ARTICLE
Zinc is an essential trace element that is widely distributed in nature.
True zinc deficiency is therefore rare, and, apart from acrodermatitis
enteropathica, only occurs in patients receiving uncompensated parenteral
feeding. The recommended daily dose of 15 mg of zinc metal is supplied
by a normal diet.
Even in the absence of any deficiency, however, zinc salts are used
for their anti-inflammatory properties in the oral treatment of inflammatory
acne. Zinc sulphate was initially used, but today gluconate is the preferred
salt (Rubozinc®) because it is better tolerated. Indeed,
it is more extensively dissociated in the stomach and hence more completely
absorbed, thus making it possible to reduce the dose of zinc metal.
Studies have shown that zinc gluconate administered at a constant dose
of 200 mg daily, equivalent to 30 mg of zinc metal, reduces inflammatory
acne lesions. This therapeutic response was achieved after one month of
treatment and was significant with respect to placebo after two months
[1, 2].
These results then raised the question of whether or not the administration
of an initial loading dose would hasten the response.
We therefore report a study comparing two groups of patients, one treated
with a constant dose and the other receiving an initial loading dose for
three weeks. Both regimens provided the same cumulative dose at three
months.
Material and methods
This was a multicenter randomized, double-blind, comparative study in
two parallel groups, and was carried out by dermatologists in office practice1
from February to June 1993. The study protocol was approved by the Ethics
Committee of the Hôpital Bichat-Claude-Bernard in Paris on January
11, 1993.
Patients
Patients of either sex and 18 or more years of age who had inflammatory
acne or acne with moderate retention could be included. They were to have
at least 15 superficial inflammatory lesions (papules and/or pustules)
and fewer than 10 deep lesions (nodules and/or macrocysts) and at least
15 comedones. They were to have received no oral treatment for at least
six weeks, and no topical treatment for at least two weeks prior to entry
into the study. Women who were pregnant or lactating, patients intolerant
or allergic to zinc gluconate, patients receiving long-term tetracyclines,
gastric protectors, or calcium- or zinc-containing drugs, or patients
who had received local or systemic corticosteroids less than one month
before the study, were not included.
Study treatment
One 100-mg zinc gluconate capsule (Rubozinc®)2
contains 15 mg of zinc metal. The patients were divided into two groups,
as shown on Table I. Daily
zinc metal doses (Zn++) were as follows (Table
I):
group 1: 60 mg for three weeks, followed by 30 mg for four weeks,
followed by 15 mg for six weeks,
group 2: 30 mg throughout the 13 weeks of the study.
Both groups therefore received the same total dose of zinc metal: 2.73
g over 3 months.
Placebo capsules were given at the same time to maintain the double-blind
design.
The patients took two capsules in the morning, and two in the evening,
half an hour before meals.
If the patients experienced gastric intolerance, they were allowed to
take all four capsules at bedtime, at least two hours after dinner.
Only topical care once or twice daily with a gentle neutral soap, a
soap-free cleanser, lotion for oily skin or a cleansing gel was allowed.
A choice of two cleansers was allowed: oat-meal cleansing bar Aderma or
Emulave fluide at pH 4.5.
Assessments
The primary efficacy criterion was the decrease in the number of inflammatory
lesions at each successive visit.
The nodules, macrocysts, papules and pustules were counted on days 0,
21, 35, 49, and 91, according to anatomical location: forehead, cheeks
and nose, chin, neck, anterior thorax, posterior thorax. The sum of each
type of inflammatory lesions was then calculated.
The secondary criteria was the physician's overall opinion rated on
a four-point scale: 0 = worsening, 1 = stationary, 2 = slight improvement,
3 = marked improvement.
Tolerance was assessed by leading interview. The investigator asked
the patient if he had experienced any of the following signs and symptoms
and if so, to describe the intensity: nausea, vomiting, diarrhoea, gastric
pain, abdominal pain, allergic reactions, photosensitisation, anorexia.
Other adverse events were collected using a non-leading interview.
Statistical methods
All statistical calculations were carried out using the SAS version
6.08 programme for Windows.
Baseline values were compared using the chi-square test or Fisher's
exact test for qualitative variables and a non-parametric test was carried
out for quantitative variables.
Within and between group variations in quantitative assessment criteria
with respect to baseline were analysed as follows: a non-parametric method
(PROC NPA1WAY Wilcoxon option) was used to analyse each time point and
an analysis of variance in parallel groups (PROC GLM) was used for overall
analysis. Qualitative variables were compared for each time point.
Results
Patient population
Sixty-seven patients were included in the study, 32 in group 1, which
received the loading dose, and 35 in group 2, which received the constant
dose. The two groups were comparable at inclusion with respect to:
patient age (mean ± s.d.): 26.1 ± 7.8 years in group
1 vs 27.3 ± 7.3 in groupe 2 (p = 0.35),
sex ratio: 56% of group 1 patients were male vs 37% in
group 2 (p = 0.15),
major personal medical history: 16% of group 1 patients had major
medical history and 84% had none, vs 17% and 83% respectively in
group 2 (p = 1.00),
family history of acne: 47% of group 1 patients had family history
of acne and 53% had none, vs 57% and 43% respectively in group
2 (p = 0.47),
age at acne onset (mean ± s.d.): 15.7 ± 2.9 years in
group 1 vs 16.7 ± 6.3 in group 2.
The two groups differed significantly with respect to frequency of previous
treatments (p = 0.023): 78% for the loading dose group and 97% for the
constant dose group. The most frequently prescribed topical treatments
were benzoyl peroxide (30%) and systemic antibiotic treatment (26%).
The two groups did not differ significantly with respect to the number
of superficial inflammatory lesions observed on day 0, by category and
for the various categories combined (primary criterion):
papules number (mean ± s.d.): 24.5 ± 12.1 in group
1 (n = 32) vs 30.5 ± 24.6 in group 2 (n = 33) (p = 0.73),
pustules number (mean ± s.d.): 8.7 ± 10.0 in group
1 (n = 32) vs 10.4 ± 8.9 in group 2 (n = 33) (p = 0.21),
papules + pustules (mean ± s.d.): 33.2 ± 17.4 in group
1
(n = 32) vs 40.8 ± 28.2 in group 2 (n = 33) (p = 0.31).
The only observed difference concerned the mean number of nodules or
macrocysts, which was higher in the constant dose group (group 2, n =
33) than in the loading dose group (group 1, n = 32): 1.8 ± 2.5 vs
0.9 ± 2.1 (p = 0.045).
The duration of treatment was very similar in the two groups: 85.8 ±
20.9 days in the loading dose group (n = 32) as compared with 87.7 ±
20.8 days in the constant dose group (n = 35) (p = 0.71).
Thirteen patients withdrew prematurely from the study; they were equally
distributed between the two groups: 6 in group vs 7 in group 2
(p = 1.00). The reasons were:
acne worsening: 1 patient (group 1), 2 patients (group 2),
intercurrent disease: 1 patient (group 1),
patient's decision: 1 patient (group 1) vs 3 patients
(group 2),
lost to follow-up: 1 patient (group 1),
gastro-intestinal intolerance: 2 patients (group 1) vs
1 patient (group 2),
pregnancy: 1 patient (group 2).
In contrast, six patients deviated with respect to the criteria for
the number of lesions at baseline:
2 patients (group 1) and 1 patient (group 2) had respectively
13, 14 and 13 papules and pustules (inclusion criteria: at least 15),
1 patient in each group had respectively 10 and 34 nodules or
cysts (inclusion criteria: less than 10),
1 patient (group 2): had 6 papules and pustules and 14 nodules
or cysts.
Given the severity of the lesions observed in 2 patients of group 2
(34 and 14 nodules or cysts), they were not included in the efficacy analysis.
Clinical efficacy
Primary criterion: change in superficial inflammatory
lesions
The primary criterion was the change in the mean of total number of
superficial inflammatory lesions (papules and pustules). It is shown in
Figure 1. All within-group
changes were very significant (p < 0.001):
in group 1, the total number of papules and pustules (mean ±
s.d.) decreased from baseline as follows:
12.7 ± 10.9 at day 21 (n = 31),
16.9 ± 10.2 at day 35 (n = 29),
15.6 ± 18.0 at day 49 (n = 29),
18.9 ± 14.8 at day 91 (n = 28);
and in group 2:
15.2 ± 15.8 at day 21 (n = 32),
20.2 ± 26.8 at day 35 (n = 31),
24.2 ± 29.2 at day 49 (n = 30),
26.3 ± 33.0 at day 91 (n = 29).
The effect of treatment was apparent by day 21 in both groups, and became
more marked with each visit.
A difference was found on day 35 (group 1: 16.1 ± 15.8; group 2:
22.4 ± 14.4; p = 0.008) but there were no differences in changes
with respect to baseline between the groups (group 1: 16.9 ±
10.2; group 2: 20.2 ± 26.8; p = 0.22). Overall analysis failed
to demonstrate any difference between the groups.
Changes in deep inflammatory lesions
The change in number of nodules or macrocysts is shown in Table
II. None of the within-group changes were significant. A difference
was observed at baseline (1.8 as compared with 0.9; p = 0.045), but the
changes with respect to baseline did not differ between the groups. Overall
analysis also failed to demonstrate any difference between the groups.
The number of nodules and macrocysts remained low, as was initially
intended. It varied only slightly during treatment in both groups, hence
the change in the number of nodules and macrocysts failed to demonstrate
any significant difference between the groups.
Physician's overall rating
The scores assigned by the physicians are given in Table
III. The distribution of the scores at each time point was similar
in the two groups. It should be noted, however, that the percentage of
patients who showed "marked improvement" was higher in the loading dose
group, at all visits, and that the number of patients who had "worsened"
was relatively higher at day 91 (22.9%) in the constant dose.
Tolerance
A list of expected adverse effects was given to the physician and patient.
In response to this interview, 57% of the patients reported an adverse
event. There was no significant difference between the two groups: 16/32
patients (50%) in the loading dose group, and 22/35 patients (63%) of
the constant dose group (p = 0.33) (Table
IV).
The most frequently reported effects were nausea and gastric pain. The
number of adverse events reported in response to the proposed list decreased
with each visit.
Furthermore, there was no difference between the two groups with respect
to the frequency of the adverse events on the list.
Other spontaneously reported adverse events posed no particular problem.
Discussion
The efficacy of zinc in the treatment of acne has been known for nearly
three decades. In 1970, an Australian surgeon, Fitzherbert, observed that
zinc-deficient subjects suffered from acne which resolved with zinc treatment
[3].
Michaëlsson reported the case of a patient with acrodermatitis
enteropathica whose acne also resolved with zinc treatment [4]. On the
basis of this experience, she conducted a controlled study with Juhlin
and Vahlquist demonstrating the superior efficacy of zinc sulphate (200
mg, equivalent to 45 mg of zinc++ daily for three months) with
respect to placebo and vitamin A [5].
Other double-blind studies have confirmed that zinc sulphate is superior
to placebo: Göransson et al. (135 mg of zinc++
daily for six weeks) [6], Hillström et al. [7] then Verma
et al. [8], the latter two using a dosage providing 90 mg of zinc++
daily for three months.
However, Weismann et al. did not arrive at the same conclusion
[9]. The time of year at which the study was conducted may have been a
factor, because, as the author underlined, the effect of sunlight may
have masked that of zinc.
As for comparative studies with tetracyclines, these results remain
controversial. Michaëlsson et al. [10] have demonstrated that
zinc treatment (135 mg of zinc++ daily for three months) was
as effective as oxytetracycline (250 mg three times daily for two weeks,
followed by twice daily for two weeks then once daily for the last eight
weeks). Cunliffe et al. did not observe the same results, but rather
a decrease in the number of pustules at three months in patients treated
with a zinc sulphate-citrate complex at an unspecified dose. In contrast,
the same author observed a decrease in all inflammatory as well as non-inflammatory
lesions after tetracycline treatment (250 mg twice daily for three months)
[11]. If the results seem somewhat inconsistent, it should be said that
the results with tetracycline were so too, as six studies supported their
efficacy in acne and six others disputed it [12]. As Göransson et
al. [6] pointed out, the differences might be linked to the methods
used to monitor and follow up the lesions.
All the studies were conducted with zinc sulphate administered at a
dose of 200 to 600 mg, equivalent to 45 to 135 mg of zinc metal daily.
To summarize, treatment may be considered effective against inflammatory
lesions provided, however, it is prescribed for at least one or two months.
The development of a new formulation, zinc gluconate (Rubozinc®)
made it possible to administer much lower doses, 200 mg/day, equivalent
to 30 mg of elemental zinc. Indeed, being more extensively dissolved in
the stomach, the formulation is also more completely absorbed.
In a double-blind, placebo controlled study, Dreno et al. [1]
demonstrated the efficacy of zinc gluconate (200 mg/day for two months)
against inflammatory lesions. It was conducted in 66 patients who had
at least 15 inflammatory lesions (pustules or nodules). Thirty-four patients
received a placebo and 32 were treated by zinc gluconate (Rubozinc®)
i.e. 30 mg Zn/day over 2 months.
The primary assessment criterion was the decrease in the number of lesions,
combined with a severity score and an inflammatory score, leading to a
global score after 2 months: it was 47 ± 30 for the placebo group
and 27 ± 15 in the zinc group (p < 0,02).
The present study aimed at determining the value, if any, of using an
initial loading dose. The results allow us to conclude that there is no
statistically significant difference between the two regimens, after three
months, as concerns their efficacy against superficial inflammatory lesions.
The same was true after one and two months of treatment.
The change in the total number of lesions and the physicians' global
assessments failed to demonstrate any advantage to using a loading dose.
Treatment safety was identical in both groups. Nausea and gastric pain
were the most frequently reported adverse effects. They were not more
frequent in the patients who received a constant dose. In general, these
effects only rarely required that treatment be stopped.
The relative high frequency of adverse events observed in this study
can probably be explained by the fact that adverse events were elicited
in response to a leading interview, which may have heightened the patients'
concern hence have led them to exagerate the actual occurrence. Adverse
events had been much more uncommon in our safety study [2] where the clinical
tolerance observed was good and the biological tolerance was excellent.
Adverse events had also been much more uncommon in the double-blind placebo-controlled
study [1] where 3 patients in the placebo group reported nausea and 11
reports (nausea, slight gastralgia, abdominal pain) occurred in the zinc
group.
__________________
1 Lichtenberg J.P., Agulhon F., Amat
P., Archimbaud A., Bazin J.C., Benadi J., Bertail M.A., Bieder C., Bremond
M.F., Cheroyan M., Coin A., Colau-Gohm C., De Véricourt A., Favereau
B., Gerbaud-Thébaud D., Gougne-Mahoudeau B., Gounod N., Kerner
R., Rannou G., Roger F.
2 Laboratoire LABCATAL, 7, rue Roger-Salengro,
BP 305, 92541 Montrouge Cedex, France.
CONCLUSION
In conclusion, this study further supports the view that 200 mg daily
of zinc gluconate (two Rubozinc® capsules before breakfast)
for three months followed by a dose decrease is an effective and well-tolerated
treatment for inflammatory acne.
Article accepted on 21/02/00
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