Journal of Dermatological Treatment.

2010; 21:9396

ORIGINAL ARTICLE

Efficacy of nitric oxide-liberating cream on pityriasis versicolor

Farideh Jowkar1, Akram Jamshidzadeh2, Soroush Pakniyat3 &
Mohammad Reza Namazi1
1Dermatology

Department and Shiraz University of Medical Science, 2Pharmacology Toxicology Department and
Shiraz University of Medical Science and 3Shiraz University of Medical Science, Shiraz, Iran

Abstract
Background: Tinea versicolor is a superficial fungal infection of the skin caused by Malassezia yeasts. Tinea versicolor is a
common disease and has a high rate of recurrence. Methods: This is a prospective, double-blind, randomized,
placebo-controlled clinical trial in Faghihi Hospital Dermatology Department. Participants were older than 10years with
a clinical diagnosis of tinea versicolor and positive KOH preparation, and were divided in two groups: active and control
(32 individuals in each). They were randomized to receive either nitric oxide (NO)-liberating cream as the active group and
placebo as a control. Creams were applied twice daily on the affected sites for 10 days. Results: Sixty-four patients were
entered into the study (31 male and 33 female). No significant difference was found between the two groups in terms of
severity, age and sex distribution. There was significant improvement with acidified nitrite cream in the active group after
10days (p = 0.000). Conclusion: NO is an important cytotoxic effector in immune defense against fungi that are too large
to phagocyte. This study shows the efficacy of an exogenous NO-releasing cream in treating tinea versicolor.

Key words: efficacy, nitric oxide, pityriasis versicolor

Introduction
Clinical studies have suggested that topical nitric
oxide (NO) might be extremely effective in killing or
inhibiting a wide range of bacteria, viruses, fungi and
yeasts associated with skin infections. Weller and
colleagues then showed that a topical cream containing acidified nitrite was clinically effective in treating
tinea pedis, commonly known as athletes foot (1). In
separate research, it was discovered that NO could
protect keratinocytes (skin cells) from apoptosis
(programmed cell death) caused by UV radiation (2).
Ormerod and colleagues showed that molluscum
contagiosum is effectively treated with topical
NO-liberating cream. In their study, they showed that
NO has antiviral effects in DNA, RNA, and
enveloped and encapsidated viruses (3).
Tinea versicolor occurs worldwide, with prevalences reported to be as high as 50% in humid, hot
environments and as low as 1.1% in the cold

temperatures of Sweden (4,5). Tinea versicolor is

a benign skin disease that causes scaly macules or
papules on the skin. As the name implies
(versi means several), the condition can lead to discoloration of the skin, with colors ranging from
white to red to brown. The condition is not
considered to be contagious because the causative
fungal pathogen is a normal inhabitant of the
skin (Malassezia furfur) (6). M. furfur is a dimorphic, lipophilic organism, which is cultured only
in media enriched with C12- to C14-sized fatty
acids (4). M. furfur is now the accepted name
for the organism. Pityrosporum orbiculare, Pityosporum
ovale, and M. ovalis are synonyms for M. furfur.
M. furfur is a member of normal human cutaneous
flora, and it is found in 18% of infants and 90100%
of adults (4,5).
The purpose of this study is to introduce a
new formula (3% topical NO cream) to treating
tinea versicolor.

Correspondence: Farideh Jowkar, Faghihi Hospital, Zand Street, Shiraz, Iran. E-mail: jowkarf@yahoo.com
(Received 19 September 2008; accepted 3 February 2009)
ISSN 0954-6634 print/ISSN 1471-1753 online 2010 Informa UK Ltd.
DOI: 10.3109/09546630902887229

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F. Jowkar et al.

Methods and materials

This study was a prospective, double-blind, randomized,
placebo-controlled clinical trial. Participants were men
and women older than 10years of age with a clinical
diagnosis of tinea versicolor and positive microscopy
on a potassium hydroxide (KOH) preparation.
Subjects were randomly divided in two groups: active
and control (32 subjects in each; 31 male and 33 female).
The two groups were matched according to severity of
disease, age and sex distribution. Pregnant and
also lactating women were excluded from the study.
Subjects with liver, renal and cardiac diseases and
also those on immunosuppressive drugs or known to have
HIV infection were also excluded from the study.
A theoretic side effect of absorption of NO in large
quantities is the reduction of heme-contained iron to
form methemoglobin; therefore, individuals who
needed large amounts of NO topical cream because
of discoloration all over their trunk and proximal
extremities (> 30% of body surface) were also excluded
from the study.
As there is no previous study and we could not
estimate the effect of this therapy, we chose a
double-blind group design in which subjects were
randomized to receive either 3% sodium nitrite
co-applied with 3% salicylic acid as the active group,
or an identical cream with 3% salicylic acid but
omitting the sodium nitrite, as a control. Another
study treating molluscum contagiosum used 5% sodium
nitrite co-applied with 5% salicylic acid (3). We chose
the same formula but with 3% sodium nitrite and 3%
salicylic acid because tinea versicolor is easier to
manage and 3% acidified cream has fewer side effects.
The identically coded and packaged creams were
applied twice daily on affected sites for 10 days. The
study was blinded for both the patients and physician.
All participants were asked to report any adverse
events during treatment, the occurrence of which
mean exclusion from the study. After 10days, patients
were followed for further examination, including
Woods lamp, to see the result of therapy and any
improvement. The cure was evaluated subjectively by
resolution of pruritus and clinically by disappearance
of lesions.
The scoring of the disease was: mild, moderate and
severe, based on the spread of discoloration on the
body surface. For example, a localized discoloration
(< 10% of body surface) was considered mild; a discoloration affecting the chest and abdomen surfaces
(> 20% of body surface) was considered severe;
any surface affected between these two ranges was
labeled moderate.
Four patients were excluded from the study
(one due to hypersensitivity to the cream in the active

group, and the other three did not return for

follow-up); 64patients completed the study.
Comparison of cure in the two groups was made
with the chi-squared test. The chi-squared tests were
performed with SPSS version 13.
Results
Sixty-four patients were entered into the study
(33 women and 31 men; mean age 21 years; age
range 1328 years). Thirty-two patients received
active treatment (acidified NO cream) and the other
32 patients received control treatment (placebo).
Staining (yellowish discoloration) was the main side
effect in the active group. Twenty-one of 32patients
in the active group developed staining; however,
it resolved within several days after the end of
the study.
Minimal irritation occurred in five patients in the
active group and four patients in the control group.
Acne was another side effect of this cream that occurred
only in one of the patients in the active group.
There was significant improvement with the
acidified nitrite cream in the active group after
10 days (p = 0.000). Twenty-eight patients in the
active group and 14 patients in the control
group were cured after 10days (Table I). As shown
in Table I, the placebo (salicylic acid alone) also had
a positive cure rate (43.8%).
There was no relation found between sex and cure
rate (p = 0.479) (Table II).
There was no relation between severity of the
disease and cure rate (p = 1.016). Fifteen out of
16 patients with mild severity, 10/12 with moderate
severity and 3/4 with severe severity in the active group
were cured after 10days of therapy (Table III).

Discussion
This study shows the efficacy of an exogenous
NO-releasing cream in treating superficial fungal
infection. Acidified nitrite cream is an effective therapy for treating pityriasis versicolor.
NO is a highly reactive molecule known to be
involved in many cell functions. Chief among the
beneficial effects of NO in the body is its role in
improving blood flow. Other biological activities
include muscle relaxation, modulation of immune
responses, reduced inflammation, and increased kidney function. Of particular interest is the fact that the
body uses the generation of NO as a means of
protecting itself against a number of pathogens and
general microbial invasion (2).

Effect of no cream on pityriasis versicolor

Table I.Results after 10days of therapy with the acidified nitrite

cream (active group) and salicylic acid alone (control group).
Cured

Uncured

Total

28

32

87.5

12.5

100

14

18

32

43.8

56.2

100

42

22

64

65.6

34.4

100

NO

Placebo

Total

Table II. Sex and cure rate.

Male

Female

Total

19

23

42

% with result

45.2

54.8

100

12

10

22

% with result

54.4

45.6

100

31

33

64

% with result

48.4

51.6

100

Cured

Uncured

Total

Table III. Severity and cure rate.

Cured

Uncured

Total

22

10

32

% with severity

68.8

31.2

100

16

24

% with severity

66.7

33.3

100

% with severity

50.0

50.0

100

42

22

64

% with severity

65.6

34.4

100

Mild

Moderate

Severe

Total

NO is an important cytotoxic effector in immune

defense against intracellular micro-organisms and
pathogens, such as fungi, that are too large to
phagocyte. NO is produced by the actions of a group
of enzymes known as NO synthases.

95

L-Arginine contains two terminal amino (NH2)

groups as part of its chemical structure. NO synthase
catalyzes the removal of the nitrogen atom from one
of these amino groups, yielding NO plus l-citrulline
as the products of the deamination of arginine. It is
worth noting that there are several different types of
NO synthases with different physiological roles.
Briefly, they are (i) neuronal nitric acid synthase
(nNOS or NOS1), which generates NO in cells and
tissues of the central and peripheral nervous systems;
(ii) inducible nitric acid synthase (iNOS or NOS2),
present in the immune and cardiovascular systems;
and (iii) endothelial (formerly called constitutive)
nitric acid synthase (eNOS or cNOS or NOS3),
present mainly in blood vessels. NO can be produced
on the surface of the skin by the reduction of nitrates
present in sweat, with bacteria normally present on
the skin first enzymatically converting nitrates to
nitrites. Production of NO from nitrite then occurs
chemically via the slight acidity of the skin (79).
Weller and his colleagues have been the lead
researchers in studying the beneficial effects of NO in
the skin. They discovered that NO produced on the
surface of the skin is beneficial in protecting against
topical fungal infections. Weller then showed that a
topical cream containing acidified nitrite was clinically
effective in treating tinea pedis, commonly known as
athletes foot (1). Molluscum contagiosum is also effectively treated with topical acidified NO cream (3).
Invivo NO often combines with superoxide anion
to form the highly cytotoxic peroxynitrite anion and
hydroxyl radical. In vitro studies have shown
that the concentrations of nitrogen oxides released
by the acidified nitrite cream are fungicidal to
Trichophyton rubrum and T. mentagrophytes var.
interdigitale (1). There is a need for such in
vitro testing for M. furfur. It seems the mentioned
mechanism is attributable to the effect of NO
on tinea versicolor.
The following sections discuss the therapeutic
modalities of tinea versicolor and are divided into
topical and oral agents.
Effective topical agents include selenium sulphide,
sodium sulfacetamide, ciclopiroxolamine, as well as
azole and allylamine antifungals (10).
Azole agents include clotrimazole, econazole
(Spectazole), ketoconazole (Nizoral), miconazole
(Micatin), oxiconazole (Oxistat), and sulconazole
(Exelderm). These agents have broad-spectrum
activity, including activity against some gram-positive
bacteria. Ketoconazole, sulconazole and oxiconazole
require only once-daily application because of their
long durability in the superficial layers of the skin.
Clotrimazole, miconazole, and econazole require
twice-daily application (1013).

96

F. Jowkar et al.

Terbinafine 1% cream is also effective in tinea

versicolor. The main problem with the use of topical
anti-fungals is the difficulty of applying cream to
such a wide body surface area (10,14). A cheaper
approach is the application of 2.5% selenium
sulphide in a detergent base. The principal advantages of selenium sulphide are its low cost and the
convenience of application. On the other hand, it is
an irritant if inadvertently applied to the face or
genitalia, necessitating care in its application. It
also stains clothes and bedding (10). Ciclopirox
(Loprox) gel is also a broad spectrum anti-fungal
medication, but it has side effects such as a skin burning sensation upon application, contact dermatitis
and pruritis.
Tinea versicolor has a high rate of recurrence, and
prophylactic treatment with topical or oral therapy
on an intermittent basis is necessary to prevent
recurrences in most cases (10).
Oral therapy does not prevent the high rate of
recurrence, and treatment with oral ketoconazole or
a topical agent may need to be repeated intermittently
throughout the year (10). Because tinea versicolor is
a benign condition and oral therapy is not without
risk, the decision to treat with an oral agent should
be made only after a complete discussion of the risks
involved (10).
Oral therapy is also effective for tinea versicolor
and is often preferred by patients because it is more
convenient and less time-consuming. Of course, oral
therapy can be used in consort with topical regimens.
Ketoconazole, fluconazole, and itraconazole are the
preferred oral agents (10,11).
Topical acidified NO cream is safer and less
expensive than currently available oral products and
some topical products in treating tinea versicolor.
Infections by bacteria, viruses, fungi or yeasts
are the underlying cause of many skin diseases
and can also give rise to complications during wound
care. A wide range of treatments has been developed
to control such disorders, including physical and
chemical methods and antimicrobial agents. Despite
the widespread use of these approaches, it is
generally recognized that our ability to halt the
invasion, persistence and spread of skin infections
remains limited.

There is, therefore, a need for an entirely different

approach to the management of infection. The topical
use of NO promises to provide an exciting and
innovative alternative to current anti-fungal and
other therapies.

Declaration of interest: The authors report no

conflicts of interest. The authors alone are responsible
for the content and writing of the paper.
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Copyright of Journal of Dermatological Treatment is the property of Taylor & Francis Ltd and its content may
not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written
permission. However, users may print, download, or email articles for individual use.