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Ketoconazole-p aminobenzoic cocrystal, an improved antimycotic drug formulation, does not induce skin sensitization on the skin of BALBc mice

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Abstract

Fungal infections are a growing global health problem. Therefore, our group has synthetized and characterized an improved antimycotic by co-crystallization of ketoconazole and para-amino benzoic acid, named KET-PABA. The aim was to increase bioavailability, biocompatibility, and efficiency of the parent drug–ketoconazole. Based on our previous results showing the cocrystal improved physical properties, such as stability in suspension, solubility, as well as antimycotic efficiency compared to ketoconazole, the current study investigated the local possible side effects induced on the skin of BALBc mice by the application of KET-PABA cocrystal, in view of a further use as a topically applied antimycotic drug. A specific test (mouse ear-swelling test) was used, combined with the histopathological examination and the measurement of pro and anti-inflammatory cytokines and inflammation mediators. KET-PABA application was safe, without signs of skin sensitization shown by the mouse ear sensitization test, or histopathology. KET-PABA strongly inhibited proinflammatory cytokines such as IL1 α, IL1 β, IL6 and TNF α, and other proinflammatory inducers such as NRF2, compared to vehicle. KET-PABA had no effect on the levels of the anti-inflammatory cytokine IL10, or proinflammatory enzyme COX2 and had minimal effects on the activation of the NF-κB pathway. Overall, KET-PABA application induced no sensitization, moreover, it decreased the skin levels of proinflammatory molecules. The lack of skin sensitization effects on BALBc mice skin along with the inhibition of the proinflammatory markers show a good safety profile for topical applications of KET-PABA and show promise for a further clinical use in the treatment of cutaneous mycosis.

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Funding

This work was supported by a grant of the Romanian National Authority for Scientific Research and Innovation, CNCS/CCCDI–UEFISCDI, project number PN–III-P2-2.1-PED-2016–1521 (157PED), within PNCDI III.

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Contributions

Conceptualization of the research was made by S.D. and I.B. I.B. and R.M. carried out the experiments and contributed to the sample preparation. D.O. and I.B. contributed to the western blot analysis. F.A. performed the statistical analysis. X.F., F.M., I.K. were responsible for the preparation and characterization of the compound tested. A.N. performed the histopathological analysis. All authors approved the final article. The manuscript was written through the contributions of all authors. All authors have given approval to the final version of the manuscript.

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Correspondence to Gabriela Adriana Filip.

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The authors declare that there are no conflicts of interest. All authors have given approval to the final version of the manuscript. The authors declare no competing financial interest.

Ethics approval

All lab animal experiments were approved by ethics committee of the University of Medicine and Pharmacy Cluj-Napoca and the Veterinary Health Directorate, Romania (authorization number 67/ 06 06 2017).

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Danescu, S., Filip, G.A., Moldovan, R. et al. Ketoconazole-p aminobenzoic cocrystal, an improved antimycotic drug formulation, does not induce skin sensitization on the skin of BALBc mice. Inflammopharmacol 29, 721–733 (2021). https://doi.org/10.1007/s10787-021-00834-7

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