, a paraneoplastic sign characterized by a sudden appearance and/or increase in the number of SKs [5Ngan V. Derm net new zealand internet Sign of Leser-Trélat DermNet New Zealand Available from: 2004. 2004 [cited 2017 Dec 30].https://www.dermnetnz.org/topics/ sign-of-leser-trelat/]. Leser-Trélat may be an indicator of stomach, ovary, uterus, or breast carcinomas, and in other rare cases an indicator of bladder, lung, or larynx carcinomas [6Stollmeier A, Rosario BA, Mayer BL, Frandoloso GA, Magalhães FLGM, Marques GL. Seborrheic keratoses as the first sign of bladder carcinoma: Case report of leser-trélat sign in a rare Association with urinary tract cancer. Case Rep Med 2016; 2016: 4259190.[http://dx.doi.org/10.1155/2016/4259190] [PMID: 27999595] , 7Nyati A, Kalwaniya S, Jain S, Soni B. Sign of leser-trélat in association with laryngeal carcinoma. Indian J Dermatol Venereol Leprol 2016; 82(1): 112.[http://dx.doi.org/10.4103/0378-6323.164222] [PMID: 26728838] ].

Thus, if the lesions undergo any abnormal or sudden change in shape or size, inflammatory changes occur, acute symptoms arise, etc. then the concern for malignancy is high and removal is indicated [1Jackson JM, Alexis A, Berman B, Berson DS, Taylor S, Weiss JS. Current understanding of seborrheic keratosis: Prevalence, etiology, clinical presentation, diagnosis, and management. J Drugs Dermatol 2015; 14(10): 1119-25.[PMID: 26461823] ]. A majority of the time, however, removal is not indicated and treatment is completed for cosmetic purposes.

2. CURRENT TOPICAL TREATMENTS

When treatment is either indicated or desired, the preferred first line of treatment is cryotherapy, using liquid nitrogen spray. In a pilot study of 25 people by Wood et. all, 60% of patients preferred cryotherapy to curettage when it came to the removal of their SKs [8Wood LD, Stucki JK, Hollenbeak CS, Miller JJ. Effectiveness of cryosurgery vs curettage in the treatment of seborrheic keratoses. JAMA Dermatol 2013; 149(1): 108-9.[http://dx.doi.org/10.1001/2013.jamadermatol.275] [PMID: 23324775] ]. However, cryotherapy is not without its downfalls: in the same study, SKs treated with cryotherapy were more likely to have leftover lesions. There is also an array of topical treatments, although the literature on most is limited and the proven efficacy of most leaves much to be desired.

Topical keratolytics are often used for SKs, although the FDA has still not approved any of these treatments [1Jackson JM, Alexis A, Berman B, Berson DS, Taylor S, Weiss JS. Current understanding of seborrheic keratosis: Prevalence, etiology, clinical presentation, diagnosis, and management. J Drugs Dermatol 2015; 14(10): 1119-25.[PMID: 26461823] ]. The most notable and perhaps the best-documented keratolytic is 0.1% tazarotene. Tazarotene exerts its effects by targeting and binding retinoic acid receptors beta and gamma, and thus leads to a decrease in proliferation of SK cells as well as a decrease in inflammatory markers [9Foster RH, Brogden RN, Benfield P. Tazarotene. Drugs 1998; 55(5): 705-11.[http://dx.doi.org/10.2165/00003495-199855050-00008] [PMID: 9585866] ]. In a small study of 15 subjects, it was shown that twice-daily application of 0.1% tazarotene cream caused SKs to be indistinguishable from the normal skin at the end of 6 months of treatment. All patients who responded to this treatment determined the topical treatment to be satisfactory, and wished to continue treatment with tazarotene in the future [10Herron MD, Bowen AR, Krueger GG. Seborrheic keratoses: A study comparing the standard cryosurgery with topical calcipotriene, topical tazarotene, and topical imiquimod. Int J Dermatol 2004; 43(4): 300-2.[http://dx.doi.org/10.1111/j.1365-4632.2004.02282.x] [PMID: 15090020] ]. Tazarotene cream has also proved to be relatively effective in the treatment of plaque psoriasis in clinical trials, as well as reducing lesions in patients with mild to moderate facial acne. However, it is contraindicated in patients that are pregnant or plan to become pregnant [9Foster RH, Brogden RN, Benfield P. Tazarotene. Drugs 1998; 55(5): 705-11.[http://dx.doi.org/10.2165/00003495-199855050-00008] [PMID: 9585866] ].

Vitamin D analogs have also been shown to have some efficacy against SKs [10Herron MD, Bowen AR, Krueger GG. Seborrheic keratoses: A study comparing the standard cryosurgery with topical calcipotriene, topical tazarotene, and topical imiquimod. Int J Dermatol 2004; 43(4): 300-2.[http://dx.doi.org/10.1111/j.1365-4632.2004.02282.x] [PMID: 15090020] , 11Mitsuhashi Y, Kawaguchi M, Hozumi Y, Kondo S. Topical vitamin D3 is effective in treating senile warts possibly by inducing apoptosis. J Dermatol 2005; 32(6): 420-3.[http://dx.doi.org/10.1111/j.1346-8138.2005.tb00772.x] [PMID: 16043912] ]. Vitamin D is present in the epidermis, and ligand-dependent Vitamin D Receptor (VDR) has been shown to play a role in keratinocyte differentiation and proliferation. VDR deficiency has been linked to a hyperproliferative response in the epidermis. Therefore, treatment with Vitamin D ligand can reverse these effects and slow proliferation [12Lư’ơ’ng Kv, Nguyễn LTH. The roles of vitamin D in seborrhoeic keratosis: Possible genetic and cellular signalling mechanisms. Int J Cosmet Sci 2013; 35(6): 525-31.[http://dx.doi.org/10.1111/ics.12080] [PMID: 23859137] ]. During one clinical study [12Lư’ơ’ng Kv, Nguyễn LTH. The roles of vitamin D in seborrhoeic keratosis: Possible genetic and cellular signalling mechanisms. Int J Cosmet Sci 2013; 35(6): 525-31.[http://dx.doi.org/10.1111/ics.12080] [PMID: 23859137] ], 116 patients with SKs were treated from 3-12 months with Vitamin D analogs (tacalcitol, calcipotriol, or maxacalcitol). After treatment, 30.2% of patients saw either complete disappearance or at least 80% reduction in the volume of their SKs, and 46.4% saw a reduction in volume between 40 and 80%. In a second study, however, calcipotriol did not result in clinical improvement and thus the results of using these Vitamin D analogs are not clear [10Herron MD, Bowen AR, Krueger GG. Seborrheic keratoses: A study comparing the standard cryosurgery with topical calcipotriene, topical tazarotene, and topical imiquimod. Int J Dermatol 2004; 43(4): 300-2.[http://dx.doi.org/10.1111/j.1365-4632.2004.02282.x] [PMID: 15090020] ].

Another viable option for treatment of SKs is 50% urea. Urea works as a keratolytic by disrupting non-covalent interactions and partially unfolding proteins, therefore loosening the outermost layers of the SKs. Subsequent scraping of lesions may allow enough removal to show cosmetically pleasing results [13Burkhart CG, Burkhart CN. Use of a keratolytic agent with occlusion for topical treatment of hyperkeratotic seborrheic keratoses. Skinmed 2008; 7(1): 15-8.[http://dx.doi.org/10.1111/j.1540-9740.2007.07221.x] [PMID: 18174808] ]. A pilot study of 20 subjects conducted by Burkhart & Burkhart [13Burkhart CG, Burkhart CN. Use of a keratolytic agent with occlusion for topical treatment of hyperkeratotic seborrheic keratoses. Skinmed 2008; 7(1): 15-8.[http://dx.doi.org/10.1111/j.1540-9740.2007.07221.x] [PMID: 18174808] ] instructed patients to apply 50% urea ointment once daily and then cover it with a bandage. They were also instructed to scrape the surface of the lesion once or twice a week for 6 weeks. Patient satisfaction after this trial was rated on a scale of 1-10. The survey was significant for reduction in the lesion’s thickness, which was rated 7.4 /10 upon completion of the trial. Also of note, patients rated their desire to continue using the topical product as an 8.3/10 [13Burkhart CG, Burkhart CN. Use of a keratolytic agent with occlusion for topical treatment of hyperkeratotic seborrheic keratoses. Skinmed 2008; 7(1): 15-8.[http://dx.doi.org/10.1111/j.1540-9740.2007.07221.x] [PMID: 18174808] ].

Benzoyl peroxide in combination with a tertiary amine is another treatment for SK that has limited reports on its efficacy, although topical benzoyl peroxide has historically been an effective treatment for acne [14Burkhart CN, Specht K, Neckers D. Synergistic activity of benzoyl peroxide and erythromycin. Skin Pharmacol Appl Skin Physiol 2000; 13(5): 292-6.[http://dx.doi.org/10.1159/000029936] [PMID: 10940820] ]. Tertiary amines have previously been shown to increase the radical formation of benzoyl peroxide, and therefore make it more effective as a topical treatment [14Burkhart CN, Specht K, Neckers D. Synergistic activity of benzoyl peroxide and erythromycin. Skin Pharmacol Appl Skin Physiol 2000; 13(5): 292-6.[http://dx.doi.org/10.1159/000029936] [PMID: 10940820] ]. In a small study conducted by Burkhart [15Burkhart CG. The search for topical treatments for seborrheic keratoses continues. Int J Dermatol 2006; 45(9): 1110.[http://dx.doi.org/10.1111/j.1365-4632.2006.02442.x] [PMID: 16961526] ], 8 patients with SKs greater in size than 2 cm and 0.3 cm in thickness were treated with benzoyl peroxide daily in addition to topical terbinafine (containing a tertiary amine), and then instructed to cover the lesion with a bandage. Four months into this treatment, none of the patients showed complete clearance of their lesion, but there was a reduction in the size of their SKs. The biggest change was a 50% reduction in size [15Burkhart CG. The search for topical treatments for seborrheic keratoses continues. Int J Dermatol 2006; 45(9): 1110.[http://dx.doi.org/10.1111/j.1365-4632.2006.02442.x] [PMID: 16961526] ]. While this study showed variable results, the large size of the SKs may have hindered success in such a short amount of time. More studies on benzoyl peroxide in combination with a tertiary amine are needed before judgment is made on the efficacy of this treatment [15Burkhart CG. The search for topical treatments for seborrheic keratoses continues. Int J Dermatol 2006; 45(9): 1110.[http://dx.doi.org/10.1111/j.1365-4632.2006.02442.x] [PMID: 16961526] ].

3. TOPICAL CONCENTRATED HYDROGEN PEROXIDE

Highly concentrated Hydrogen Peroxide (H2O2) has recently been indicated as a feasible treatment for SK. Hydrogen peroxide is a highly reactive species, and even localized concentrations must be carefully controlled. The oxidizing power of H2O2 can generate reactive oxygen species (ROS) that directly damage the mutated SK cells, ultimately resulting in apoptosis and necrosis of the SK [16Dubois JC, Jarratt M, Beger BB, Bradshaw M, Powala CV, Shanler SD. A-101, a proprietary topical formulation of high-concentration hydrogen peroxide solution. Dermatol Surg 2017; 0: 1-11.[http://dx.doi.org/10.1097/DSS.0000000000001302] [PMID: 28902028] ]. Clearly, the danger in this method is having the ability to carefully and precisely control the ROS in order to minimize damage to healthy, normal skin around the abnormal lesions. Currently, the most common concentrations of H2O2 available to the public are 3% and 30% [17Romantsova OV, Ulybin VB. Safety issues of high-concentrated hydrogen peroxide production used as rocket propellant. Acta Astronaut 2015; 109: 231-4.[http://dx.doi.org/10.1016/j.actaastro.2014.10.022] ]. It is possible to purchase these concentrations of H2O2 on websites such as e-bay and Amazon. A major concern is that if 35-40% H2O2 becomes a common-place treatment for SKs, non-physicians may try to self-medicate in order to save time or money by using similar concentrations available for purchase online. Untrained individuals using topical concentrated hydrogen peroxide could result in irreparable damage.

In a multicenter, double-blind, study by DuBois et al. [16Dubois JC, Jarratt M, Beger BB, Bradshaw M, Powala CV, Shanler SD. A-101, a proprietary topical formulation of high-concentration hydrogen peroxide solution. Dermatol Surg 2017; 0: 1-11.[http://dx.doi.org/10.1097/DSS.0000000000001302] [PMID: 28902028] ], 119 subjects were placed into three treatment groups: A-101 40% solution, A-101 32.5% solution, or vehicle solution (control). A-101 is a topical, highly concentrated solution of H2O2. The solutions were applied to the target lesion (in this particular study, all lesions were on the face) at Days 1 and 22 of the study, unless a second treatment was contraindicated. Three scales were used to determine the efficacy of the solutions: Physician’s Lesion Assessment (PLA), Subject’s Self Assessment (SSA), and Local Skin Reaction (LSR) Assessment. On day 106, patients’ lesions were measured and graded appropriately. Results showed a mean reduction in PLA by 1.7 for A-101 40%, 1.4 for A-101 32.5%, and 0.1 for the vehicle alone. In addition, 68%, 62%, and 5% of subjects, respectively, had lesions that were judged as “clear” or “near clear” on Day 106 [16Dubois JC, Jarratt M, Beger BB, Bradshaw M, Powala CV, Shanler SD. A-101, a proprietary topical formulation of high-concentration hydrogen peroxide solution. Dermatol Surg 2017; 0: 1-11.[http://dx.doi.org/10.1097/DSS.0000000000001302] [PMID: 28902028] ].

Concentrated liquid hydrogen peroxide is not widely used at the moment, and for good reason. In a law enforcement training article [18Hydrogen peroxide bomb - law enforcement training article Internet Blue Sheepdog Available from [cited 2017 Dec 26]http://www.bluesheepdog.com/ hydrogen-peroxide-bomb/], it is described how liquid bombs can be made from concentrated H2O2 in combination with acetone or ethanol, and even less conspicuous compounds such as black pepper or sugary drink powders [18Hydrogen peroxide bomb - law enforcement training article Internet Blue Sheepdog Available from [cited 2017 Dec 26]http://www.bluesheepdog.com/ hydrogen-peroxide-bomb/]. This method has been used in several terrorist attacks, most notably the attack on the London transit system in 2005. In 2006, liquid concentrated hydrogen peroxide bombs were created with the intention of blowing up several airplanes, but this attack was stopped [18Hydrogen peroxide bomb - law enforcement training article Internet Blue Sheepdog Available from [cited 2017 Dec 26]http://www.bluesheepdog.com/ hydrogen-peroxide-bomb/].

Solid hydrogen peroxide bombs can also be created from a liquid concentrated hydrogen peroxide base. Solid hydrogen peroxide bombs are much more unstable and dangerous to handle than their liquid counterpart [18Hydrogen peroxide bomb - law enforcement training article Internet Blue Sheepdog Available from [cited 2017 Dec 26]http://www.bluesheepdog.com/ hydrogen-peroxide-bomb/]. They have also been used in a variety of attempted attacks, including one solid hydrogen peroxide bomb that detonated early outside of a University of Oklahoma football game in 2005, killing the student carrying it [18Hydrogen peroxide bomb - law enforcement training article Internet Blue Sheepdog Available from [cited 2017 Dec 26]http://www.bluesheepdog.com/ hydrogen-peroxide-bomb/].

In addition, concentrated hydrogen peroxide has recently been utilized as a new way to produce rocket propellant [17Romantsova OV, Ulybin VB. Safety issues of high-concentrated hydrogen peroxide production used as rocket propellant. Acta Astronaut 2015; 109: 231-4.[http://dx.doi.org/10.1016/j.actaastro.2014.10.022] ]. However, the H2O2 used for fuel must be concentrated to 90% or higher to eliminate deleterious side effects such as decomposition upon contact with various surfaces. This highly concentrated hydrogen peroxide is made in three steps: isopropyl alcohol autoxidation, hydrogen peroxide extraction, and acetone extraction. In addition to these main three steps, there are concurrent steps that lead to the explosive nature of H2O2, so this process must be very carefully controlled [19Hydrogen Peroxide. Funk & Wagnalls New World Encyclopedia [serial on the Internet]. 1. Available from: Funk & Wagnalls New World Encyclopedia. (2017), [cited December 20, 2017]:].

Taking all of this into consideration, while concentrated hydrogen peroxide may at first brush seem like an easy and reasonable topical fix for SKs, much more thought must go into employing proper safety measures before the topical is released in prescription form or even widely used by physicians. Even a small amount of this solution ending up in the wrong hands or non-physicians hoping to self medicate could have tragic repercussions.

CONCLUSION

Seborrheic Keratosis (SK) is one of the most common lesions in older patients, and dermatologists are particularly skilled at diagnosing and treating them. SKs do not normally need to be removed for biological reasons, but they should be monitored closely for any changes that may suggest malignancy. Topical treatments for SKs have historically varied in their efficacy and desirable results. There are still no FDA approved topical treatments, although many have been used with a spectrum of outcomes. Recently, concentrated hydrogen peroxide has been proven to be a fierce competitor in the race to find a topical treatment for SKs. Of notable concern, however, is the use of concentrated hydrogen peroxide to make liquid bombs, solid bombs, and rocket propellant. This treatment still has a long way to go in order to be deemed safe and effective for all to use, but hopefully, subsequent studies will continue to produce evidence that H2O2 can be an effective first-line treatment for SK.

CONSENT FOR PUBLICATION

Not applicable.

CONFLICT OF INTEREST

The authors declare no conflict of interest, financial or otherwise.

ACKNOWLEDGEMENTS

Declared none.

REFERENCES

[1] Jackson JM, Alexis A, Berman B, Berson DS, Taylor S, Weiss JS. Current understanding of seborrheic keratosis: Prevalence, etiology, clinical presentation, diagnosis, and management. J Drugs Dermatol 2015; 14(10): 1119-25.[PMID: 26461823]
[2] Roh NK, Hahn HJ, Lee YW, Choe YB, Ahn KJ. Clinical and histopathological investigation of seborrheic keratosis. Ann Dermatol 2016; 28(2): 152. Mar 31
[3] Nakamura S, Nishioka K. Enhanced expression of p16 in seborrhoeic keratosis; A lesion of accumulated senescent epidermal cells in G1 arrest. Br J Dermatol 2003; 149(3): 560-5.[http://dx.doi.org/10.1046/j.1365-2133.2003.05589.x] [PMID: 14510989]
[4] Ranasinghe GC, Friedman AJ. Managing seborrheic keratoses: Evolving strategies for optimizing patient outcomes. J Drugs Dermatol 2017; 16(11): 1064-8.[PMID: 29141054]
[5] Ngan V. Derm net new zealand internet Sign of Leser-Trélat DermNet New Zealand Available from: 2004. 2004 [cited 2017 Dec 30].https://www.dermnetnz.org/topics/ sign-of-leser-trelat/
[6] Stollmeier A, Rosario BA, Mayer BL, Frandoloso GA, Magalhães FLGM, Marques GL. Seborrheic keratoses as the first sign of bladder carcinoma: Case report of leser-trélat sign in a rare Association with urinary tract cancer. Case Rep Med 2016; 2016: 4259190.[http://dx.doi.org/10.1155/2016/4259190] [PMID: 27999595]
[7] Nyati A, Kalwaniya S, Jain S, Soni B. Sign of leser-trélat in association with laryngeal carcinoma. Indian J Dermatol Venereol Leprol 2016; 82(1): 112.[http://dx.doi.org/10.4103/0378-6323.164222] [PMID: 26728838]
[8] Wood LD, Stucki JK, Hollenbeak CS, Miller JJ. Effectiveness of cryosurgery vs curettage in the treatment of seborrheic keratoses. JAMA Dermatol 2013; 149(1): 108-9.[http://dx.doi.org/10.1001/2013.jamadermatol.275] [PMID: 23324775]
[9] Foster RH, Brogden RN, Benfield P. Tazarotene. Drugs 1998; 55(5): 705-11.[http://dx.doi.org/10.2165/00003495-199855050-00008] [PMID: 9585866]
[10] Herron MD, Bowen AR, Krueger GG. Seborrheic keratoses: A study comparing the standard cryosurgery with topical calcipotriene, topical tazarotene, and topical imiquimod. Int J Dermatol 2004; 43(4): 300-2.[http://dx.doi.org/10.1111/j.1365-4632.2004.02282.x] [PMID: 15090020]
[11] Mitsuhashi Y, Kawaguchi M, Hozumi Y, Kondo S. Topical vitamin D3 is effective in treating senile warts possibly by inducing apoptosis. J Dermatol 2005; 32(6): 420-3.[http://dx.doi.org/10.1111/j.1346-8138.2005.tb00772.x] [PMID: 16043912]
[12] Lư’ơ’ng Kv, Nguyễn LTH. The roles of vitamin D in seborrhoeic keratosis: Possible genetic and cellular signalling mechanisms. Int J Cosmet Sci 2013; 35(6): 525-31.[http://dx.doi.org/10.1111/ics.12080] [PMID: 23859137]
[13] Burkhart CG, Burkhart CN. Use of a keratolytic agent with occlusion for topical treatment of hyperkeratotic seborrheic keratoses. Skinmed 2008; 7(1): 15-8.[http://dx.doi.org/10.1111/j.1540-9740.2007.07221.x] [PMID: 18174808]
[14] Burkhart CN, Specht K, Neckers D. Synergistic activity of benzoyl peroxide and erythromycin. Skin Pharmacol Appl Skin Physiol 2000; 13(5): 292-6.[http://dx.doi.org/10.1159/000029936] [PMID: 10940820]
[15] Burkhart CG. The search for topical treatments for seborrheic keratoses continues. Int J Dermatol 2006; 45(9): 1110.[http://dx.doi.org/10.1111/j.1365-4632.2006.02442.x] [PMID: 16961526]
[16] Dubois JC, Jarratt M, Beger BB, Bradshaw M, Powala CV, Shanler SD. A-101, a proprietary topical formulation of high-concentration hydrogen peroxide solution. Dermatol Surg 2017; 0: 1-11.[http://dx.doi.org/10.1097/DSS.0000000000001302] [PMID: 28902028]
[17] Romantsova OV, Ulybin VB. Safety issues of high-concentrated hydrogen peroxide production used as rocket propellant. Acta Astronaut 2015; 109: 231-4.[http://dx.doi.org/10.1016/j.actaastro.2014.10.022]
[18] Hydrogen peroxide bomb - law enforcement training article Internet Blue Sheepdog Available from [cited 2017 Dec 26]http://www.bluesheepdog.com/ hydrogen-peroxide-bomb/
[19] Hydrogen Peroxide. Funk & Wagnalls New World Encyclopedia [serial on the Internet]. 1. Available from: Funk & Wagnalls New World Encyclopedia. (2017), [cited December 20, 2017]:

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(Almac Sciences, Northern Ireland)

"In principle, all scientific journals should have open access, as should be science itself. Open access journals are very helpful for students, researchers and the general public including people from institutions which do not have library or cannot afford to subscribe scientific journals. The articles are high standard and cover a wide area."


Hubert Wolterbeek
(Delft University of Technology, The Netherlands)

"The widest possible diffusion of information is critical for the advancement of science. In this perspective, open access journals are instrumental in fostering researches and achievements."


Alessandro Laviano
(Sapienza - University of Rome, Italy)

"Open access journals are very useful for all scientists as they can have quick information in the different fields of science."


Philippe Hernigou
(Paris University, France)

"There are many scientists who can not afford the rather expensive subscriptions to scientific journals. Open access journals offer a good alternative for free access to good quality scientific information."


Fidel Toldrá
(Instituto de Agroquimica y Tecnologia de Alimentos, Spain)

"Open access journals have become a fundamental tool for students, researchers, patients and the general public. Many people from institutions which do not have library or cannot afford to subscribe scientific journals benefit of them on a daily basis. The articles are among the best and cover most scientific areas."


M. Bendandi
(University Clinic of Navarre, Spain)

"These journals provide researchers with a platform for rapid, open access scientific communication. The articles are of high quality and broad scope."


Peter Chiba
(University of Vienna, Austria)

"Open access journals are probably one of the most important contributions to promote and diffuse science worldwide."


Jaime Sampaio
(University of Trás-os-Montes e Alto Douro, Portugal)

"Open access journals make up a new and rather revolutionary way to scientific publication. This option opens several quite interesting possibilities to disseminate openly and freely new knowledge and even to facilitate interpersonal communication among scientists."


Eduardo A. Castro
(INIFTA, Argentina)

"Open access journals are freely available online throughout the world, for you to read, download, copy, distribute, and use. The articles published in the open access journals are high quality and cover a wide range of fields."


Kenji Hashimoto
(Chiba University, Japan)

"Open Access journals offer an innovative and efficient way of publication for academics and professionals in a wide range of disciplines. The papers published are of high quality after rigorous peer review and they are Indexed in: major international databases. I read Open Access journals to keep abreast of the recent development in my field of study."


Daniel Shek
(Chinese University of Hong Kong, Hong Kong)

"It is a modern trend for publishers to establish open access journals. Researchers, faculty members, and students will be greatly benefited by the new journals of Bentham Science Publishers Ltd. in this category."


Jih Ru Hwu
(National Central University, Taiwan)


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