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Journal of Cosmetics, Dermatological Sciences and Applications, 2018, 8, 264-271
http://www.scirp.org/journal/jcdsa
ISSN Online: 2161-4512
ISSN Print: 2161-4105
DOI:
10.4236/jcdsa.2018.84028 Dec. 21, 2018 264 J. Cosmetics, Dermatological Sciences and Applications
The Safety of Oral Ketoconazole in the
Treatment of Skin Diseases (Single Blinded,
Therapeutic, Comparative Study)
Khalifa E. Sharquie1,2*, Adil A. Noaimi1,2, Wasnaa S. Al-Salam3
1Department of Dermatology, College of Medicine, University of Baghdad, Baghdad, Iraq
2Iraqi and Arab Board for Dermatology & Venereology, Baghdad Teaching Hospital, Baghdad, Iraq
3Department of Dermatology, Baghdad Teaching Hospital, Baghdad, Iraq
Abstract
Background
: Ketoconazole was introduced in 1981 as the first in a series of
antifungal agents that are characterized by nitrogen-containing ring. Ketoco-
nazole acts against many different kinds of fungi such as candida, dermato-
phytes and as pergillus. Also oral ketoconazole had proved its effectiveness in
the treatment of cutaneous Leishmaniasis.
Objective: To evaluate the safety
of oral ketoconazole in the treatment of different skin diseases like cutaneous
Leishmaniasis (CL), tineacapitis, tineacorporis and tineaversicolor.
Patients
and Methods:
This is a single, blinded, therapeutic,
controlled study that was
carried out in the Department of Dermatology, Baghdad Teaching Hospital,
Baghdad, Iraq, during the time, January 2015 to July 2016. In total, 951 pa-
tients with acute cutaneous leishmaniasis, tineacapitis, tineacorporis and ti-
neaversicolor were enrolled in this study.
The diagnosis was confirmed by
smear and histopathology. Patients were divided into two groups: 51 patients
in Group 1; 24 of them were treated with oral ketoconazole tablets 200
mg
twice daily for 6 weeks and 27 of them were treated orally with
a combination
of zinc sulfate 10 mg/kg/day and ketoconazole for 6 weeks. All patients were
seen regularly every 2 weeks for 6 weeks of
treatment period, then monthly
for the next three months as follow up period. Liver enzymes monitoring was
done for every patient in this study every two weeks. Elevated liver enzymes
were considered as features of hepatotoxicity in the examined patien
ts. While
group 2 included 900 patients and was divided into 3 subgroups: A: 600 pa-
tients with tineacapitis and tineacorporis, B: 100 patients with tineaversicolor,
and C: 200 patients with CL. All patients in group 2 were treated with oral KC
tablets 200 mg twice daily for 6 weeks. The dose of oral KC in children is 3.3 -
6.6 mg/Kg/day. All patients in group 2 were not investigated for ketoconazole
How to cite this paper:
Sharquie, K.E.
,
Noaimi
, A.A. and Al-Salam, W.S. (2018
)
The Safety of Oral Ketoconazole in the
Treatment of
Skin Diseases
(Single Blinded,
Therapeutic, Comparative Study)
.
Journal
of Cosmetics
,
Dermatological Sciences and
Applications
,
8
, 264-271.
https:
//doi.org/10.4236/jcdsa.2018.84028
Received:
July 11, 2018
Accepted:
December 18, 2018
Published:
December 21, 2018
Copyright © 201
8 by authors and
Scientific
Research Publishing Inc.
This work is licensed under the Creative
Commons Attribution International
License (CC BY
4.0).
http://creativecommons.org/licenses/by/4.0/
Open Access
K. E. Sharquie et al.
DOI:
10.4236/jcdsa.2018.84028 265 J. Cosmetics, Dermatological Sciences and Applications
biochemical side effects but watched for any clinical symptoms and signs of
any side effects.
Results:
After six weeks, 951 patients had
completed the
treatment. In the first group (51 patients), only two out 27 patients (7.4%)
from the combined group showed elevated liver enzymes while the ketoco-
nazole treated group showed no increase in liver enzymes, hence onl
y 3.9%
showed elevated liver enzymes that went to normal during follow up. In the
second group (900 patients) there were no clinical symptoms and signs in fa-
vor of hepatic toxicity or other related organs.
Conclusion: Ketoconazole has
been used tremendously in treating of different skin diseases including fungal
and Leishmania infection but without side effects, accordingly this drug
seems safe to be used in treatment of different skin diseases whether adults or
children.
Keywords
Cutaneous Leishmaniasis, Ketoconazole, Drug Safety
1. Introduction
Ketoconazole (KC) was introduced in 1981 as the first in a series of antifungal
agents that are characterized by nitrogen-containing ring [1]. Oral KC acts by
inhibiting the enzyme cytochrome P450 14
α
-demethylase which leads to the in-
hibition of the conversion of lanosterol to ergosterol and this will change cell
membrane permeability. In addition, ketoconazole inhibits biosynthesis of trig-
lycerides and phospholipids by fungi as well as inhibition of several oxidative
and peroxidative enzymes involved in detoxification process in fungi. All these
will lead to cellular necrosis [2].
KC is an antifungal, with activity against many kinds of fungi such as candida,
histoplasma, coccidioides, blastomyces and as pergillus [3]. KC is also used a
potent inhibitor of human drug metabolism especially with cyclosporine [4]. KC
is also used in the treatment of prostate carcinoma and Cushing disease because
of its ability to inhibit adrenal steroidogenesis [5].
KC was the first broad spectrum antifungal drug approved by the Food &
drugs agency (FDA) in 1981, however; posts marketing there were reports of
drug-related hepatotoxicity resulting in US market withdrawal of the drug [6].
The most common reported side effects are the reversible gastrointestinal
disturbances, which occur in 3% - 10% of patients [7]. In addition, gynecomas-
tia, irregular menstrual cycle, decrease libido and impotency were recorded fol-
lowing oral KC due to its anti-androgenic effect [7].
In 1984, cases of KC associated hepatotoxicity, rarely fatal, were reported [8].
A number of reviews, case survey, and registry reports from around the world
have been published since 2002, dealing with the general topic of drug induced
hepatitis, liver injury, liver failure, in all of these publications KC was mentioned
not at all, or only minimally as a potential cause of liver injury [9] [10]. Toxicity
K. E. Sharquie et al.
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10.4236/jcdsa.2018.84028 266 J. Cosmetics, Dermatological Sciences and Applications
produced by KC and N-desacetyl-ketoconazole (bio-transformer of KC) evident
as cellular leakage of alanine transaminase (ALT) or lactic dehydrogenase (LDH)
was dose and concentration dependent, and associated with covalent binding to
hepatic protein as well as glutathione depletion [11]. In 2013, after more than
three decades of clinical usage of KC, FDA and European medicines agency
(EMA) concurrently issued the warning about the dangers of oral KC [12] [13].
On the other hand its usage was limited only when other effective antifungal
drugs were not available or not tolerated and potential benefit of ketoconazole
outweighs its potential risks [14].
Cutaneous Leishmaniasis (CL) is an endemic disease in many countries in-
cluding Iraq and many drugs were used in treatment of CL and KC is one of
them. In Sharquieetal study, we used KC singly and in combination with oral
zinc sulphate, and the results were very encouraging [15].
So the aim of the present work is to record the side effect of systemic KC dur-
ing therapy and follow up of different skin diseases.
2. Patients and Methods
This is a single, blinded, the rapeutic, controlled study that was carried out in the
Department of Dermatology and Venereology, Baghdad Teaching Hospital,
Medical City, Baghdad, Iraq from January 2015 to July 2016. A total of 951 pa-
tients were enrolled in this study. The cases were divided accordingly into two
groups, the first group included 51 patients with CL which were tested with liver
enzymes assays at pre and during treatment with KC. The second group in-
cluded 900 patients treated with KC but without liver enzymes assays and pa-
tients were watched for clinical symptoms and signs of any side effects related to
ketoconazole use.
A history was taken from each patient regarding the followings: age, gender,
address, duration of the lesions and their number, recurrence of the lesion, his-
tory of previous therapy. Also family history, past medical history, obstetric his-
tory regarding the female in reproductive period and past drug history. Formal
consent was taken from each patient before starting the therapy. Also, the ethical
approval for this study was given by the scientific committee of the Scientific
Council of Dermatology and Venereology-Iraqi Board for Medical Specializa-
tions.
Therapeutic groups
Patients were divided into two groups:
The first group included 51 patients with CL treated with KC with liver en-
zymes assessment and were divided into two subgroups:
A. Ketoconazole group: where 24 patients were enrolled in this group. Pa-
tients with lesions of leishmaniasis were treated with oralketoconazole tablet 200
mg twice daily for 6 weeks. Patients were seen regularly every 2 weeks for 6
weeks of therapy time, after then monthly for the next three months as follow up
period. Ketoconazole was supplied from Pharma International Company, Jor-
K. E. Sharquie et al.
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10.4236/jcdsa.2018.84028 267 J. Cosmetics, Dermatological Sciences and Applications
dan. We dida baseline, laboratory tests including serum gamma-glutamyl trans-
ferase (SGGT), alkaline phosphatase, ALT, AST, total bilirubin (TBL), proth-
rombin time (PT), international normalization ratio (INR), and viral hepatitis
serology. While the dose in children was 3 mg/kg and with similar regeme.
B. Combination group: 27 patients were enrolled in this study group. The
patients lesions were received a combination of oral zinc sulfate capsule in a dose
of 10 mg/kg and ketoconazole tablet 200 mg twice daily for 6 weeks. And treated
patients were monitored regularly every 2 weeks for 6 weeks of therapy, and then
after monthly for the next three months as follow up time. Also, SGGT, alkaline
phosphatase, ALT, AST, TBL, PT, INR, and viral hepatitis serology were carried
out.
The second group included 900 patients treated with KC without liver en-
zymes assessment and divided accordingly into 3 subgroups
1) A total of 600 patients with tineacapitis and tineacorporis
2) A total of 100 patients with tineaversicolor
3) A total 200 patients with CL (Cutaneous Leishmaniasis).
All patients with liver problems including alcoholic were excluded from the
present study. Pregnant and lactating women were not included in the present
work.
3. Results
A total 0f 951 patients were enrolled in this study.
The first group included 51 patients with acute CL. The gender distribution
was almost equal with 27 (53%) males and 24 (47%) females and their ages range
from 1 to 80 years with a mean ± SD of 33.7 ± 1.82 years. All patients in this
study had multiple lesions with overall total number of 248.
The second group included 900 patients dived into two groups;
1) In total 600 patients were affected with tineacapitis and tineacorporis, the
gender distribution was almost equal with 306 (51%) males and 294 (49%) fe-
males and their ages range from 5 to 30 years with a mean ± SD of 18.6 ± 1.43
years.
2) In total 100 patients were affected with tineaversicolor, 69 (69%) males and
31 (31%) females and their ages range from 5 to 30 years with a mean ± SD of
19.2 ± 1.64 years.
3) In total 200 patients were affected with CL, the gender distribution was al-
most equal with 108 (54%) males and 92 (46%) females and their ages range
from 5 to 30 years with a mean ± SD of 17.4 ± 1.49 years .
Group 1:
A. CL group treated with oral Ketoconazole and assessed by liver enzymes
A total of 24 patients with 105 lesions were included in this group. The mean
duration of lesions of CL was 6.5 ± 0.8 weeks with a range of 4 - 12 weeks and
the cure rate was 50%
Liver Enzymes study
K. E. Sharquie et al.
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10.4236/jcdsa.2018.84028 268 J. Cosmetics, Dermatological Sciences and Applications
Liver enzymes assays were performed every 2 weeks and did not show any
remarkable changes.
B. CL treated with oral zinc sulphate and Ketoconazole and assessed by
liver enzymes
A total of 27 patients with 143 lesions were included in this group. The mean
duration of lesions of CL was 7.00 ± 0.75 weeks with a range of 4 - 12 weeks and
the cure rate was 96%.
Liver Enzymes study
Liver enzymes assays were performed every 2 weeks. There was elevation of
liver enzymes in two patients (7.4%) in this group after 4 week of treatment with
oral ketoconazole (Table 1). The oral ketoconazole was stopped immediately
and the patients continued on oral zinc sulphate. Liver enzymes went to normal
after 8 weeks of the start of the treatment. So only 3.9% of total cases of Leish-
maniasis showed elevated liver enzymes.
Group 2:
1) A total of 600 patients with tineacapitis and tineacorporis were treated with
oral ketoconazole for 6 weeks. The mean duration of lesions was 8.24 ± 0.735
weeks with a range of 5 - 14 weeks. All patients have excellent response to KC.
There was no clinical evidence of liver injury or other organ related clinical side
effects.
2) A total of 100 patients with tineaversi color were treated with oral KC for 6
weeks. The mean duration of lesions of was 11.33 ± 0.92 weeks with a range of 7
- 16 weeks. All patients had excellent response to KC. There was no clinical evi-
dence of liver or other organs injury in all treated group.
3) A total of 200 patients with CL were treated with oral KC for 6 weeks. The
mean duration of lesions of was 7.35 ± 0.86 weeks with a range of 4 - 12 weeks.
All patients had satisfactory response to KC. There was no clinical evidence of
liver or other organ injury in all treated group.
4. Discussion
Oral ketoconazole is a potent antifungal drug [1] [3] and this was confirmed by
the present study as it had been used successfully for the treatment of tineacapi-
tis, tineacorporis and tineaversicolor.
Table 1. Showing elevated liver enzymes in two patients in Group 1B.
Patients Weeks after
staring ALT (U/L) AST (U/L) ALKP (U/L) Bilirubin
mg/100ml
First
0 37 30 120 0.4
4 250 162 250 0.3
8 30 20 120 0.4
Second
0 26 22 110 0.2
4 100 120 320 0.2
8 22 25 120 0.2
Normal values <50 <50 <279 <1.2
K. E. Sharquie et al.
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10.4236/jcdsa.2018.84028 269 J. Cosmetics, Dermatological Sciences and Applications
Oral ketoconazole was used by
Alsaleh et al.
study [16], from Kuwaitas a
therapy for leishmaniasis who used a higher oral dose 600 mg/day ketoconazole
with cure 60% and oral 800 mg/day ketoconazole with cure rate 66.7% at the end
of six weeks of treatment [16]. This diversity of cure rate could be explained by
the higher dose of ketoconazole and the different scoring system and no side ef-
fects were reported. While Sharquie
et al.
(15) used ketoconazole as a single
therapy for leishmaniasis and gave 50% cure rate, and in a combination of oral
ketoconazole and zinc sulfate gave a cure rate of 96%, and by using Tuckey HSD
test suggests that this combination has synergistic effect.
In the present study we identified transient elevation of liver enzymes in 3.9%
from the first group with leishmaniasis without apparent clinical hepatotoxicity
started at the fourth week of the initiation of treatment and resolved sponta-
neously after 4 weeks of stopping ketoconazole treatment. In addition, all pa-
tients in the second group with different types of fungal infection did not show
any clinical features of hepatic toxicity or other organ toxicity following 6 weeks
of treatment with oral KC.
These results are compatible with Salmanpour
et al.
who used oral KC (600
mg/day for adults and 10 mg/kg per day for children for 30 days) in the treat-
ment of 64 patients with CL and found a very good response to oral ketocona-
zole with minimal side effects, none necessitating discontinuation of the medica-
tion [17]. Also Kubba
et al
. confirmed ketoconazole as effective and safe use of
oral KC in the treatment CL [18].
In addition, Peterson
et al.
[19], who performed a case-control trial of six
months course of oral ketoconazole versus placebo in twelve patients with chronic
mucocutaneous candidiasis with subsequent cross-over, shows marked benefi-
cial effects in all patients except one patient (8%) developed elevation of ALT
and ALP without jaundice that improved with lowering the dose. Also another
study [20] showed similar results done by Macnair
et al.
The study, which in-
cluded 988 patients treated with oral ketoconazole and monitored with liver en-
zymes assay, found little evidence of hepatic injury as they only identified 3 cases
(0.3%) of hepatitis during therapy all resolved with stopping therapy [20].
Moreover, another population based study of drug induced liver injury was
conducted in Iceland identified 96 patients over a two year period, none of
which was attributed to ketoconazole [21].
On the other hand, there are studies that oppose these results. In a study per-
formed on liver transplant patients due to hepatic failure, they found 6 (4%) out
of 137 were related to induced acute liver failure by ketoconazole [22].
In addition, the European medicines agency committee in 2013 recommended
that a ban be imposed on the use of oral ketoconazole in humans throughout the
European Union after concluding that the risk of serious liver injury outweighs
its benefits [12]. In the United States of America, FDA issued a warning that oral
ketoconazole can cause severe liver injury [13].
Furthermore, oral ketoconazole was discontinued in Australia in 2013 [23],
K. E. Sharquie et al.
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10.4236/jcdsa.2018.84028 270 J. Cosmetics, Dermatological Sciences and Applications
and in China in 2015 [24] for similar reasons.
It is interesting that in the present study, the elevated liver enzymes was iden-
tified in the combined treated group only using oral ketoconazole and zinc sul-
fate, while the other group who are using ketoconazole alone did not show any
elevation of hepatic enzymes suggesting drug-drug interaction might play a role
in this elevation of liver enzymes.
5. Conclusion
In conclusion, KC had been used in treating different skin diseases including
fungal and Leishmania infections but without clinical features of liver toxicity.
Liver enzymes were elevated in 3.9% of Leishmania treated cases but went to
normal levels after stopping therapy.
Disclosure
This study was an independent study and not funded by any drug companies.
Conflicts of Interest
The authors declare no conflicts of interest regarding the publication of this pa-
per.
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