Efficacy of human salivary mucin MUC7-derived peptide and histatin 5 in a murine model of candidiasis

Intini, Giuseppe; Aguirre, Alfredo; Bobek, Libuse A.

doi:10.1016/s0924-8579(03)00243-7

Cited by 7 publications

(8 citation statements)

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“…Our own study showed that neither MUC7 16-mer nor full-length Hsn5 was effective in the treatment of a murine model of vaginal candidiasis (15). Based on the results of studies with the other D-isomer peptides, we obtained the D-amino-acid isomer of MUC7 12-mer and initiated investigation of this peptide's potential for therapeutic use against oral candidiasis.…”

mentioning

confidence: 99%

Human Salivary Mucin MUC7 12-Mer-land 12-Mer-dPeptides: Antifungal Activity in Saliva, Enhancement of Activity with Protease Inhibitor Cocktail or EDTA, and Cytotoxicity to Human Cells

Wei

Bobek

2005

Antimicrob Agents Chemother

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MUC7 12-mer-L exhibits potent in vitro antifungal activity in low-ionic-strength buffers. In this study, we investigated the anticandidal activity and stability of MUC7 12-mer-L and its all-D-amino-acid isomer, along with Hsn5 12-mer (P113) and magainin-II, in human clarified and unclarified saliva in the absence or presence of protease inhibitor cocktail (PIC, which includes EDTA) or EDTA alone. In the absence of PIC or EDTA in saliva, only MUC7 peptides showed significant candidacidal activity. At a 100 M concentration in clarified saliva and unclarified saliva, MUC7 12-mer-D demonstrated 94 versus 64% killing, respectively; MUC7 12-mer-L showed 57 versus 32% killing; Hsn5 12-mer showed 16 versus 0% killing; and magainin-II showed no killing. Addition of PIC or EDTA to either saliva caused the enhancement of antifungal activities of all peptides, although to different degrees. Taken together, the results suggest that EDTA (a metal-dependent protease inhibitor and/or divalent cation chelator) enhanced the antifungal activity of all four peptides mainly by chelation of divalent cations present in saliva (known to inhibit peptide antifungal activity), and PIC enhanced the activity of the three L peptides above that achievable by EDTA alone through inhibition of all classes of proteases. Peptide stability in saliva monitored by sodium dodecyl sulfate-polyacrylamide gel electrophoresis showed no degradation of MUC7 12-mer-D and 23, 60, and 75% degradation of MUC7 12-mer-L, Hsn5 12-mer, and magainin-II, respectively. Cytotoxicity assays determined that, at 100 M peptide concentrations, MUC7 12-mer-D and 12-mer-L caused 3.5 and 4.3% hemolysis in phosphate-buffered saline and no toxicity to the HOK-16B cell line (derived from normal human oral keratinocytes). In summary, MUC7 12-mer peptides appear to be excellent candidates for investigation of antifungal activity in in vivo models of oral candidiasis.Candidiasis is the most common oral fungal infection diagnosed in humans. Due to the emergence of pathogens resistant to conventional antifungals and the toxicity of some antimycotics, intense efforts have been made to develop more effective antifungal agents for clinical use (1-3). Cationic antimicrobial peptides (CAMPs) have become attractive as novel candidates for this purpose. The native CAMPs contribute to innate host defense against a number of bacterial and fungal pathogens. They have been discovered from various natural sources, including humans, mammals, plants, insects, and bacteria (12, 13, 31). Among these, the well-characterized human salivary histatins and frog skin magainins show activity against a variety of microorganisms (18,31,32). MUC7, the low-molecular-mass human salivary mucin (comprised of 357 amino acid residues), exerts antimicrobial activity by binding to and clearing microorganisms from the oral cavity (25). While the full-length MUC7 has no appreciable candidacidal activity (11), we have shown that peptides derived from its N-terminal region have significant and broadspectrum fungicidal and...

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mentioning

confidence: 99%

Human Salivary Mucin MUC7 12-Mer-land 12-Mer-dPeptides: Antifungal Activity in Saliva, Enhancement of Activity with Protease Inhibitor Cocktail or EDTA, and Cytotoxicity to Human Cells

Wei

Bobek

2005

Antimicrob Agents Chemother

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“…[20] On the 4th day about 0.1 mL (10 6 cfu/mL) Candida albicans suspension in sterile saline with Tween 80 was inoculated into the mouse vaginal cavity with a tuberculin syringe. [13] The infection was confirmed both with microscopy and microbiological evaluation. Infected animals were randomly divided into groups according to therapy design.…”

Section: Microbiological Studiesmentioning

confidence: 94%

“…Therefore, the effect of Compritol types on the drug release and the interactions with nonsystemic antacids were investigated in vitro by USP dissolution apparatus I (basket) method. Murine vulvo-vaginal candidiasis model [13,14] was used to determine the change in the therapeutic effect of KTZ formulations in vivo. The efficacy of the dosage forms was evaluated microbiologically.…”

Section: Ketoconazolementioning

confidence: 99%

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In Vitro Release—In Vivo Microbiological and Toxicological Studies on Ketoconazole Lipid Granules

Özyazıcı

Gökçe

Özer

et al. 2007

Pharmaceutical Development and Technology

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In some multidrug therapy programs, ketoconazole (KTZ) may be administered with some antacids that could modify its dissolution rate and reduce its absorption, thus leading to therapeutic failures. The primary aim of this study was to evaluate the influence of Compritol HD5 ATO and Compritol 888 ATO on this interaction in comparison with commercial KTZ tablets. The second aim was to prepare lipid granules of KTZ that could be an alternative to the commercial formulation. Therefore, six KTZ sustained-release granules were prepared with different lipid concentrations, because they were found to be more suitable than tablets that are dissolved only in gastric medium. The results confirmed that the dissolution rate of KTZ granules was significantly reduced in the presence of antacids. The ideal formulation was selected as granules including 5% of Compritol lipids in relation to the suitability of the target profile. Therapeutic effects of orally administered, ideal KTZ granule formulations, and commercial tablets were evaluated in vivo by the experimental model of murine vulvo-vaginal candidiasis (VVC) with and without antacids. It was found that formulations were very effective on VVC, and the therapeutic effect decreased significantly in the presence of antacids. Histopathological studies were carried out for vagina, stomach, and liver tissues and hepatoxicity was also examined. The levels of reduced glutathione (GSH) were measured to assess the oxidative stress induced by KTZ and function of the liver. It was observed that orally administered formulations of KTZ were successful in treating candidiasis in mice without irritancy in stomach. However, liver tissues were damaged. The decreased GSH levels indicated toxicity in our study. This study suggested that in vitro release and in vivo microbiological-toxicological properties of KTZ were affected by antacids and drug-excipient interactions. Lipid granules of KTZ prepared with Compritol 888 ATO could be proposed as a new KTZ solid dosage form with optimum dissolution and therapeutic characteristics.

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“…Numbers above the sequences correspond to the actual amino acid position numbers of the native MUC7. Histatin 5 has also been examined for efficacy against C. albicans infection in a murine model of vulvo-vaginal candidiasis and a rat model of oral candidiasis in comparison with clotrimazole, the "gold standard" in candidiasis treatment (Intini et al 2003;and unpublished data), but the results showed that histatin 5 delivered in Pluronic F127 gel was not effective in either model. have been published.…”

Section: Histatinsmentioning

confidence: 99%

Innate Humoral Defense Factors

et al. 2005

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Efficacy of human salivary mucin MUC7-derived peptide and histatin 5 in a murine model of candidiasis

Cited by 7 publications

References 30 publications

Human Salivary Mucin MUC7 12-Mer-land 12-Mer-dPeptides: Antifungal Activity in Saliva, Enhancement of Activity with Protease Inhibitor Cocktail or EDTA, and Cytotoxicity to Human Cells

Human Salivary Mucin MUC7 12-Mer-land 12-Mer-dPeptides: Antifungal Activity in Saliva, Enhancement of Activity with Protease Inhibitor Cocktail or EDTA, and Cytotoxicity to Human Cells

In Vitro Release—In Vivo Microbiological and Toxicological Studies on Ketoconazole Lipid Granules

Innate Humoral Defense Factors

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