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Dermatology Online Journal

Title
Urea: a comprehensive review of the clinical literature

Permalink
https://escholarship.org/uc/item/11x463rp

Journal
Dermatology Online Journal, 19(11)

Authors
Pan, Michael
Heinecke, Gillian
Bernardo, Sebastian
et al.

Publication Date
2013

License
CC BY-NC-ND 4.0

Peer reviewed

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University of California
 Volume 19 Number 11
November 2013
Review
Urea: a comprehensive review of the clinical literature
Michael Pan BA, Gillian Heinecke MD, Sebastian Bernardo MD, Cindy Tsui, and Jacob Levitt MD
Dermatology Online Journal 19 (11): 1
Icahn School of Medicine at Mount Sinai, Department of Dermatology, New York, New York
Correspondence:
Jacob Levitt, MD
Department of Dermatology
5 East 98th Street
5th Floor, Box 1048
New York, NY 10029
Tel: 914-661-1726
Fax: 212-987-1197
Email: jacoblevittmd@gmail.com

Abstract
Introduction: Urea is an organic compound that has been used clinically for dermatological diseases for more than a century. Urea
is a potent emollient and keratolytic agent, making urea an effective monotherapy for conditions associated with dry and scaly
skin. A systematic review of the literature is needed to provide clinicians with evidence-based applications of urea in the treatment
of dermatological diseases.

Methods: A PubMed search was conducted using the term “urea” combined with “skin,” “ichthyosis,” “psoriasis,” “xerosis,”
“emollient,” “onychomycosis,” “dermatitis,” and “avulsion.” A total of 81 publications met inclusion criteria and were evaluated.
Treatment indication(s), test agents, number of subjects, treatment protocols, results, and side effects were recorded.

Results: Effective treatment with urea has been reported for the following conditions: ichthyosis, xerosis, atopic
dermatitis/eczema, contact dermatitis, radiation induced dermatitis, psoriasis/seborrheic dermatitis, onychomycosis, tinea pedis,
keratosis, pruritus, and dystrophic nails. Furthermore, urea has been used with other medications as a penetration enhancing agent.
Mild irritation is the most common adverse event, proving urea to be a safe and tolerable topical drug without systemic toxicity.

Discussion/Conclusion: Urea is a safe, effective dermatologic therapy with wide-ranging clinical utility and minimal, non-
systemic side effects. In order to optimize patient care, dermatologists should be well informed with regards to urea’s indications
and efficacy.

Keywords: urea, ichthyosis, xerosis, dermatitis, eczema, psoriasis, onychomycosis, pruritus, tinea pedis, avulsion

Introduction
The efficacy and safety of urea in the treatment of skin diseases has been reported for more than a century. Urea is an organic
compound chemically structured as a carbonyl group attached to two amine residues. Physiologically, urea plays an important role
in the metabolism and excretion of nitrogen-containing products. Since it was first described, a substantial and evolving literature
has been established describing its therapeutic role in the treatment of a myriad of dermatologic conditions. Urea has been
employed as a proteolytic agent for wound debridement as well as a topical bacteriostatic agent in wounds [1–4]. As far back as
1957, urea was viewed as an old, forgotten therapy when Kligman wrote, “it sometimes happens in the enthusiastic search for new
therapeutic agents that some old stand-by has been overlooked, whose luster has worn off, but which none the less may have some
useful application in moments when the miracle drugs falter. In the world of topical therapy, urea is such a drug [5].” We seek to
reacquaint the medical community with the versatile clinical applications of urea by conducting a systematic review of the
literature and summarizing published findings examining the efficacy of urea in treating dermatological conditions.
Current labeling of urea products includes indications for: (1) debridement and promotion of normal healing of hyperkeratotic
surface lesions, particularly where healing is retarded by local infection, necrotic tissue, fibrinous or purulent debris, or eschar; (2)
hyperkeratotic conditions such as dry, rough skin, dermatitis, psoriasis, xerosis, ichthyosis, eczema, keratosis, keratosis pilaris,
keratosis palmaris, keratoderma, corns, and calluses; and (3) damaged, ingrown, and devitalized nails [6–12]. Although the
mechanism of action of urea in skin is still unknown, studies suggest that the keratolytic and hydrating effects of topical urea is
owing to breakage of hydrogen bonds in the stratum corneum, loosening epidermal keratin, and increasing water-binding sites
[13]. Commercially available products containing prescription-grade urea concentrations are listed in Table 1 [6–12].

Table 1. Common commercially available prescription-grade urea products

Trade Name Manufacturer* Formulation Vehicle

Carmol 40[6] Doak Dermatologics 40% urea Lotion, cream, or gel
U-Kera E[7] TaroPharma 40% urea Emollient cream
Urealac[8] Hi-Tech Pharmacal Co. 50% urea Topical suspension with lactic acid and salicyclic acid
Umecta[9] Innocutis 40% urea Emulsion, topical suspension, nail film suspension
with applicator, or mousse
Vanamide[10] Dermik Laboratories 40% urea Cream
Kerol[11] Doak Dermatologics 50% urea Emulsion in zinc undecylenate and lactic acid
RE U40[12] River’s Edge 40% urea Foam

*Manufacturer may differ

Methods
A PubMed search was conducted from inception to December 2011 using the term “urea” combined with “skin,” “ichthyosis,”
“psoriasis,” “xerosis,” “emollient,” “onychomycosis,” “dermatitis,” and “avulsion.” The search results were reviewed for clinical
trials, case reports, and case series examining the usage and efficacy of urea to treat dermatologic conditions. Additional articles
were identified within the citations of qualifying publications that met inclusion criteria but were not returned in the initial
PubMed search. The following information was recorded from these publications: the dermatologic condition being studied, test
agents, number of subjects, treatment protocol, results, and side-effect profile.

Results
We obtained and reviewed 284 articles on urea therapies. Of these articles, 81 met our criteria of: 1) being a clinical study, case
series or case report, 2) having urea as one of the experimental agents, and 3) describing a dermatological application for urea.
The articles were then categorized by treatment for the following conditions: ichthyosis (11 articles), hydration of xerotic/healthy
skin (14 articles), atopic dermatitis/eczema (10 articles), contact dermatitis (1 article), radiation-induced dermatitis (1 article),
psoriasis/seborrheic dermatitis (14 articles), onychomycosis (5 articles), tinea pedis (4 articles), keratosis (13 articles), pruritus (1
article), dystrophic nails (2 articles), and penetration enhancement (5 articles). For each disease, we provide a summary of the
literature highlighting the clinical efficacy and safety of urea treatment and a table detailing clinical trials or case reports for the
more studied diseases.
 Figure 1. Patient with hyperkeratotic skin before (1A) and after (1B) treatment with 40% urea cream (U-Kera E [7]) for 12 days. Visible
clinical improvement in skin texture is observed.

Ichthyosis
Ichthyosis refers to a heterogeneous subset of dermatologic conditions characterized by dry, thickened, and scaly skin. Although
the most common form of ichthyosis is ichthyosis vulgaris, a variety of other disorders exhibit ichthyosiform scale. Topical urea
has been shown to be an effective therapeutic option for patients with these disorders in a number of studies and expert opinions
[14,15]. Urea (10%) was found to be equally or slightly more efficacious in controlling ichthyotic symptoms than 1%
hydrocortisone cream [16], 2% salicylic acid ointment, and paraffin-based moisturizers [17]. The beneficial effects of urea on
ichthyotic skin can be attributed to its water binding, barrier regenerating, desquamating, and anti-microbial properties [18,19].
Reports of only occasional mild burning or irritation associated with the use of topical urea preparations support an excellent
safety profile. The studies are outlined in Table 2 [14–17,20–26].

Table 2. Clinical studies of urea in patients with ichthyosis

Disease Subtype Test Agent Comparison N Study Treatment Results Safety (N)* Year Reference
Agent Design Protocol
Bullosa of 10% urea 5% lactic acid 1 CT BL BID x 8 Greater improvements with No adverse 1998 [20]
Siemens lotion lotion weeks test agent based on global effects
severity scale reported
Congenital 10% urea Urea-free base 2 CT BL QD x 4 weeks Test agent produced “soft No adverse 1968 [21]
cream cream skin with visible changes like effects
erythema” reported
Epidermolytic 10% urea None 1 CS QD 90% improvement after 6 No adverse 2009 [22]
hyperkeratosis months effects
(EHK) reported
Keratitis- 5% and None 1 CR QD x 2 weeks Marked improvement in No adverse 2007 [23]
ichthyosis- 10% urea hyperkeratosis and effects
deafness (KID) cream palmoplantar keratoderma reported
syndrome after 2 weeks of therapy
Laevis 10% urea Urea-free base 2 CT BL QD x 4 weeks Test agent produced “normal No adverse 1968 [21]
cream cream appearance of skin” effects
reported
Lamellar 5% urea None 5 CS BID x 6 Improvement was observed in Mild 2011 [15]
emulsion weeks and 4 all treated areas burning,
month pruritus and
maintenance irritation (2)
Lamellar 10% urea 5% lactic acid 11 CT BL BID x 8 Greater improvements with No adverse 1998 [20]
lotion lotion weeks test agent based on global effects
severity scale reported
Linearis 10% urea Urea-free base 1 CT BL Max 4 weeks Test agent produced “normal No adverse 1968 [21]
cream cream appearance of skin” effects
reported
Unspecified type 10% urea None 30 CT BL BID x 4 Both test agents improved Burning 1975 [24]
with history of or cream (pH weeks skin conditions sensation
present eczema 6 and 3) (2) with pH
 3
preparation
Unspecified type 10% urea 1% 19 CT BL BID x 2 Improved response to urea No adverse 1969 [16]
with history of or cream hydrocortison weeks (3), hydrocortisone (1), and effects
present eczema e cream no difference (12) reported
Vulgaris 10% urea Glycerol- 27 CT BL BID x 4 Urea reduced scaling, No adverse 2011 [25]
lotion based cream weeks roughness, redness and effects
cracking in comparison to reported
control
Vulgaris 10% urea 5% lactic acid 34 CT BL BID x 8 Greater improvements with No adverse 1998 [20]
lotion lotion weeks test agent based on global effects
severity scale reported
Vulgaris 10% urea None 5 OL QD x 2-4 Marked improvement in No adverse 1989 [14]
cream weeks treated areas effects
reported
Vulgaris 10% urea Urea-free base 6 CT BID x 3 Test agent increased the water No adverse 1973 [26]
cream cream, 0.1% weeks uptake by 100% compared to effects
retinoic acid the control reported

Vulgaris 10% urea 2% salicylic 37 CT BL BID x 2 Test agent showed greater No adverse 1972 [17]
cream acid ointment, weeks clinical improvement effects
paraffin reported

Vulgaris 10% urea Urea-free base 2 CT BL QD x 4 weeks Test agent produced “soft No adverse 1968 [21]
cream cream skin with visible changes like effects
erythema” reported
X-linked 10% urea 5% lactic acid 6 CT BL BID x 8 Greater improvements with No adverse 1998 [20]
recessive lotion lotion weeks test agent based on global effects
severity scale reported
X-linked 10% urea Urea-free base 8 CT BID x 3 Test agent increased the water No adverse 1973 [26]
recessive cream cream, 0.1% weeks uptake by 100% compared to effects
retinoic acid the control reported

X-linked 10% urea 2% salicylic 47 CT BL BID x 2 Test agent showed greater No adverse 1972 [17]
recessive cream acid ointment, weeks clinical improvement effects
paraffin reported

Abbreviations: CT - controlled trial, OL - open label, CS – case series, CR – case report, BL – bilateral comparison (test versus
control), QD – once daily, BID – twice daily, TID – thrice daily
*Safety profile is reported only for test agents containing urea.

Xerosis
Numerous randomized controlled trials support the use of urea in the treatment of xerosis. Typically administered in
concentrations less than or equal to 10%, the hydrating properties of urea can offer clinical benefit to patients with xerosis [27,28].
In many studies, transepidermal water loss (TEWL) is used as the primary parameter for assessing skin hydration. Several
experiments have shown that urea can reduce TEWL in both xerotic and healthy skin [29]. Cream was shown to be a slightly
better vehicle than foam in one study [30]. Studies on the hydrating effects of urea in patients with either xerotic or healthy skin
are outlined in Table 3[14,16,29,31–33] and Table 4[30,34–40], respectively.

Table 3. Clinical studies of the hydrating effects of urea in patients with xerosis
Test Agent Comparison N Study Treatment Results Safety (N)* Year Reference
Agent design Protocol
10% urea lotion with None 15* OL BID x 4 Test agent improved skin Mild burning 2011 [31]
dexpanthenol * weeks dryness and pruritus (1)

15% urea Untreated 12 CT BL BID x 2 Test agent reduced TEWL in all No adverse 2009 [29]
weeks individuals effects
reported
40% urea 12% ammonium 25 CT BL QD x 2 Test agent improved roughness, No adverse 2002 [32]
lactate weeks thickness and dryness in less effects
time reported
10% urea cream 12% ammonium 36 CT BID x 3 Test agent lowered TEWL and No adverse 1998 [33]
lactate BL weeks dryness effects
reported
10% urea None 10 OL QD x 2-4 Test agent reduced chapping and No adverse 1989 [14]
weeks. scaling of skin effects
reported
10% urea cream 1% 14 CT BID x 2 Improvement with: test (4), No adverse 1969 [16]
hydrocortisone BL weeks comparison (2), and no effects
cream difference (7) reported
Abbreviations: CT - controlled trial, OL - open label, CS – case series, CR – case report, BL – bilateral comparison (test versus
control), QD – once daily, BID – twice daily, TID – thrice daily, TEWL – transepidermal water loss
*Safety profile is reported only for test agents containing urea.
**Subjects were hemodialyzed patients with concurrent pruritus

Table 4. Clinical studies of the hydrating effects of urea in healthy subjects

Test Agent Comparison N Study Treatment Results Safety (N)* Year Reference
Agent design Protocol
2-10% urea in cream Untreated 61 CT 3 separate Cream was better than foam in No adverse 2011 [30]
or foam BL studies reducing TEWL and improving effects reported
conducted, hydration
varying
protocols
Urea with vitamins Urea alone 10 CT QD x 2 weeks Combination treatment superior in No adverse 2008 [34]
and ceramides improving hydration and increasing effects reported
gene expression of transglutamine-
1, loricrin and filaggrin

Urea/NaCl emulsion Urea alone 23 CT BL BID x two Both agents equally effective in No adverse 2002 [35]
weeks skin hydration effects reported
5% urea cream 5% hydrogenated 13 CT BID x 2 weeks Test agent decreased TEWL and No adverse 1997 [36]
canola oil BL reduced the irritant effects of effects reported
sodium lauryl sulfate at day 14
10% urea emulsion Various 72 CT BID or TID x TEWL and irritation to sodium No adverse 1996 [37]
formulations max 20 days lauryl sulfate was decreased after effects reported
pre-treatment with test agent
2-4% urea cream None 6 OL Moisturizer x 1 Test agent improves water retention No adverse 1995 [38]
hour followed by various parameters that effects reported
by 0.25 – 24h quantified stratum corneum
exposure to SLS dynamic function
irritant
10% urea emulsion Urea-free vehicle 54 CT Heels treated Test agent increased the amount of No adverse 1995 [39]
TID x 3 days cutaneous free water in the effects reported
presence of high relative humidity
Moisturizers with Urea-free vehicle 26 CT Measured Test agent potently humidified skin No adverse 1992 [40]
varying urea content epidermal and removed scale agent effects reported
hydration 3
hours after
application

Abbreviations: CT - controlled trial, OL - open label, CS – case series, CR – case report, BL – bilateral comparison (test versus
control), QD – once daily, BID – twice daily, TID – thrice daily, TEWL – transepidermal water loss
*Safety profile is reported only for test agents containing urea.

Atopic Dermatitis/Eczema
Urea has been shown to improve stratum corneum hydration, water-binding capacity, and TEWL in eczematous skin [41]. The use
of urea in atopic dermatitis has been studied most often using a concentration of 10% alone or in combination with 1%
hydrocortisone [42]. Combination therapy with betamethasone-17-valerate has also been found to be clinically effective [43].
Nearly all studies demonstrated clinical improvement with urea treatment. Occasional stinging and burning were common side
effects. The studies are outlined in Table 5 [21,24,41,43–48].
Table 5. Clinical studies of urea in patients with atopic dermatitis
Test Agent Comparison N Study Treatment Results *Safety (N) Year Reference
Agent design Protocol
10% urea cream None 10 OL Observation Test agent improved stratum No adverse 1989 [41]
performed 2 corneum hydration, water- effects reported
hours after binding capacity, and TEWL
application
10% urea + 1% 0.1% 46 CT QD x 3 weeks No statistical difference No adverse 1979 [44]
hydrocortisone hydrocortisone-17- between agents effects reported
butyrate
10% urea cream, 10% urea cream, 30** CT BL BID x 4 Test agent showed statistically Burning 1975 [24]
pH 6 pH 3 weeks improved efficacy and sensation in
acceptability more acidic
preparation (13)
1% hydrocortisone 0.1% 36 CT TID x 2-4 Comparable efficacy in No adverse 1974 [45]
in 10% urea betamethasone 17 BL weeks majority of patients for both effects reported
valerate agents
1% hydrocortisone 0.1% 49 CT QD x 2 weeks No statistical difference No adverse 1974 [46]
in 10% urea betamethasone 17 BL between two agents effects reported
valerate
1% hydrocortisone Acidic 1% 41 CT QD x 2 weeks Non-acidic test agent was No adverse 1974 [46]
in 10% urea hydrocortisone in BL clinically superior to acidic effects reported
10% urea preparation
10% urea +1% 1% hydrocortisone 48 CT TID up to 5 Test agent was clinically Stinging (23) 1973 [47]
hydrocortisone cream BL weeks superior to hydrocortisone
cream alone.
1% hydrocortisone 0.1% 50 CT BID x 2-3 Test agent was less effective Excoriated skin 1973 [48]
in 10% urea betamethasone-17- BL weeks than comparison agent. (6)
valerate
10% urea + 0.1% 0.1% 42 CT QD x 10 days Test agent showed greater No adverse 1971 [43]
betamethasone-17- betamethasone-17- BL improvement with normal skin effects reported
valerate valerate alone restored in 18 patients

10% urea +1% Base cream 12 CT BL QD up to 4 All patients treated with test Burning/itching 1968 [21]
hydrocortisone weeks agent developed (1)
cream softer/smoother skin
Abbreviations: CT - controlled trial, OL - open label, CS – case series, CR – case report, BL – bilateral comparison (test versus
control), QD – daily, BID – twice daily, TID – thrice daily, TEWL – transepidermal water loss
*Safety profile is only reported for test agents containing urea.
**Subjects were diagnosed with ichthyosis with a history of or present atopic dermatitis

Contact Dermatitis
One randomized controlled double-blinded study investigated the use of 1% hydrocortisone/10% urea/1% lactic acid (Calmuril-
Hydrocortisone) cream compared to 0.05% betamethasone-17, 21-dipropionate (Diproderm) cream in 100 subjects diagnosed with
contact dermatitis. Subjects were asked to rub the cream twice daily for seven days onto the affected skin; clinical assessment was
performed on the first, third, and seventh days. Diproderm cream was significantly more effective than the urea-containing
Calmuril-Hydrocortisone cream. Smarting was reported less frequently in patients treated with Diproderm (n=2) than Calmuril-
Hydrocortisone (n=7). The authors caution to avoid long-term treatment with steroid-containing creams to minimize the risk of
dermatrophia [49].

Radiation-Induced Dermatitis
There are limited studies investigating the use of urea in the treatment of radiation-induced dermatitis. One controlled trial
investigated the effects of a lotion containing 3% urea, polidocanol, and hyaluronic acid applied three times per day in 98 subjects
with breast cancer to prevent acute radiation dermatitis. The control group of 174 subjects received a less intensive standard
therapy. Treatment was started two to three weeks prior to radiation therapy and throughout the radiation treatment. The
proportion of subjects who did not develop radiation dermatitis was significantly higher in the group that used the lotion
containing urea (27.6% compared to 15.5%). The authors concluded that patients with breast cancer who received intensive use of
the lotion were half as likely to develop radiation dermatitis during radiotherapy. Only two patients reported adverse reactions
during the study, one with follicular keratosis and another with an allergic reaction [50].

Psoriasis/Seborrheic Dermatitis
In psoriasis, urea improves stratum corneum hydration, water-binding capacity, and TEWL [41]. The majority of studies of urea in
psoriasis were performed as part of combination therapies with dithranol. In one study, 10% urea monotherapy was found to be
effective with few side effects [51]. Urea (40%) with 1% bifonazole was found to be effective in the treatment of scalp seborrheic
dermatitis and scalp psoriasis [52]. Reported side effects were limited to occasional stinging and burning. An unwanted side effect
that occurs when urea is combined with dithranol is the staining of the skin and clothes to a purplish brown color. The studies are
outlined in Table 6 [21,41,51–62].

Table 6. Clinical studies of urea in patients with psoriasis

Test Agent Comparison N Study Treatment Results Safety (N)* Year Reference
Agent design Protocol
40% urea plus 1% None 71 OL Multi-month 73.2% of patients improved No adverse 2000 [54]
bifonazole ointment protocol after 2 weeks reactions reported

10% urea ointment Vehicle alone or 10 CT TID x 2 Urea reduced scaling, No adverse 1996 [51]
no treatment BL weeks erythema and induration and reactions reported
increased epidermal
hydration
10% urea cream None 10 OL Observed 2h Significant increase in water No adverse 1989 [41]
after content and decrease in reactions reported
application TEWL and hygroscopicity
12% urea and 12% Cream base 30 CT BID x 3 No statistical difference Burning sensation 1985 [55]
sodium chloride BL weeks between treatments (2)

12% urea and 12% Cream base 40 CT BID x 1 week Urea cream had statistically No adverse 1985 [56]
sodium chloride BL significant improvement on reactions reported
scaling

0.1% dithranol plus None 41 OL BID x 6 Clinical improvement from Mild irritation 1983 [57]
17% urea weeks baseline was 64% and 77% reported; 3
at two centers patients withdrew
due to dithranol-
related soreness
0.2% dithranol in 0.1% dithranol in 20 CT BID x 6 0.2% dithranol + urea cream 2 patients 1982 [52]
17% urea 17% urea BL weeks had improved reduction in withdrew due to
erythema and scaling severe irritation
and burning

0.1% dithranol in 0.1% dithranol in 35 CT QD x 4 weeks No statistical difference Less 1981 [58]
17% urea cream Lassar's paste BL between two treatments inflammation,
base stinging, itching,
discoloration with
test agent at 4
weeks
0.1% dithranol in Salicylic acid 2% 40 CT BID x 6 No statistical difference Transient irritation 1981 [59]
17% urea in strong coal tar BL weeks between two treatments and skin
solution 10% coloration (2)

0.1% dithranol in a None 20 OL QD until Mean time to clearance was Staining of hair (2) 1980 [60]
17% urea base clearance 8.8 days; rapid reduction in and irritation in
both induration and scaling post auricular skin
within first few days of (3)
treatment
0.1% dithranol plus 0.1% 23 CT BID x 6 No statistical difference Skin discoloration 1979 [53]
17% urea betamethasone- BL weeks between two treatments
17-valerate

0.1% dithranol in a 17% urea base 8 CT BID x 3 54% vs. 26% clinical Stinging and pain 1978 [61]
17% urea base BL weeks improvement of scaling with (7) and skin
combination therapy vs. urea discoloration (1)
monotherapy, respectively
0.1% dithranol plus 0.05% clobetasol 43 CT QD x 3 weeks Urea combination produced Stinging and skin 1978 [62]
17% urea propionate 80% of the clinical effect of staining
comparison agent
10% urea cream Urea-free base or 5 CT BL QD x 5 days Urea cream resulted in soft Itching or burning 1968 [21]
fluocinolone to 4 weeks and pliable skin but (1)
acetonide erythema was unchanged
ointment

Abbreviations: CT - controlled trial, OL - open label, CS – case series, CR – case report, BL – bilateral comparison (test versus
control), QD – daily, BID – twice daily, TID – thrice daily, TEWL – transepidermal water loss
*Safety profile is only reported for test agents containing urea.

Onychomycosis
Combination therapies consisting of urea with a variety of antifungal agents have been found to partially cure onychomycosis in
some patients. By softening the nail bed, urea facilitates greater penetration of antifungal medications. Pretreating nails with a
preparation of urea and hydrogen peroxide plus thioglycolic acid has been found to increase ungula flux of terbinafine ten fold.
Moreover, this pretreatment has been found to augment the fungicidal activity of ciclopirox and amorolfine [63]. Combination
therapy of urea with topical bifonazole or topical fluconazole has been shown to be clinically superior to monotherapy [64,65].
One study showed that 40% urea applied twice daily causes chemical avulsion of nails in patients with onychomycosis, facilitating
the removal of fungal keratin without anesthesia or bleeding [66]. The studies are outlined in Table 7 [64–68].

Table 7. Clinical studies of urea in patients with onychomycosis

Test Agent Comparison N Study Treatment Results Safety (N)* Year Reference
Agent design Protocol
Fluconazole 1% Fluconazole 1% 70 CT QD x 6-12 Test agent produced higher rate Redness and 2011 [65]
with urea 40% months of negative cultures and clinical tingling at
improvement application site (1)

Solution of 1% None 13 OL QD x 12-18 Test agent showed complete No adverse 2005 [67]
fluconazole and months clinical cure (4) and good reactions reported
20% urea clinical response (8)

40% Urea nail None 10 OL BID x 1-2 Test agent showed keratinolysis No adverse 2002 [66]
lacquer weeks of nail plate, ease of affected reactions reported
nail removal and lack of
unpleasant smell
40% urea\1% None 70 OL QD x 3 Overall 62.5% improvement Erosions (2) with 1998 [64]
bifonazole cream months rate and 50% mycological cure one
rate discontinuation

40% urea/1% 40% urea/1% 22 CT QD x 6 Test agent produced superior No adverse 1992 [68]
bifonazole bifonazole months response compared to either reactions reported
ointment with oral ointment or monotherapy
griseofulvin ointment alone
Abbreviations: CT - controlled trial, OL - open label, CS – case series, CR – case report, BL – bilateral comparison (test versus
control), QD – daily, BID – twice daily, TID – thrice daily
*Safety profile is only reported for test agents containing urea.

Tinea Pedis
Urea can decrease the fissuring and scaling associated with dermatophytoses [69]. Although urea monotherapy has been reported
to have antimicrobial properties, it has also been studied in combination with antifungal creams and appears to enhance efficacy
over topical antifungal monotherapy, with only rare instances of self-limited irritation. A study compared 1% lanoconazole with or
without 10% urea in 43 patients with hyperkeratotic type tinea pedis. Therapy was applied daily after a bath for 12 weeks. The
authors observed a 96% improvement in the combined therapy group compared to 70% improvement in the lanoconazole
monotherapy group. No adverse events were reported [70]. Urea in combination with topical bifonazole[64], ciclopirox[71], or
butenafine hydrochloride[72] was also found to be effective with minimal adverse effects.

Emollient/Keratolytic
Various in vitro and in vivo studies have established the emollient and keratolytic properties of urea. Common study endpoints
include reduction of TEWL, stratum corneum hydration, and clinical assessment. Urea has been shown to change certain physical
properties of the skin. Early studies have shown that urea can induce conformational changes in proteins by causing unfolding,
solubilization, and denaturation [73]. By possibly breaking hydrogen bonds and interfering with the quaternary structure of
keratin, urea disperses and denatures keratin without disrupting the epidermal water barrier [26,74]. Several studies have also
shown that urea decreases the DNA synthesis index of epidermal cells, leading to a thinning of the epidermis and reduction of
basal epidermal cells. An early hypothesis was formed that pretreatment or concomitant treatment with urea can enhance efficacy
of other topical therapies [75–77]. Salicylic acid is frequently combined with urea to produce a significant keratolytic effect [78].
Urea can enhance debridement in vascular and diabetic ulcers [69]. Studies investigating the emollient/keratolytic effects of urea
in different skin conditions are outlined in Table 8 [14,16,33,40,41,78–85].

Table 8. Clinical studies of the emollient/keratolytic effects of urea

Skin Type Test Agent Comparison N Study Treatment Results Safety (N)* Year Reference
Agent design Protocol
Healthy 40% urea in Drug-free 78 CT BL BID x 7 Test agent increased No adverse 2007 [80]
canola oil vehicle weeks TEWL after long term effects noted
exposure
Healthy 5% ammonium Drug-free 22 CT BID x 7 days Test agents improved No adverse 2002 [79]
lactate with 3 or vehicle and then SLS stratum corneum effects
5% urea irritant hydration and barrier reported
applied TID function
x 1 day
Healthy 40% urea with None 20 OL Single Test agent proven No adverse 2001 [78]
salicylic acid application keratolytic using the effects
silver nitrate test reported
Healthy 10% urea + 2% None 10 OL Single The degree of stratum No adverse 1995 [81]
salicylic acid. exposure corneum removal was not effects
followed by increased after 6h reported
removal by exposure to test agent
adhesive tape
Healthy Moisturizers Urea-free 26 CT Single Test agents are very No adverse 1992 [40]
with varying vehicle application potent skin humidifier effects
urea content and descaling agent reported
Healthy 10% urea/5% Base ointment 5 CT QD up to 6 Only ULB cream showed No adverse 1989 [82]
lactic acid/4.3% days penetration at days 3 and effects noted
betaine (ULB); 6
10% urea alone

Healthy 5% salicylic 5% and 10% 6 CT Single 4-hour Test agent had increased No adverse 1987 [83]
acid with 10% salicylic acid application keratolysis than 5% effects noted
urea ointment alone on back skin salicylic acid

Hyperkeratotic 30% urea None 10 CS BID x 4 Significant improvements No adverse 2008 [84]
emollient foam weeks in skin condition and effects noted
patients' ratings of quality
of life
Psoriatic 10% urea cream None 20 OL Observed 2h Test agent improved No adverse 1989 [41]
after stratum corneum effects
application hydration, water-binding reported
capacity, and TEWL
Various 10% and 20% None 158 OL BID x 8 Test agents moisturizes Irritation 1990 [85]
urea with and weeks and promotes penetration (2), flared
without 1% of hydrocortisone stasis ulcer
hydrocortisone (2)
Xerotic 10% urea cream 12% 36 CT BID x 3 Test agent lowered No adverse 1998 [33]
ammonium BL weeks TEWL and dryness effects
lactate reported

Xerotic 10% urea None 10 OL QD x 2-4 Test agent reduced No adverse 1989 [14]
weeks chapping and scaling of effects
skin reported
Xerotic 10% urea cream 1% 14 CT BL BID x 2 Improved with: urea (4), No adverse 1969 [16]
hydrocortisone weeks comparison (2), and no effects
cream difference (7) reported

Abbreviations: CT - controlled trial, OL - open label, CS – case series, CR – case report, BL – bilateral comparison (test versus
control), QD – daily, BID – twice daily, TID – thrice daily, TEWL – transepidermal water loss
*Safety profile is only reported for test agents containing urea.

Pruritus
There is limited evidence that topical urea application can improve symptoms of pruritus. An early study investigated the
antipruritic effects of two urea solutions and their urea-free placebos. Patients with pruritic dermatoses received intradermal
injections of trypsin as an irritant followed by a measurement of the duration of itch sensation. Thereafter, test or placebo solution
was applied followed by a second round of trypsin injections and measurement of itch duration. The urea solutions provided a
significant prophylactic antipruritic effect when compared to placebo in every case [86].

In a separate clinical study, 15 patients with pruritic dermatoses were asked to apply a urea solution to pruritic skin and instructed
not to reuse the solution until itching returned. Pruritus resolved within minutes for the majority of patients and most patients
expressed satisfaction with the antipruritic effect [86].

Chemical Nail Avulsion / Dystrophic Nails

Urea 40% has been used successfully under occlusion to achieve chemical avulsion of the nail in a number of studies. An early
study with 35 patients showed that both 22% and 40% urea applied under occlusion could avulse nails in less than 10 days [87].
Non-dystrophic nails were not affected. Infrequent and transient side effects of maceration and irritation were reported. In
onychomycosis, once the dystrophic nail is removed, subsequent treatment with topical antifungal drugs is facilitated. The failure
to achieve avulsion is usually owing to lack of gross nail dystrophy, inadequate occlusion of the dressing, water immersion by the
patient, and/or the use of an outdated urea preparation. Benefits of chemical over surgical avulsion include decreased risk of
bleeding and infection as well as enhanced function [88].

Penetration Enhancement
A number of studies support the capacity of urea to enhance penetration of drug substances into the skin. A variety of substances
have been studied, including topical steroids and topical antifungal drugs. Urea is thought to alter the physical and chemical
properties of keratin, enhancing permeation of mono-substances. Urea can also alter the permeation kinetics of the horny layer of
the skin by changing the binding capacity, leading to decreased penetration and increased retention time [89].

Many studies have looked at the concomitant use of urea in topical steroid application. An early study assessed the penetration of
topical cortisol in four different vehicles: 10% urea in a cream base, 10% urea in a stabilizing emulsified base, and two control
creams. The skin of a pig was used. The urea-cream base penetrated the skin with a 30-fold increase in efficacy compared to the
emulsified base [90]. A second study found that 10% urea increases the penetration of hydrocortisone and triamcinolone acetonide
by 50%, increasing the therapeutic effect of the drugs [91]. A third study used a powder-cream base containing a hyperosmolar
urea solution absorbed in starch granules, suspended within a continuous lipid phase of an aqueous-lipid emulsion incorporating
1% hydrocortisone. When tested in adults, the vehicle increased efficacy and increased penetration of hydrocortisone, producing
an effectiveness comparable to that of 0.1% betamethasone-17-valerate [44]. An in vitro study using guinea pig skin, however,
showed that 10% urea decreased the percutaneous absorption of hydrocortisone [92].
Conclusion
Urea has been used safely and effectively in large populations of patients across a wide variety of disease settings. Urea is
moisturizing and keratolytic, making it useful in diseases of dry and scaly skin such as ichthyosis, xerosis, and psoriasis. Urea
enhances skin penetration and overall clinical benefit of other drugs such as corticosteroids and antifungals when used
concomitantly. Urea therapy has been associated with few adverse effects and is generally well tolerated. Both the safety and
efficacy of urea have been largely established over the past hundred years and urea should continue to be considered by clinicians
as a viable treatment option for patients.

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