Ketoconazole does not decrease fungal amount in patients with seborrhoeic dermatitis

Zani, Marcelo B.; Soares, Renan Cardoso; Arruda, Ana Carolina Belini Bazán; Arruda, Lúcia Valéria Ramos de; Paulino, Luciana Campos

doi:10.1111/bjd.14501

Cited by 17 publications

(12 citation statements)

References 14 publications

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“…Furthermore, M globosa tends to show increased growth in summer when temperatures are high and people sweat more, yet seasonal risk for SD is lowest in summer and higher in cold and dry winter . Besides, decrease in Malassezia count was not always detected in vivo even with improved SD symptoms upon ketoconazole treatment . Many of the cited papers consider the role of Malassezia in susceptible individuals, yet the factors involved in individual susceptibility are still far too poorly understood, making their identification an important frontier for future SD research.…”

Section: Sd Aetiology: Malassezia Yeast—cause or Associated Factor?mentioning

confidence: 99%

Seborrheic dermatitis—Looking beyond Malassezia

Wikramanayake

Borda

Miteva

et al. 2019

Experimental Dermatology

101

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Seborrhoeic Dermatitis (SD) is a very common chronic and/or relapsing inflammatory skin disorder whose pathophysiology remains poorly understood. Yeast of the genus Malassezia has long been regarded as a main predisposing factor, even though causal relationship has not been firmly established. Additional predisposing factors have been described, including sebaceous activity, host immunity (especially HIV infection), epidermal barrier integrity, skin microbiota, endocrine and neurologic factors, and environmental influences. Genetic studies in humans and mouse models—with particularly interesting insights from examining the Mpzl3 knockout mice and their SD‐like skin phenotype, and patients carrying a ZNF750 mutation—highlight defects in host immunity, epidermal barrier and sebaceous activity. After synthesizing key evidence from the literature, we propose that intrinsic host factors, such as changes in the amount or composition of sebum and/or defective epidermal barrier, rather than Malassezia, may form the basis of SD pathobiology. We argue that these intrinsic changes provide favourable conditions for the commensal Malassezia to over‐colonize and elicit host inflammatory response. Aberrant host immune activity or failure to clear skin microbes may bypass the initial epidermal or sebaceous abnormalities. We delineate specific future clinical investigations, complemented by studies in suitable SD animal models, that dissect the roles of different epidermal compartments and immune components as well as their crosstalk and interactions with the skin microbiota during the process of SD. This research perspective beyond the conventional Malassezia‐centric view of SD pathogenesis is expected to enable the development of better therapeutic interventions for the management of recurrent SD.

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Section: Sd Aetiology: Malassezia Yeast—cause or Associated Factor?mentioning

confidence: 99%

Seborrheic dermatitis—Looking beyond Malassezia

Wikramanayake

Borda

Miteva

et al. 2019

Experimental Dermatology

101

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“…Using quantitative RT‐PCR, we have previously shown that amounts of Malassezia and total fungi did not decrease in SD patients under ketoconazole therapy 3 . Nevertheless, symptoms improved, suggesting mechanisms of action other than antifungal activity.…”

Section: Figurementioning

confidence: 93%

Ketoconazole beyond antifungal activity: Bioinformatics‐based hypothesis on lipid metabolism in dandruff and seborrheic dermatitis

Goularte-Silva

Paulino

2021

Experimental Dermatology

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Ketoconazole is an antifungal commonly used for symptom management of inflammatory skin diseases, such as dandruff and seborrheic dermatitis (D/SD). 1 Traditionally, lipophilic yeasts from Malassezia genus have been associated with D/SD; however, their role as causal agents has been questioned. 2 It has been shown that ketoconazole susceptibility varies among species, S1 and mechanisms of resistance have been described in dandruff-isolated strains. S2 Clinical trials indicate that ketoconazole is efficient in managing D/SD symptoms S3 ; however, they did not assess antifungal activity directly.Using quantitative RT-PCR, we have previously shown that amounts of Malassezia and total fungi did not decrease in SD patients under ketoconazole therapy. 3 Nevertheless, symptoms improved, suggesting mechanisms of action other than antifungal activity. There is evidence of immunosuppressive activity, S4 but it is not sufficient for explaining symptom improvement. The lipid composition of stratum corneum is potentially important for skin barrier disruption and chronic inflammation; and Malassezia metabolites, such as fatty acids and indoles, have been implicated in stratum corneum damage. S5 We argue that ketoconazole shifts host lipid profile from skin, which affects Malassezia lipid metabolism. The resulting alteration in lipid availability, including Malassezia-produced fatty acids, impacts bacterial communities and favours biotin-producing bacteria. Biotin has been implicated in inflammatory response, cell proliferation and biosynthesis of fatty acids 4 potentially improving symptoms of D/SD (Figure 1).In order to investigate effects of ketoconazole in D/SD skin homeostasis, we performed bioinformatics analyses. Chemical-protein interaction database surveys (Appendix S1) indicated that ketoconazole interacts with cytochrome enzymes (Figure S1). Functional analysis revealed lipid and steroid metabolism pathways (Table S1), suggesting that ketoconazole shifts sebum secretion. Ketoconazole-associated host and Malassezia lipid profile shifts might affect bacterial microbiota. It has been shown that

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“…Malassezia yeasts are found in healthy skin of all individuals, but dandruff and seborrheic dermatitis patients seem to have disruptions in the SC barrier, allowing oleic acid penetration ( 67 ). Treatment with ketoconazole-based topical antifungal improved inflammation symptoms associated with dandruff and seborrheic dermatitis but did not decrease the total fungi amount in scalp skin, indicating other mechanism pathways are more related to disease progression ( 68 ).…”

Section: Skin Diseases and Their Relationship With Hklksmentioning

confidence: 99%

Human Tissue Kallikreins-Related Peptidases Are Targets for the Treatment of Skin Desquamation Diseases

et al. 2022

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Human tissue Kallikrein-related peptidases (hKLKs) are serine proteases distributed in several tissues that are involved in several biological processes. In skin, many are responsible for skin desquamation in the Stratum Corneum (SC) of the epidermis, specially hKLK5, hKLK7, hKLK6, hKLK8, and hKLK14. In SC, hKLKs cleave proteins of corneodesmosomes, an important structure responsible to maintain corneocytes attached. As part of skin desquamation, hKLKs are also involved in skin diseases with abnormal desquamation and inflammation, such as Atopic Dermatitis (AD), psoriasis, and the rare disease Netherton Syndrome (NS). Many studies point to hKLK overexpression or overactive in skin diseases, and they are also part of the natural skin inflammation process, through the PAR2 cleavage pathway. Therefore, the control of hKLK activity may offer successful treatments for skin diseases, improving the quality of life in patients. Diseases like AD, Psoriasis, and NS have an impact on social life, causing pain, itchy and mental disorders. In this review, we address the molecular mechanisms of skin desquamation, emphasizing the roles of human tissue Kallikrein-related peptidases, and the promising therapies targeting the inhibition of hKLKs.

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Ketoconazole does not decrease fungal amount in patients with seborrhoeic dermatitis

Cited by 17 publications

References 14 publications

Seborrheic dermatitis—Looking beyond Malassezia

Seborrheic dermatitis—Looking beyond Malassezia

Ketoconazole beyond antifungal activity: Bioinformatics‐based hypothesis on lipid metabolism in dandruff and seborrheic dermatitis

Human Tissue Kallikreins-Related Peptidases Are Targets for the Treatment of Skin Desquamation Diseases

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