Abstract
Background
Acne vulgaris is a worldwide dermatological condition that has a complex pathophysiology in which androgens play an important role. Flutamide is a first-generation non-steroidal antiandrogen that can be used for acne treatment.
Aim
To evaluate the potential therapeutic efficacy and safety of topical flutamide in the treatment of acne vulgaris.
Methods
A andomized controlled study included two equal groups, each had 27 patients, with a total of 54 patients with mild to moderate acne vulgaris having inflammatory (papules and pustules) and non-inflammatory (comedones) lesions. For eight weeks, Group (A) received 1% Flutamide topical gel on the face twice daily, whereas Group (B) served as the control group.
Result
After 8 weeks of topical Flutamide 1% gel application twice daily, there was a significant reduction in papules count, and a highly significant reduction in pustules number from baseline.
Limitations
We recommend that topical Flutamide 1% gel be tried on a larger number of patients with acne vulgaris, for longer therapeutic duration and follow up periods after treatment.
Conclusion
Patients with acne vulgaris may find topical Flutamide 1% gel to be a viable, efficient, and safe solution with few adverse effects.
Introduction
Acne vulgaris is a worldwide skin disease with a complex pathophysiology. The four main phases of this pathophysiology include hyperkeratinization of the pilosebaceous unit, increased sebum production, anaerobic bacteria, and inflammatory reaction. 1
Sebocytes are the primary site for production and metabolism of sex hormones by 5α reductase and aromatase enzymes converting cholesterol to dihydrotestosterone (DHT) and estradiol, respectively. 2 Acne is a result of stimulation of sebum production and enhancement of ductal keratinocyte differentiation and plugging by androgens and their precursor substrates. 3
The effect of androgens in acne has been well known, so several antiandrogen strategies aimed at androgen modulation have been tried as combined oral contraceptive pills, spironolactone and Clascosterone. 4
Flutamide is a first-generation nonsteroidal antiandrogen used for treatment of advanced prostate cancer (PCa). It is also used for hirsutism and acne. It binds to androgen receptors and blocks testosterone and dihydrotestosterone interaction with receptors by competitive inhibition. 5
In the present study, we aimed to evaluate the potential therapeutic efficacy and safety of topical flutamide in the treatment of acne vulgaris.
Patients and Methods
This interventional randomized controlled study included 54 patients with mild to moderate acne vulgaris having inflammatory (papules and pustules) and non-inflammatory (comedones) of different sizes, distributions, and durations. The protocol of the study was approved by the IRB at Zagazig University (IRB 6597), Egypt, and approved by Clinicaltrials.gov (NCT05478330). Written consent was obtained from each patient prior to inclusion in the study. Patients with a background of systemic disease as chronic renal failure or hepatic insufficiency and pregnant or lactating women were excluded from participation. Patients had a history of acne treatment with systemic or topical antibiotics, retinoids, or hormonal therapy including antiandrogen and oral contraceptives within the past 3 months were excluded from the study.
The global acne grading system (GAGS) measured the severity of the lesions. Six regional subscores were added together to create the overall severity score. Each is calculated by multiplying the factors (1 for ≥1 comedone, 2 for ≥ 1 papule, 3 for 1 ≥ pustule, and 4 for ≥ 1 nodule), which are 2 for the forehead, 2 for each cheek, 1 for the nose, 1 for the chin, and 3 for both the chest and back. 6,7
Patients were classified into 2 groups (A and B), each containing 27 patients. Group A; Flutamide-treated patients were treated with 1% Flutamide topical gel that was applied on entire face twice daily for 8 weeks.
Group B; the control group were treated with topical placebo gel containing the same components as that of the other group except the active substance (flutamide) which was also administrated on entire face twice daily for 8 weeks.
Total lesion count and Acne severity index were assessed for each patient in both groups before and after the treatment course. Response to treatment was evaluated by the decrease in the number of comedones, papules, and pustules and by photographic comparison taken before treatment and at 2, 4, 6 and 8 weeks (at termination of therapy). The response was considered: marked response if there was a reduction of the comedones, papules and pustules by (75% to 100%), moderate response if comedones, papules and pustules regressed in number or size by (50 to 75%), mild response if the number or size of comedones, papules, and pustules decreased by (25 to 50%), and no response if the condition seems to be the same as the initial one at start of treatment.
Preparation of Flutamide 1% Gel
A flutamide formulation was prepared by dispersing the drug in propylene glycol, then mixing tween 80 with oleic acid. After adding the dispersion with tween 80 to oleic acid, distilled water was gradually added to form gel- like liquid crystals which were packed in suitable containers. 8 A gel-like liquid crystalline preparation containing 1% flutamide was prepared according to the following formulation: Flutamide liquid crystals contain 1 g of flutamide, 20 g of tween, 10 g of oleic acid, 10 g of propylene glycol, and up to 100 g of water.
Results
This study included 54 acne vulgaris patients, 4 males and 50 females, with an age range from 16 to 27 years old. They were stratified randomly and assigned to two equal groups; there was no significant difference between both groups regarding basic characteristics ensuring homogeneity (Supplemental Table 1).
After 8 weeks of treatment with topical flutamide 1% gel, there was a significant reduction in papules count (P < .05) and a highly significant reduction in pustules count (P < .001) but no significant reduction in the number of comedo count or TLC from baseline. Before treatment, comedones ranged from 12 to 71 with a mean of 39.15 and after 8 weeks of treatment, comedo ranged from 9 to 78 with a mean of 36.59, while papules ranged from 7 to 41 with a mean of 21.15 and after treatment ranged from 4 to 35 with a mean of 15.59, and finally pustules ranged from 1 to 6 with a mean of 2.89 and after treatment range from 0 to 2 with a mean of 0.70 (Supplemental Table 2).
In the vehicle group, there were no significant changes in the number of comedones, papules, pustules, or TLC from baseline after 8 weeks of treatment. There was a high significant difference (P < .001) in the number of pustules between both groups.
At the end of study regarding the degree of improvement, there was a high significant difference (P < .001) between flutamide and control groups. Levels of improvement with flutamide were mild in 11 patients, moderate in 10 patients and marked improvement in 5 patients, (Figure 1). Only one patient didn’t improve after treatment in the flutamide group. On the other hand, after the application of the placebo, only 8 patients showed mild improvement; the rest didn’t show any significant improvement.
Female patient, 21 years old with mild acne severity before (
The fifty-four patients were asked about any side effects either in flutamide group or control group, there was an insignificant difference between both groups. For the fluatmide treated group, 15 cases (55.6%) showed no side effects, while 12 cases (44.4%) showed minimal side effects in the form of scaling (7.4%), stinging (22.2%), erythema (7.4%) and dryness (25.9%) (5 cases showed stinging only , 1 case showed dryness only, 2 cases showed dryness and erythema, 2 cases showed dryness and scaling, and 2 cases showed dryness and stinging), while for the control group, only (22.2%) of patients showed side effects (2 cases showed stinging, 1 case showed dryness, 2 cases showed erythema, and 1 case showed scaling). No patients reported any systemic side effects due to flutamide (hot flushes, decreased libido, impotence, or GIT upsets), and the liver function test didn’t show any significant changes after treatment.
Discussion
Acne vulgaris is a cutaneous chronic inflammatory condition that has a complicated pathogenesis. Androgens, insulin, and insulin-like growth factor-1 are the principal hormones associated with acne vulgaris. 9 Flutamide is a selective androgen receptor antagonist, which has been considered as a potential therapy for adult-onset acne due to its antiandrogenic properties. 10,11 It is a competitive androgen receptor inhibitor used off-label to treat acne reducing the overall acne score and lesion count in several studies. 12,13
This study included 54 patients, divided randomly into two equal groups. The flutamide group and control group included 27 patients in each. The obtained results showed that after 8 weeks of topical Flutamide1% gel application, there was a significant reduction in the papules and pustules count from the baseline but with no significant reduction in comedones number or in the TLC. There was high significant difference in degree of improvement between flutamide and vehicle groups.
In the present study, the formulations of topical Flutamide 1% gel preparation contained oleic acid that may acts synergistically by several mechanisms: (i) promoting skin barrier homeostasis; (ii) antioxidative activities; (iii) antiinflammatory properties; (iv) direct and indirect (up- regulation of antimicrobial peptides) antimicrobial properties. 14 As Münster et al., reported that lipid coating or lipophilic material properties may favor higher uptake into hair follicles, because the hair follicles are filled with sebum and provide a relatively lipophilic environment. 15
The obtained data agree with the study of Cwieidzihski et al., who evaluated the effect of a 2.5% solution of topical Flutamide in 80 acne vulgaris patients for a period of 16 weeks. They observed that inflammatory lesions (papules, pustules and nodules) responded better to flutamide than to placebo (P = .01). There was no significant difference between the effect of Flutamide (−48.6%) and of placebo (−45.3%) on non nflammatory lesions (comedones). 16
Regarding side effects, in the Flutamide treated patients’ group, 15 cases showed no side effects, while 12 cases showed minimal side effects in the form of scaling, stinging, erythema, and dryness. The results are in parallel with the study of Cwieidzihski et al., who showed side effects in (65%) of flutamide treated group including scaling (62.5%) that was the most frequent adverse effect observed, which was generally more severe in intensity than the other reactions such as erythema, pruritus, burning/stinging, vesicles and yellow face. 16
The results of this study demonstrated the safety and efficacy of flutamide 1% topical gel in the treatment of inflammatory lesions (papules and pustules) in patients with acne vulgaris to minimize the unnecessary systemic side effects associated with the oral administration as the topical application allow delivery of high drug levels at the site of action , so it may be used as an adjuvant therapy with other lines of treatment for achieving better results and reducing complications of the disease. Further studies on a larger scale of patients and for longer therapeutic periods are needed to prove its beneficial effect in acne vulgaris treatment
Supplemental Material
Tables - Supplemental material for Efficacy and Safety of Topical Flutamide 1% Gel as an Adjunctive Therapy in the Treatment of Patients With Acne Vulgaris
Supplemental material, Tables, for Efficacy and Safety of Topical Flutamide 1% Gel as an Adjunctive Therapy in the Treatment of Patients With Acne Vulgaris by Amany Nassar, Ayman El Sayed, Afnan Samy and Reham Essam in Journal of Cutaneous Medicine and Surgery
Footnotes
Ethics Approval
Declaration of Conflicting Interests
The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The authors received no financial support for the research, authorship, and/or publication of this article.
Supplemental Material
Supplemental material for this article is available online.
References
Supplementary Material
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