The Safety of Oral Ketoconazole in the Treatment of Skin Diseases (Single Blinded, Therapeutic, Comparative Study)

Background: Ketoconazole was introduced in 1981 as the first in a series of antifungal agents that are characterized by nitrogen-containing ring. Ketoconazole acts against many different kinds of fungi such as candida, dermatophytes 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 patients with acute cutaneous leishmaniasis, tineacapitis, tineacorporis and tineaversicolor 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 patients. While group 2 included 900 patients and was divided into 3 subgroups: A: 600 patients 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 © 2018 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/


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 14α-demethylase which leads to the inhibition of the conversion of lanosterol to ergosterol and this will change cell membrane permeability. In addition, ketoconazole inhibits biosynthesis of triglycerides 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, gynecomastia, irregular menstrual cycle, decrease libido and impotency were recorded following oral KC due to its anti-androgenic effect [7].
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 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 including 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 during therapy and follow up of different skin diseases.

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 patients 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 included 900 patients treated with KC but without liver enzymes assays and patients 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, history of previous therapy. Also family history, past medical history, obstetric history 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 Specializations.

Therapeutic groups
Patients were divided into two groups: The first group included 51 patients with CL treated with KC with liver enzymes assessment and were divided into two subgroups: All patients with liver problems including alcoholic were excluded from the present study. Pregnant and lactating women were not included in the present work.

Results
A total 0f 951 patients were enrolled in this study. 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 Leishmaniasis 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 evidence 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.

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 tineacapitis, tineacorporis and tineaversicolor. 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 effects 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% 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 beneficial 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 included 988 patients treated with oral ketoconazole and monitored with liver enzymes 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 performed 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. and in China in 2015 [24] for similar reasons.
It is interesting that in the present study, the elevated liver enzymes was identified in the combined treated group only using oral ketoconazole and zinc sulfate, 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.

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.