BACKGROUND: Microsporum audouinii has resurged recently. Infections with the dermatophyte are difficult to treat, which raises the question if we treat M. audouinii infections with the most effective antifungal (AF) agent.
OBJECTIVE: The aims of this study was to investigate an outbreak of tinea capitis (TC) in Denmark, address the challenges in outbreak management and to conduct two reviews regarding previous outbreaks and minimal inhibitory concentration (MIC).
METHODS: We used Wood\'s light, culture, direct microscopy, and PCR for screening and antifungal susceptibility testing (AFST) for treatment optimization. We performed two reviews to explore M. audouinii outbreaks and MIC values using broth microdilution method.
RESULTS: Of 73 screened individuals, 10 had confirmed M. audouinii infections. Clinical resistance to griseofulvin was observed in 4 (66%) cases. While previous outbreaks showed high griseofulvin efficacy, our study favoured terbinafine, fluconazole and itraconazole in our hard-to-treat cases. AFST guided the choice of AF. Through the literature search, we identified five M. audouinii outbreaks, where differences in management included the use of Wood\'s light and prophylactic topical AF therapy. Terbinafine MIC values from the literature ranged from 0.002 to 0.125 mg/L.
CONCLUSIONS: Use of Wood\'s light and preventive measurements were important for limiting infection. The literature lacked MIC data for griseofulvin against M. audouinii, but indicated sensitivity for terbinafine. The clinical efficacy for M. audouinii treatment was contradictory favouring both terbinafine and griseofulvin. AFST could have a key role in the treatment of difficult cases, but lack of standardisation of AFST and MIC breakpoints limits its usefulness.

The extensive and repeated application of chemical fungicides results in the rapid development of fungicide resistance. Novel antifungal pesticides are urgently required. Natural products have been considered precious sources of pesticides. It is necessary to discover antifungal pesticides by using natural products. Herein, 42 various griseofulvin derivatives were synthesized. Their antifungal activities were evaluated in vitro. Most of them showed good antifungal activity, especially 3d exhibited a very broad antifungal spectrum and the most significant activities against 7 phytopathogenic fungi. In vivo activity results suggested that 3d protected apples and tomatoes from serious infection by phytopathogenic fungi. These proved that 3d had the potential to be a natural product-derived antiphytopathogenic fungi agent. Furthermore, docking analysis suggested that tubulin might be one of the action sites of 3d. It is reasonable to believe that griseofulvin derivatives are worth further development for the discovery of new pesticides.

A sensitive and selective LC-MS/MS method was developed and validated for the quantitation of a novel Gαi2 inhibitor, GT-14, in rat plasma using a SCIEX 6500+ triple QUAD LC-MS system equipped with an ExionLC UHPLC unit. GT-14 (m/z 265.2 → 134.1) and griseofulvin (Internal Standard, IS) (m/z 353.1 → 285.1) were detected in a positive mode by electrospray ionization (ESI) using multiple reaction monitoring (MRM). The assay was linear in the concentration range of 0.78-1000 ng/mL in rat plasma. Both accuracy and precision values were within the acceptance criteria of ±15 %, as established by FDA guidance. The matrix effect was negligible from plasma, with signal percentages of 98.5-106.9 %. The mean recovery was 104.5 %, indicating complete extraction of GT-14 from plasma. GT-14 was found to be stable under different experimental conditions. The validated method was successfully applied to evaluate plasma protein binding and in vivo pharmacokinetics of GT-14 in rats.

Crystallization of amorphous pharmaceutical solids are widely reported to be affected by the addition of polymer, while the underlying mechanism require deep study. Herein, crystal growth behaviors of glassy griseofulvin (GSF) doped with various 1% w/w polymer were systematically studied. From the molecular structure, GSF cannot form the hydrogen bonding interactions with the selected polymer poly(vinyl acetate), polyvinyl pyrrolidone (PVP), 60:40 vinyl pyrrolidone-vinyl acetate copolymer (PVP/VA 64), and poly(ethylene oxide) (PEO). 1% w/w polymer exhibited weak or no detectable effects on the glass transition temperature (Tg) of GSF. However, crystal growth rates of GSF was altered from 4.27-fold increase to 2.57-fold decrease at 8 ℃ below Tg of GSF. Interestingly, the ability to accelerate and inhibit the growth rates of GSF crystals correlated well with Tg of polymer, indicating the controlling role of segmental mobility of polymer. Moreover, ring-banded growth of GSF was observed in the polymer-doped systems. Normal compact bulk and ring-banded crystals of GSF were both characterized as the thermodynamically stable form I. More importantly, formation of ring-banded crystals of GSF can significantly weaken the inhibitory effects of polymer on the crystallization of glassy GSF.

Amorphous solid dispersions (ASDs) represent an important approach for enhancing oral bioavailability for poorly water soluble compounds; however, assuring that these ASDs do not recrystallize to a significant extent during storage can be time-consuming. Therefore, various efforts have been undertaken to predict ASD crystallization levels with kinetic models. However, only limited success has been achieved due to limits on crystal content quantification methods and the complexity of crystallization kinetics. To increase the prediction accuracy, the accelerated stability assessment program (ASAP), employing isoconversion (time to hit a specification limit) and a modified Arrhenius approach, are employed here for predictive shelf-life modeling. In the current study, a model ASD was prepared by spray drying griseofulvin and HPMC-AS-LF. This ASD was stressed under a designed combinations of temperature, relative humidity and time with the conditions set to ensure stressing was carried out below the glass transition temperature (Tg) of the ASD. Crystal content quantification method by X-ray powder diffraction (XRPD) with sufficient sensitivity was developed and employed for stressed ASD. Crystallization modeling of the griseofulvin ASD using ASAPprime® demonstrated good agreement with long-term (40 °C/75 %RH) crystallinity levels and support the use of this type of accelerated stability studies for further improving ASD shelf-life prediction accuracy.

Marine microorganisms have long been recognized as potential sources for drug discovery. Griseofulvin was one of the first antifungal natural products and has been used as an antifungal agent for decades. In this study, 12 new griseofulvin derivatives [(±)-1-2, (+)-3, (±)-4, 10-12, and 14-15] and two new griseofulvin natural products (9 and 16) together with six known analogues [(-)-3, 5-8, and 13] were isolated from the mangrove-derived fungus Nigrospora sp. QQYB1 treated with 0.3% NaCl or 2% NaBr in rice solid medium. Their 2D structures and absolute configurations were established by extensive spectroscopic analysis (1D and 2D NMR, HRESIMS), ECD spectra, computational calculation, DP4 + analysis, and X-ray single-crystal diffraction. Compounds 1-4 represent the first griseofulvin enantiomers with four absolute configurations (2S, 6\'S; 2R, 6\'R; 2S, 6\'R; 2R, 6\'S), and compounds 9-12 represent the first successful production of brominated griseofulvin derivatives from fungi via the addition of NaBr to the culture medium. In the antifungal assays, compounds 6 and 9 demonstrated significant inhibitory activities against the fungi Colletotrichum truncatum, Microsporum gypseum, and Trichophyton mentagrophyte with inhibition zones varying between 28 and 41 mm (10 μg/disc). The structure-activity relationship (SAR) was analyzed, which showed that substituents at C-6, C-7, C-6\' and the positions of the carbonyl and double bond of griseofulvin derivatives significantly affected the antifungal activity.
UNASSIGNED: The online version contains supplementary material available at 10.1007/s42995-023-00210-0.

3D electron diffraction (3D ED) has shown great potential in crystal structure determination in materials, small organic molecules, and macromolecules. In this work, an automated, low-dose and low-bias 3D ED protocol has been implemented to identify six phases from a multiple-phase melt-crystallisation product of an active pharmaceutical ingredient, griseofulvin (GSF). Batch data collection under low-dose conditions using a widely available commercial software was combined with automated data analysis to collect and process over 230 datasets in three days. Accurate unit cell parameters obtained from 3D ED data allowed direct phase identification of GSF Forms III, I and the known GSF inclusion complex (IC) with polyethylene glycol (PEG) (GSF-PEG IC-I), as well as three minor phases, namely GSF Forms II, V and an elusive new phase, GSF-PEG IC-II. Their structures were then directly determined by 3D ED. Furthermore, we reveal how the stabilities of the two GSF-PEG IC polymorphs are closely related to their crystal structures. These results demonstrate the power of automated 3D ED for accurate phase identification and direct structure determination of complex, beam-sensitive crystallisation products, which is significant for drug development where solid form screening is crucial for the overall efficacy of the drug product.

This study aimed to evaluate the current management of tinea capitis in the United States, specifically focusing on patients aged 0-2 months, 2 months to 2 years, and 2 years to 18 years. An online survey, distributed through the Pediatric Dermatology Research Alliance and the Society of Pediatric Dermatology, revealed the following preferences: fluconazole for those under 2 months, griseofulvin for those aged 2 months to 2 years, and terbinafine for those aged 2 years and older. There exists inter-provider variation in tinea capitis treatment regimens within the pediatric dermatology community.

Tinea capitis is a dermatophyte scalp infection with a marked prevalence among the pediatric population. However, in the last few years, its epidemiology has changed due to increasing population migration worldwide. Host-specific and environmental factors contribute to the pathogenesis of tinea capitis. Clinically, tinea capitis may present as a subtle hair loss accompanied by scalp scaling, alopecia with scaly patches, or alopecia with black dots. A more severe form of tinea capitis is represented by kerion celsi, which clinically presents as a tender plaque covered by pustules and crusts. If left untreated, this dermatophytic infection may resolve with permanent scarring and alopecia. The pathological changes found in tinea capitis are reflected by a spectrum of clinical changes. Zoophilic infections typically prompt an extensive inflammatory reaction, while anthropophilic dermatophytoses often lack inflammation and result in more persistent lesions. Tinea capitis typically requires systemic antifungal therapy. Griseofulvin, terbinafine, itraconazole, and fluconazole are the main antifungal agents used. Currently, the duration of antifungal therapy varies based on the clinical presentation and type of dermatophyte involved. Through the reported cases and literature review, we aim to emphasize the importance of the early recognition of atypical variants of tinea capitis in immunocompetent children for the prompt initiation of systemic antifungal therapy, minimizing the need for prolonged treatment. Additionally, we emphasize the importance of regular laboratory testing during systemic antifungal therapy, particularly liver enzyme tests, to prevent adverse events, especially in cases requiring long-term treatment.

In response to the urgent demand for innovative antibiotics, theoretical investigations have been employed to design novel analogs. Because griseofulvin is a potential antibacterial agent, we have designed novel derivatives of griseofulvin to enhance its antibacterial efficacy and to evaluate their interactions with bacterial targets using in silico analysis. The results of this study reveal that the newly designed derivatives displayed the most robust binding affinities towards PBP2, tyrosine phosphatase, and FtsZ proteins. Additionally, molecular dynamics (MD) simulations underscored the notable stability of these derivatives when engaged with the FtsZ protein, as evidenced by root mean square deviation (RMSD), root mean square fluctuation (RMSF), radius of gyration (Rg), and solvent-accessible surface area (SASA). Importantly, this observation aligns with expectations, considering that griseofulvin primarily targets microtubules in eukaryotic cells, and FtsZ functions as the prokaryotic counterpart to microtubules. These findings collectively suggest the promising potential of griseofulvin and its designed derivatives as effective antibacterial agents, particularly concerning their interaction with the FtsZ protein. This research contributes to the ongoing exploration of novel antibiotics and may serve as a foundation for future drug development efforts.