Clinical trial

Oxford, UK
International
IJD
Blackwell
1365-4632
45 Publishing
Journal Ltd,
Ltd
of Dermatology
2006

Oral zinc sulfate in the treatment of rosacea: A double-blind,

Zinc sulfate
Sharquie
CLINICAL et al.
TRIAL
in rosacea

placebo-controlled study
Khalifa E. Sharquie, PhD, Rafid A. Najim, PhD, and Hala N. Al-Salman, FIBMS (D&V)

From the Departments of Dermatology and Abstract

Pharmacology, College of Medicine, Background Rosacea is a skin problem not uncommonly encountered world-wide. There is a
University of Baghdad, Baghdad, Iraq need for an effective and well-tolerated treatment for this disease.
Objective To evaluate the efficacy and side-effects of zinc sulfate in rosacea in a randomized,
Correspondence
Prof. Rafid A. Najim controlled, double-blind trial.
Chairman of Department of Pharmacology Patients and methods Patients with rosacea who attended the outpatient Clinic of
College of Medicine Dermatology and Venereology in Baghdad Teaching Hospital were recruited into this study
University of Baghdad between October 2002 and August 2004. A disease severity score was calculated for each
PO Box 61208
patient. The patients were randomly allocated to receive either zinc sulfate 100 mg or identical
Baghdad 12114
Iraq placebo capsules three times per day. Zinc sulfate and placebo capsules were given in a
E-mail: rafidnajim@yahoo.com double-blind manner. Following 3 months of starting the treatment, the patients crossed
over, i.e. patients on placebo crossed over to zinc sulfate and those on zinc sulfate crossed
over to placebo.
Results Twenty-five patients with rosacea were included in this study: 16 (64%) females and
nine (36%) males. Nineteen patients completed the study: 11 (58%) females and eight (42%)
males. Patient age ranged from 21 to 64 years with a mean ± SD of 48.2 ± 9.3 years. Duration
of the disease ranged from 1 to 14 years with a mean ± SD of 4.4 ± 3.2 years. In the group
started on zinc sulfate, the score before therapy ranged from 5 to 11 with a mean ± SD of
8 ± 2.0. The mean started to decrease directly after the first month of therapy with zinc sulfate
to a significantly lower level. After shifting to placebo treatment, the mean started to rise
gradually in the fifth month but remained significantly lower than the levels before therapy. In the
group started on placebo, the score before therapy ranged from 5 to 9 with a mean ± SD of
7 ± 1.3. The mean remained high in the first 3 months of therapy while the patients were on
placebo. After shifting to zinc sulfate, the mean started to decrease after the fourth month to
significantly low levels. No important side-effects were reported apart from mild gastric upset in
three (12%) patients on zinc sulfate.
Conclusion Zinc sulfate was found to be a good option in the treatment of rosacea, as it was
safe, effective and lacking important side-effects.

have side-effects and can not be tolerated by the patients for

Introduction
Rosacea is a chronic relapsing disease characterized by
inflammatory eruption of the flush area of the face in the form
of erythema, papules, pustules, and telangiectasia; induration
and thickening of the affected skin and hypertrophy of the
sebaceous glands leads to phyma.1,2 The etiology of rosacea is
still not well known and it appears that rosacea may have a
multifactorial etiology such as a genetic disposition, gastro-
intestinal factors, infection, and others.3 Many medications
have been used to control the activity of the disease including
topical and systemic therapies, such as topical and systemic
antibiotics,1,2 metronidazol1 and retinoid1 topical antifungal,1
azeliac acid,1 tacrolimus,4 and others. Many of these drugs
long-term therapy.
Zinc sulfate can be used in the treatment of many skin
diseases such as cutaneous leishmaniasis,5 recalcitrant viral
warts,6 perifolliculitis capitis abscedens et suffodiens,7 acne
vulgaris,8 and others. It proved to be safe and effective.
The aim of this study was to evaluate the efficacy and safety
of oral zinc sulfate in the treatment of rosacea.
Patients and Methods
A randomized, placebo-controlled, double-blind trial of oral zinc
sulfate in the treatment of rosacea. The study was approved by the
Ethics Committee at the institution. 857

© 2006 The International Society of Dermatology International Journal of Dermatology 2006, 45, 857– 861
858 Clinical trial Zinc sulfate in rosacea
Table 1 Disease severity score (Sharquie score)
Score 0 1 2 3
Erythema Absent Mild Moderate Severe
Papule 0 <5 5 –10 > 10
Pustule 0 <5 5 –10 > 10
Telangiectasia Absent <5 5 –10 > 10
Rhinophyma – ve + ve
Patients
Patients with rosacea who attended the outpatient Clinic of
Dermatology and Venereology, Baghdad Teaching Hospital, were
recruited into this study between October 2002 and August 2004.
Patients included in the trial comprised those with grade I, II and
III rosacea, including those with eye involvement. Pregnant women
and patients with severe steroid-induced rosacea were excluded
from the trial.
Twenty-five patients with rosacea started the trial. Six of whom
defaulted for unknown reasons. Nineteen completed the course of
the study.
Patients were instructed to stop any other medications at least
1 month before being admitted to the trial. The nature of the study was
explained to the patients and their formal consent was obtained.
Full history was taken from the patients, including the name,
age, sex, social status, job, history of the disease itself, including
the age of onset, duration, complaint of the patient, family history
of the same disease or any other skin diseases, drug history
(topical and systemic), presence of other skin diseases, other
systemic diseases such as hypertension, diabetes or others,
involvement of other systems such as eye involvement, and
gastrointestinal problems. Exacerbating factors comprised sun
exposure, heat and psychological factors, and habits comprised
smoking and alcohol.
Examination of the patients and assessment of their disease
was carried out according to the disease severity score (Sharquie
score). This scale gives an individual score for the severity of
erythema (as measured according to a color chart), the number of
papules, pustules and telangiectasia, and the presence or
absence of rhinophyma (Table 1). All patients were photographed
at baseline and then every month, in the same place with fixed
illumination and distance, using a digital camera. Final
assessment was carried out by a single physician viewing the
photographs blinded to the patient’s treatment status, visit month,
and previous photographs.
Zinc sulfate 100 mg was placed in gelatin capsules using
glucose powder as an excipient. Identical capsules filled with
glucose powder only were used as a placebo. Patients were
randomly allocated to receive either the zinc sulfate 100-mg
capsules or the identical placebo capsules, three times daily. Zinc
sulfate and placebo capsules were given in a double-blind manner.
Patients were instructed to take the drug after meals. After
3 months of starting the treatment, the patients were crossed over,
International Journal of Dermatology 2006, 45, 857– 861
Sharquie et al.
i.e. patients on placebo crossed over to zinc sulfate, and those on
zinc sulfate crossed over to placebo.
Follow up
Patients were followed up for 6 months. They were observed every
2 weeks. Lesions were assessed by observing the severity of
erythema and counting the number of papules, pustules and
telangiectasia. Patients were asked about any side-effects of the
therapy and any new complaint. Photographs were taken of every
patient monthly for comparison.
A monthly ophthalmological examination of the patients
was carried out by an ophthalmologist with a complete
ophthalmological assessment to observe and re-evaluate
the eye condition.
Statistical analysis
Statistical analyses were performed using SPSS (Statistical
Package for Social Sciences, SPSS Inc, Chicago, USA) version 10
software. Results are expressed as mean ± SD. Within each group
a paired t-test was used to evaluate the effect of treatment with zinc
sulfate for 3 months. For the group started on zinc sulfate
(group A), the mean severity scores at baseline and month 3 were
compared. For the group started on placebo (group b), the mean
severity scores at months 3 and 6 were compared. P > 0.05 was
considered to be the minimum for statistical significance.
Results
Twenty-five patients with rosacea were included in this study.
They were randomized into 13 patients receiving zinc sulfate
and 12 receiving placebo: 16 (64%) females and nine (36%)
males. Six (24%) patients defaulted from the study, five of them
were receiving placebo and one was receiving zinc sulfate.
Nineteen patients completed the study: 11 (58%) females and
eight (42%) males. The ages of the patients ranged between
21 and 64 years with a mean ± SD of 48.2 ± 9.3 years. The
duration of the disease ranged between 1 and 14 years with a
mean ± SD of 4.4 ± 3.2 years. Positive family history was
found in six (24%) patients.
Eye involvement occured in nine (36%) patients: as blephar-
itis in four patients, chalazion in two patients and conjunctivitis
in three patients. Gastrointestinal symptoms were found
in six (24%) patients in the form of irritable bowel disease.
The presenting symptoms of the patients were: burning in
20 (80%) patients, itching in 16 (64%) patients, erythema in
four (16%) patients, and one (4%) patient only was asymp-
tomatic. Sites of the lesions were in the cheek in 23 (92%)
patients, nose in 22 (88%) patients, forehead in 12 (48%)
patients and scalp in three (12%) patients.
Systemic diseases were found in eight (32%) patients; six
(24%) of whom had hypertension and two (8%) had diabetes.
Five (20%) patients were smokers and one (4%) patient was
a smoker and alcoholic. The aggravating factors of the disease
© 2006 The International Society of Dermatology
Sharquie et al.
Figure 1 Disease severity score in groups A (
; started on zinc
sulfate, then crossed over to placebo) and B (; started on
placebo, then crossed to zinc sulfate) during the 6-month study
period
were mainly the sun in 12 (48%) patients, psychological
stress in 20 (80%) patients and heat in five (20%) patients.
In group A (who received zinc sulfate at the start of treat-
ment), the score before therapy ranged between 5 and 11 with
a mean ± SD of 8 ± 2.0. The mean started to decrease directly
after the first month of therapy with zinc sulfate to 5.7, 3.4
and 1.6 for the first, second and third months, respectively.
Comparing the score at 3 months with the baseline, the decrease
was statistically significant using the dependent Student’s
t-test (P < 0.01).
After shifting to placebo treatment, the mean started to rise
gradually in the fifth month but remained significantly lower
than levels before therapy. The means were 1.9, 1.8 and 2.6
for the fourth, fifth and sixth months, respectively (Fig. 1).
In group B, who received placebo at the beginning, the score
before therapy ranged between 5 and 9 with a mean ± SD of
7 ± 1.3. The mean remained high and even increased in the
first 3 months of therapy while the patients were on placebo.
The means were 7.3, 7.4 and 7.6 for the first, second and third
months, respectively.
After shifting to zinc sulfate the means started to decrease
after the fourth month to significantly lower levels (5.9, 3.9
and 1.9) for the fourth, fifth, and sixth months, respectively.
© 2006 The International Society of Dermatology
Zinc sulfate in rosacea Clinical trial 859
Comparing the scores at 6 months with 3 months, the decrease
was statistically significant using the dependent Student’s
t-test (P < 0.01) (Fig. 1).
Papules and pustules showed a significant decrease in their
numbers 1 month after starting treatment with zinc sulfate
and become zero after 3 months of therapy in all patients. It
remained statistically significant even after shifting to placebo
in group A. Erythema was also reduced, but it needed longer
duration to show a significant response. The improvement of
erythema started to become statistically significant after the
second month of starting zinc sulfate. There was no significant
effect of zinc sulfate on telangiectasia (Fig. 2). All eye involve-
ment disappeared after 3 months’ treatment with zinc sulfate.
No important side-effects were reported apart from mild
gastric upset in three (12%) patients only, who were on zinc
sulfate.
Discussion
No previous report regarding rosacea in Iraq in international
literature was found. Therefore it is worthwhile to comment
about the study sample. It was found that the age of the patients
ranged between 21 and 64 with a mean ± SD of 48.24 ± 9.3
years. This is similar to previously published literature.1
There was a female predominance with a female: male ratio
of 1.7 : 1, which is less than that mentioned in the literature,1,2
which is possibly owing to the small sample of patients.
Positive family history was found in 24% of the patients. Eye
involvement was found in 36% of the patients compared with
50% reported in the literature.9 Gastrointestinal manifestations
were found in 24% of the patients.
The present work shows that zinc sulfate in a 100-mg dose
three times daily is effective in controlling rosacea lesions.
The effect of zinc sulfate on the papules and pustules become
statistically significant 1 month after starting therapy, which
continued for 3 months after shifting to placebo in group A.
Therefore, the effect of zinc sulfate continues after stopping
the drug. This mean that zinc sulfate has both therapeutic and
prophylactic effects.
These results are comparable to systemic azithromycin and
metronidazole, which are used to treat rosacea and result in
significant improvement of the papules and pustules, continu-
ing for 4 weeks after treatment;10 whereas, 0.1% tacrolimus
ointment showed no significant effect on papulopustular
rosacea.4
Erythema showed a gradual reduction which becomes
statistically significant after the second month of treatment
with zinc sulfate, which is comparable to other therapies.4,10
Zinc sulfate had no significant effect on telangiectasia, similar
to other modalities mentioned in the literature.1
The mechanisms of action of zinc sulfate can only be
speculated. Several mechanisms could possibly account for the
action of zinc in rosacea. One possible mechanism by which
International Journal of Dermatology 2006, 45, 857– 861
860 Clinical trial Zinc sulfate in rosacea
Figure 2 Effect of therapy on erythema, papules, pustules and telangiectasia in A (patient started on zinc sulfate, then crossed over to
placebo or B (patients started on placebo, then crossed over to zinc sulfate) during the 6-month study period
zinc acts may be as a free radical scavenger. An increase in free
radical production and a decrease in antioxidants have been
reported in rosacea.11 Zinc is known as a free radical scavenger.12
Zinc has been reported to have a wide range of activity
against several organisms ranging from viruses13 to leishma-
nia.14 Demodex mites, bacteria and other invaders play a role
in the pathogenesis of rosacea.15 Therefore, a possible action
of zinc on these organisms can be speculated, but further
evidence is needed.
An association of Helicobacter pylori infection of gastric
mucosa and rosacea has been found.1,2 Eradication of H. pylori
was reported to induce a remission in rosacea.16 It was reported
that zinc as zinc carbonate had a significant effect on H. pylori
in a patient with peptic ulcer.17 Therefore this may represent
yet another mechanism of zinc in the treatment of rosacea.
No important side-effects were recorded, apart from mild
gastric upset. This is may be owing to the low dose of zinc
sulfate (300 mg/day) given in the three divided doses.
Oral zinc sulfate is an effective therapeutic option in rosacea
and it may also have a prophylactic effect. It is safe, with no
important side-effects, and is well tolerated by the patients.
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