Vaginal Ovule Loaded with Bismuth Lipophilic Nanoparticles and Cetylpyridinium Chloride Inhibits Human Cervical Carcinoma and Candida albicans Growth.

Bismuth lipophilic nanoparticles (BisBAL NPs) and cetylpyridinium chloride (CPC) are antineoplastic and antimicrobial in vitro. As a next pre-clinical step, a clinically viable dosage form for vaginal application was developed. Compendial pharmacopeial tests (mass uniformity, disintegration, and compressive mechanics) and inductively coupled plasma optical emission spectroscopy were conducted on in-house developed glycerinated gelatin (60:15 v/w) vaginal ovules containing BisBAL NP-CPC. The antimycotic activity of BisBAL NP-CPC vaginal ovules was analyzed using disk diffusion and cell viability XTT assays. The antitumor properties of BisBAL NP-CPC vaginal ovules were assessed by cell viability MTT tests. BisBAL NP-CPC and drug-free vaginal ovules deposited into ex vivo porcine vaginas disaggregated without signs of adverse cytotoxicity within the timespan of clinical efficacy. BisBAL NP-CPC vaginal ovules demonstrated antifungal efficacy comparable to miconazole: C. albicans growth inhibition haloes in diffusion tests were 23 ± 0.968 mm (n = 3) for BisBAL NP-CPC and 20.35 ± 0.899 mm (n = 3) for miconazole. Likewise, BisBAL NP-CPC vaginal ovules reduced HeLa cell growth by 81%, outperforming the clinical reference of 500 µM 5-fluouracil, which induced a 70% growth inhibition. BisBAL NP-CPC incorporated into glycerinated gelatin vaginal ovules constitute an innovative drug delivery system for topical antimycotic and anti-cervical carcinoma treatments.

Carbon Dots as Bioactive Antifungal Nanomaterials.

Nowadays, the widespread diffusion of infections caused by opportunistic fungi represents a demanding threat for global health security. This phenomenon has also worsened by the emergence of contagious events in hospitalisation environments and by the fact that many fungi have developed harsh and serious resistance mechanisms to the traditional antimycotic drugs. Hence, the design of novel antifungal agents is a key factor to counteract mycotic infections and resistance. Within this context, nanomaterials are gaining increasing attention thanks to their biocidal character. Among these, carbon dots (CDs) represent a class of zero-dimensional, photoluminescent and quasi-spherical nanoparticles which, for their great and tuneable features, have found applications in catalysis, sensing and biomedicine. Nevertheless, only a few works define and recapitulate their antifungal properties. Therefore, we aim to give an overview about the recent advances in the synthesis of CDs active against infective fungi. We described the general features of CDs and fungal cells, by highlighting some of the most common antimycotic mechanisms. Then, we evaluated the effects of CDs, antimicrobial drugs-loaded CDs and CDs-incorporated packaging systems on different fungi and analysed the use of CDs as fluorescent nano-trackers for bioimaging, showing, to all effects, their promising application as antifungal agents.

Fungal-mediated synthesis of silver nanoparticles: a novel strategy for plant disease management.

Various traditional management techniques are employed to control plant diseases caused by bacteria and fungi. However, due to their drawbacks and adverse environmental effects, there is a shift toward employing more eco-friendly methods that are less harmful to the environment and human health. The main aim of the study was to biosynthesize silver Nanoparticles (AgNPs) from Rhizoctonia solani and Cladosporium cladosporioides using a green approach and to test the antimycotic activity of these biosynthesized AgNPs against a variety of pathogenic fungi. The characterization of samples was done by using UV-visible spectroscopy, SEM (scanning electron microscopy), FTIR (fourier transmission infrared spectroscopy), and XRD (X-ray diffractometry). During the study, the presence of strong plasmon absorbance bands at 420 and 450 nm confirmed the AgNPs biosynthesis by the fungi Rhizoctonia solani and Cladosporium cladosporioides. The biosynthesized AgNPs were 80-100 nm in size, asymmetrical in shape and became spherical to sub-spherical when aggregated. Assessment of the antifungal activity of the silver nanoparticles against various plant pathogenic fungi was carried out by agar well diffusion assay. Different concentration of AgNPs, 5 mg/mL 10 mg/mL and 15 mg/mL were tested to know the inhibitory effect of fungal plant pathogens viz. Aspergillus flavus, Penicillium citrinum, Fusarium oxysporum, Fusarium metavorans, and Aspergillus aflatoxiformans. However, 15 mg/mL concentration of the AgNPs showed excellent inhibitory activity against all tested fungal pathogens. Thus, the obtained results clearly suggest that silver nanoparticles may have important applications in controlling various plant diseases caused by fungi.

Updates on antifungal pharmacotherapy in elasmobranchs: pharmacokinetics of 4 mg/kg voriconazole after IM and IV administration in undulate skates (Raja undulata) maintained under human care.

Introduction: Fungal diseases are frequently associated with elevated mortality rates in elasmobranchs. Currently, there is a notable absence of scientifically validated therapeutic medications that can ensure both effectiveness and safety when administered to this group of animals. The empirical prescription of azole antifungal agents, particularly voriconazole, has been posited as a potentially efficacious treatment approach for addressing most common mycoses in sharks and rays. However, there are still no published pharmacokinetic studies supporting its use in elasmobranchs and there is a lack of scientific base for its utilization in elasmobranchs. Methods: For this study, voriconazole was administered intravenously (IV) and intramuscularly (IM), at a single dose of 4 mg/kg to six adult undulate skates (Raja undulata). A washout period of 8 weeks was left between each route of administration. Blood samples were collected both before and at ten predetermined intervals after each dosing (0.25, 0.5, 1, 1.5, 2, 4, 8, 12, 24, and 36 h after drug administration). Plasma concentrations were quantified using a validated high-performance liquid chromatography method, and pharmacokinetic (PK) data was analyzed through non-compartmental methods. Results: The mean extrapolated concentration at 0 h (C0) after IV administration was 27.19 ± 7.15 µg/mL and the mean peak plasma concentrations (Cmax) ± SEM after IM administration resulted 2.98 ± 0.28 µg/mL at a mean time to maximum concentration (T max) of 1.33 ± 0.17 h. Terminal half-lives were calculated and resulted 11.18 ± 1.32 h for IV injections and 9.59 ± 1.38 h for IM injections. The area under the curve extrapolated to infinity was determined as 58.14 ± 2.79 h·µg/ml following IV injections and 37.60 ± 6.67 h·µg/ml following IM injections. The IM-administered voriconazole exhibited a mean absolute bioavailability of 64.67 ± 11.47%. Discussion: These discoveries provide backing for the possible application of voriconazole through the intramuscular route in undulate skates and support using lower dosage regimens compared to those required for oral administration, emphasizing the importance of conducting further pharmacokinetic studies with antifungals in elasmobranchs.

Production, optimization and characterization of partially purified anti-mycotic compound from marine soil derived streptomycetes originating at unexplored region of Bay of Bengal, India.

Sixty-eight morphologically distinct isolates of marine actinomycetes were derived from seashore, mangrove, and saltpan ecosystems located between the Palk Strait and Gulf of Mannar region, Bay of Bengal, Tamilnadu. Twenty-five (36.8%) isolates exhibited anti-mycotic activity against Candida albicans and Cryptococcus neoformans in preliminary screening, and 4 isolates with prominent activity were identified and designated at the genus level as Streptomyces sp. VPTS3-I, Streptomyces sp. VPTS3-2, Streptomyces sp. VPTSA1-4 and Streptomyces sp. VPTSA1-8. All the potential antagonistic isolates were further characterized with phenotypic and genotypic properties including 16S rRNA gene sequencing and identified species level as Streptomyces afghaniensis VPTS3-1, S. matensis VPTS3-2, S. tuirus VPTSA1-4 and S. griseus VPTSA1-8. In addition, the active fractions from the potential antagonistic streptomycetes were extracted with organic solvents by shake flask culture method and the anti-mycotic efficacies were evaluated. The optimization parameters for the production of the anti-mycotic compound were found to be pH between 7 and 8, the temperature at 30ᵒC, the salinity of 2%, incubation of 9 days, and starch and KNO3 as the suitable carbon and nitrogen sources respectively in starch casein medium.

Humic substance/metal-oxide multifunctional nanoparticles as advanced antibacterial-antimycotic agents and photocatalysts for the degradation of PLA microplastics under UVA/solar radiation.

As a result of the accumulation of plastic in the environment, microplastics have become part of the food chain, boosting the resistance of fungi and bacteria which can frequently encounter human beings. Employing photocatalytic degradation is a possible route towards the removal of chemical and biological pollutants, such as plastics and microplastic wastes as well as microorganisms. Using biowaste materials to design hybrid nanoparticles with enhanced photocatalytic and antimicrobial features would uphold the principles of the circular bioeconomy. Here, two unexpensive semiconductors-namely titanium dioxide (TiO2) and zinc oxide (ZnO) - were synthetized through solvothermal synthesis and combined with humic substances deriving from agrifood biomass. The preparation led to hybrid nanoparticles exhibiting enhanced ROS-generating properties for simultaneous applications as antimicrobial agents against different bacterial and fungal strains and as photoactive catalysts to degrade polylactic acid (PLA) microplastics under UVA and solar irradiation. In comparison to bare nanoparticles, hybrid nanoparticles demonstrated higher antibacterial and antimycotic capabilities toward various pathogenic microorganisms as well as advanced photocatalytic activity in the degradation of PLA with a carbonyl index reduction in the range of 15-23%, thus confirming a noteworthy ability in microplastics photodegradation under UVA and solar irradiation.

Combating Black Fungus: Using Allicin as a Potent Antifungal Agent against Mucorales.

Invasive fungal (IF) diseases are a leading global cause of mortality, particularly among immunocompromised individuals. The SARS-CoV-2 pandemic further exacerbated this scenario, intensifying comorbid IF infections such as mucormycoses of the nasopharynx. In the work reported here, it is shown that zygomycetes, significant contributors to mycoses, are sensitive to the natural product allicin. Inhibition of Mucorales fungi by allicin in solution and by allicin vapor was demonstrated. Mathematical modeling showed that the efficacy of allicin vapor is comparable to direct contact with the commercially available antifungal agent amphotericin B (ampB). Furthermore, the study revealed a synergistic interaction between allicin and the non-volatile ampB. The toxicity of allicin solution to human cell lines was evaluated and it was found that the half maximal effective concentration (EC50) of allicin was 25-72 times higher in the cell lines as compared to the fungal spores. Fungal allicin sensitivity depends on the spore concentration, as demonstrated in a drop test. This study shows the potential of allicin, a sulfur-containing defense compound from garlic, to combat zygomycete fungi. The findings underscore allicin's promise for applications in infections of the nasopharynx via inhalation, suggesting a novel therapeutic avenue against challenging fungal infections.

A Hyperbranched Polyol Process for Designing and Manufacturing Nontoxic Cobalt Nanocomposite.

A method for the design and synthesis of a metallopolymer composite (CoNP) based on cobalt nanoparticles using the hyperbranched polyol process was developed. It was shown that hyperbranched polyester polyols in a melted state can be both a reducing agent and a stabilizer of metal nanoparticles at the same time. The mechanism of oxidation of hyperbranched polyol was studied using diffuse reflectance IR spectroscopy. The process of oxidation of OH groups in G4-OH started from 90 °C and finished with the oxidation of aldehyde groups. The composition and properties of nanomaterials were determined with FT-IR and UV-Vis spectroscopy, Nanoparticle Tracking Analysis (NTA), thermogravimetric analysis (TG), powder X-ray diffraction (XRD), NMR relaxation, and in vitro biological tests. The cobalt-containing nanocomposite (CoNP) had a high colloidal stability and contained spheroid polymer aggregates with a diameter of 35-50 nm with immobilized cobalt nanoparticles of 5-7 nm. The values of R2 and R1 according to the NMR relaxation method for CoNPs were 6.77 mM·ms-1 × 10-5 and 4.14 mM·ms-1 × 10-5 for, respectively. The ratio R2/R1 = 0.61 defines the cobalt-containing nanocomposite as a T1 contrast agent. The synthesized CoNPs were nonhemotoxic (HC50 > 8 g/mL) multifunctional reagents and exhibited the properties of synthetic modulators of the enzymatic activity of chymosin aspartic proteinase and exhibited antimycotic activity against Aspergillus fumigatus. The results of the study show the unique prospects of the developed two-component method of the hyperbranched polyol process for the creation of colloidal multifunctional metal-polymer nanocomposites for theranostics.

The Austrian landscape of diagnostic capacity and access to treatment for invasive fungal infections.

INTRODUCTION: Immunosuppression after chemotherapy, stem cell transplantation or solid organ transplantation are the main risk factors for invasive fungal infections in Austria. Here, we aim to describe the status of laboratory mycology and the access to antifungal treatment in Austria. METHODS: Between October and November 2021, hospitals were contacted to participate in our online survey: www.clinicalsurveys.net/uc/IFI_management_capacity/. Centres were required to provide information on their institutional profile; self-assessment of burden of invasive fungal infections; access to microscopy, culture, serology, antigen detection and molecular testing; and availability of antifungal agents and therapeutic drug monitoring. RESULTS: Responses were collected from university hospitals and laboratories in Graz, Innsbruck, Linz and Vienna. The four hospitals can provide tertiary care and were highly specialised, including management of patients with severe immunosuppression. All sites consider the incidence of invasive fungal infections to be moderate. Access to microscopy, culture, serology, antigen detection and molecular testing is provided regardless of laboratory. The maximum capacity to identify fungi varies from institution to institution. All currently marketed antifungal agents are available at the four sites. CONCLUSION: Austria is currently well equipped to deal with the emerging threat of invasive fungal infections. However, hospitals may consider preparing for the potential endemicity of certain infections in the near future.

Microfluidizing Technique Application for Algerian Cymbopogon citratus (DC.) Stapf Effects Enhanced Volatile Content, Antimicrobial, and Anti-Mycotoxigenic Properties.

Medicinal plant extracts are a promising source of bioactive minor contents. The present study aimed to evaluate the distinguished volatile content of Algerian Cymbopogon citratus (DC.) Stapf before and after the microfluidization process and their related antimicrobial and anti-mycotoxigenic impacts and changes. The GC-MS apparatus was utilized for a comparative examination of Algerian lemongrass essential oil (LGEO) with its microfluidization nanoemulsion (MF-LGEO) volatile content. The MF-LGEO was characterized using Zetasizer and an electron microscope. Cytotoxicity, antibacterial, and antifungal activities were determined for the LGEO and MF-LGEO. The result reflected changes in the content of volatiles for the MF-LGEO. The microfluidizing process enhanced the presence of compounds known for their exceptional antifungal and antibacterial properties in MF-LGEO, namely, neral, geranial, and carvacrol. However, certain terpenes, such as camphor and citronellal, were absent, while decanal, not found in the raw LGEO, was detected. The droplet diameter was 20.76 ± 0.36 nm, and the polydispersity index (PDI) was 0.179 ± 0.03. In cytotoxicity studies, LGEO showed higher activity against the HepG2 cell line than MF-LGEO. Antibacterial LGEO activity against Gram-positive bacteria recorded an inhibitory zone from 41.82 ± 2.84 mm to 58.74 ± 2.64 mm, while the zone ranged from 12.71 ± 1.38 mm to 16.54 ± 1.42 mm for Gram-negative bacteria. Antibacterial activity was enhanced to be up to 71.43 ± 2.54 nm and 31.54 ± 1.01 nm for MF-LGEO impact against Gram-positive and Gram-negative pathogens. The antifungal effect was considerable, particularly against Fusarium fungi. It reached 17.56 ± 1.01 mm and 13.04 ± 1.37 mm for LGEO and MF-LGEO application of a well-diffusion assay, respectively. The MF-LGEO was more promising in reducing mycotoxin production in simulated fungal growth media due to the changes linked to essential compounds content. The reduction ratio was 54.3% and 74.57% for total aflatoxins (AFs) and ochratoxin A (OCA) contents, respectively. These results reflect the microfluidizing improvement impact regarding the LGEO antibacterial, antifungal and anti-mycotoxigenic properties.

Invasive Fungal Infections after Liver Transplantation.

Invasive fungal infections represent a major challenge in patients who underwent organ transplantation. Overall, the most common fungal infections in these patients are candidiasis, followed by aspergillosis and cryptococcosis, except in lung transplant recipients, where aspergillosis is most common. Several risk factors have been identified, which increase the likelihood of an invasive fungal infection developing after transplantation. Liver transplant recipients constitute a high-risk category for invasive candidiasis and aspergillosis, and therefore targeted prophylaxis is favored in this patient population. Furthermore, a timely implemented therapy is crucial for achieving optimal outcomes in transplanted patients. In this article, we describe the epidemiology, risk factors, prophylaxis, and treatment strategies of the most common fungal infections in organ transplantation, with a focus on liver transplantation.

[Pharmacological importance of novel spiro derivatives against human pathogenic fungi]. / Farmakologicheskoe znachenie novykh spiro 1,4-digidropiridinov protiv patogennykh dlia cheloveka gribov.

Human mycoses have become a threat to health world-wide. Unfortunately there are only a limited number of antimycotic drugs in use. In the present study, antifungal activity of earlier synthesized spiro-1,4-dihydropyridines (1,4-DHPs) was investigated. The antifungal activity of spiro-1,4-DHPs compounds were screened against Aspergillus flavus, A. fumigatus, and Candida albicans by using Disc Diffusion and Modified Microdilution method. Among six spiro-1,4-DHPs compounds tested all of them showed stronger antifungal activity possibly through inhibiting the synthesis of chitin in cell wall against A. flavus, A. fumigatus, and C. albicans as compared to fluconazole, a standard antifungal drug. The combination of compounds showed that the synthesized compounds had synergistic, additive effects as compared to currently used drugs as an antifungal agent. These results indicated that these designed compounds were potential chitin synthase inhibitors and had excellent antimycotic activity for the treatment of fungal infections.

Incidence of Invasive Fungal Infections in Liver Transplant Recipients under Targeted Echinocandin Prophylaxis.

Invasive fungal infections (IFIs) are one of the most important infectious complications after liver transplantation, determining morbidity and mortality. Antimycotic prophylaxis may impede IFI, but a consensus on indication, agent, or duration is still missing. Therefore, this study aimed to investigate the incidence of IFIs under targeted echinocandin antimycotic prophylaxis in adult high-risk liver transplant recipients. We retrospectively reviewed all patients undergoing a deceased donor liver transplantation at the Medical University of Innsbruck in the period from 2017 to 2020. Of 299 patients, 224 met the inclusion criteria. We defined patients as being at high risk for IFI if they had two or more prespecified risk factors and these patients received prophylaxis. In total, 85% (190/224) of the patients were correctly classified according to the developed algorithm, being able to predict an IFI with a sensitivity of 89%. Although 83% (90/109) so defined high-risk recipients received echinocandin prophylaxis, 21% (23/109) still developed an IFI. The multivariate analysis identified the age of the recipient (hazard ratio-HR = 0.97, p = 0.027), split liver transplantation (HR = 5.18, p = 0.014), massive intraoperative blood transfusion (HR = 24.08, p = 0.004), donor-derived infection (HR = 9.70, p < 0.001), and relaparotomy (HR = 4.62, p = 0.003) as variables with increased hazard ratios for an IFI within 90 days. The fungal colonization at baseline, high-urgency transplantation, posttransplant dialysis, bile leak, and early transplantation showed significance only in a univariate model. Notably, 57% (12/21) of the invasive Candida infections were caused by a non-albicans species, entailing a markedly reduced one-year survival. The attributable 90-day mortality rate of an IFI after a liver transplant was 53% (9/17). None of the patients with invasive aspergillosis survived. Despite targeted echinocandin prophylaxis, there is still a notable risk for IFI. Consequently, the prophylactic use of echinocandins must be critically questioned regarding the high rate of breakthrough infections, the increased occurrence of fluconazole-resistant pathogens, and the higher mortality rate in non-albicans Candida species. Adherence to the internal prophylaxis algorithms is of immense importance, bearing in mind the high IFI rates in case algorithms are not followed.

Invasive Fungal Breakthrough Infections under Targeted Echinocandin Prophylaxis in High-Risk Liver Transplant Recipients.

Invasive fungal infections (IFIs) are frequent and outcome-relevant complications in the early postoperative period after orthotopic liver transplantation (OLT). Recent guidelines recommend targeted antimycotic prophylaxis (TAP) for high-risk liver transplant recipients (HR-LTRs). However, the choice of antimycotic agent is still a subject of discussion. Echinocandins are increasingly being used due to their advantageous safety profile and the increasing number of non-albicans Candida infections. However, the evidence justifying their use remains rather sparse. Recently published data on breakthrough IFI (b-IFI) raise concerns about echinocandin efficacy, especially in the case of intra-abdominal candidiasis (IAC), which is the most common infection site after OLT. In this retrospective study, we analyzed 100 adult HR-LTRs undergoing first-time OLT and receiving echinocandin prophylaxis between 2017 and 2020 in a tertiary university hospital. We found a breakthrough incidence of 16%, having a significant impact on postoperative complications, graft survival, and mortality. The reasons for this may be multifactorial. Among the pathogen-related factors, we identified the breakthrough of Candida parapsilosis in 11% of patients and one case of persistent IFI due to the development of a secondary echinocandin resistance of an IAC caused by Candida glabrata. Consequently, the efficacy of echinocandin prophylaxis in liver transplantation should be questioned. Further studies are necessary to clarify the matter of breakthrough infections under echinocandin prophylaxis.

Using inorganic nanoparticles to fight fungal infections in the antimicrobial resistant era.

Fungal infections pose a serious threat to human health and livelihoods. The number and variety of clinically approved antifungal drugs is very limited, and the emergence and rapid spread of resistance to these drugs means the impact of fungal infections will increase in the future unless alternatives are found. Despite the significance and major challenges associated with fungal infections, this topic receives significantly less attention than bacterial infections. A major challenge in the development of fungi-specific drugs is that both fungi and mammalian cells are eukaryotic and have significant overlap in their cellular machinery. This lack of fungi-specific drug targets makes human cells vulnerable to toxic side effects from many antifungal agents. Furthermore, antifungal drug resistance necessitates higher doses of the drugs, leading to significant human toxicity. There is an urgent need for new antifungal agents, specifically those that can limit the emergence of new resistant species. Non-drug nanomaterials have primarily been explored as antibacterial agents in recent years; however, they are also a promising source of new antifungal candidates. Thus, this article reviews current research on the use of inorganic nanoparticles as antifungal agents. We also highlight challenges facing antifungal nanoparticles and discuss possible future research opportunities in this field. STATEMENT OF SIGNIFICANCE: Fungal infections pose a growing threat to human health and livelihood. The rapid spread of resistance to current antifungal drugs has led to an urgent need to develop alternative antifungals. Nanoparticles have many properties that could make them useful antimycotic agents. To the authors' knowledge, there is no published review so far that has comprehensively summarized the current development status of antifungal inorganic nanomaterials, so we decided to fill this gap. In this review, we discussed the state-of-the-art research on antifungal inorganic nanoparticles including metal, metal oxide, transition-metal dichalcogenides, and inorganic non-metallic particle systems. Future directions for the design of inorganic nanoparticles with higher antifungal efficacy and lower toxicity are described as a guide for further development in this important area.

Mechanisms by which small molecules of diverse chemotypes arrest Sec14 lipid transfer activity.

Phosphatidylinositol (PtdIns) transfer proteins (PITPs) enhance the activities of PtdIns 4-OH kinases that generate signaling pools of PtdIns-4-phosphate. In that capacity, PITPs serve as key regulators of lipid signaling in eukaryotic cells. Although the PITP phospholipid exchange cycle is the engine that stimulates PtdIns 4-OH kinase activities, the underlying mechanism is not understood. Herein, we apply an integrative structural biology approach to investigate interactions of the yeast PITP Sec14 with small-molecule inhibitors (SMIs) of its phospholipid exchange cycle. Using a combination of X-ray crystallography, solution NMR spectroscopy, and atomistic MD simulations, we dissect how SMIs compete with native Sec14 phospholipid ligands and arrest phospholipid exchange. Moreover, as Sec14 PITPs represent new targets for the development of next-generation antifungal drugs, the structures of Sec14 bound to SMIs of diverse chemotypes reported in this study will provide critical information required for future structure-based design of next-generation lead compounds directed against Sec14 PITPs of virulent fungi.

Experimental Examination of Solubility and Lipophilicity as Pharmaceutically Relevant Points of Novel Bioactive Hybrid Compounds.

The important physicochemical properties of three novel bioactive hybrid compounds with different groups (-CH3, -F and -Cl) were studied, including kinetic and thermodynamic solubility in pharmaceutically relevant solvents (buffer solutions and 1-octanol) as well as partition coefficient in system 1-octanol/buffer pH 7.4. The aqueous solubility of these chemicals is poor and ranged from 0.67 × 10-4 to 1.98 × 10-3 mol·L-1. The compounds studied are more soluble in the buffer pH 2.0, simulating the gastrointestinal tract environment (by an order of magnitude) than in the buffer pH 7.4 modelling plasma of blood. The solubility in 1-octanol is significantly higher; that is because of the specific interactions of the compounds with the solvent. The prediction solubility behaviour of the hybrid compounds using Hansen's three-parameter approach showed acceptable results. The experimental solubility of potential drugs was successfully correlated by means of two commonly known equations: modified Apelblat and van't Hoff. The temperature dependencies of partition coefficients of new hybrids in the model system 1-octanol/buffer pH 7.4 as a surrogate lipophilicity were measured by the shake flask method. It was found that compounds demonstrated a lipophilic nature and have optimal values of partition coefficients for oral absorption. Bioactive assay manifested that prepared compounds showed antifungal activities equal to or greater than fluconazole. In addition, the thermodynamic aspects of dissolution and partition processes have been examined. Bioactive assay manifested that prepared compounds showed antifungal activities equal to or greater than the reference drug.

Insight into the Inclusion Complexation of Fluconazole with Sulfonatocalix[4]naphthalene in Aqueous Solution, Solid-State, and Its Antimycotic Activity.

The study aims to assess the interaction between fluconazole and sulfonatocalix[4]naphthalene towards enhancing its dissolution performance and antimycotic activity. A solubility study was carried out at different pH conditions, and the results revealed the formation of a 1:1 molar ratio fluconazole-sulfonatocalix[4]naphthalene inclusion complex with an AL type phase solubility diagrams. The solid powder systems of fluconazole-sulfonatocalix[4]naphthalene were prepared using kneaded and co-evaporation techniques and physical mixtures. DCS, PXRD, TGA-DTG, FT-IR, and in vitro dissolution performance characterize the prepared systems. According to physicochemical characterization, the co-evaporation approach produces an amorphous inclusion complex of the drug inside the cavity of sulfonatocalix[4]naphthalene. The co-evaporate product significantly increased the drug dissolution rate up to 93 ± 1.77% within 10 min, unlike other prepared solid powders. The antimycotic activity showed an increase substantially (p ≤ 0.05, t-test) antimycotic activity of fluconazole co-evaporate mixture with sulfonatocalix[4]naphthalene compared with fluconazole alone against clinical strains of Candida albicans and Candida glabrata. In conclusion, sulfonatocalix[4]naphthalene could be considered an efficient complexing agent for fluconazole to enhance its aqueous solubility, dissolution performance, and antimycotic activity.

Allicin as a Volatile or Nebulisable Antimycotic for the Treatment of Pulmonary Mycoses: In Vitro Studies Using a Lung Flow Test Rig.

Fungal infections of the lung are an increasing problem worldwide and the search for novel therapeutic agents is a current challenge due to emerging resistance to current antimycotics. The volatile defence substance allicin is formed naturally by freshly injured garlic plants and exhibits broad antimicrobial potency. Chemically synthesised allicin was active against selected fungi upon direct contact and via the gas phase at comparable concentrations to the pharmaceutically used antimycotic amphotericin B. We investigated the suppression of fungal growth by allicin vapour and aerosols in vitro in a test rig at air flow conditions mimicking the human lung. The effect of allicin via the gas phase was enhanced by ethanol. Our results suggest that allicin is a potential candidate for development for use in antifungal therapy for lung and upper respiratory tract infections.

Ciclopirox Hydroxypropyl Chitosan (CPX-HPCH) Nail Lacquer and Breathable Cosmetic Nail Polish: In Vitro Evaluation of Drug Transungual Permeation Following the Combined Application.

BACKGROUND: Onychomycosis produces nail chromatic alterations that lead patients to mask them with cosmetic enamels. Objectives: Evaluate drug transungual permeation and antimycotic activity against selected strains after application of CPX-HPCH nail lacquer (NL) on the nail pre-covered with breathable cosmetic polish. METHODS: CPX transungual permeation after applying CPX-HPCH NL once or twice a day on bovine hoof membranes pre-covered with a breathable cosmetic nail polish was compared to that obtained applying CPX-HPCH NL directly on the membrane. The relevant experimental permeates underwent an in vitro susceptibility test. RESULTS: After CPX-HPCH NL application once a day, the drug transungual flux in the presence of cosmetic product tended to decrease while maintaining the antifungal activity. Two daily applications of CPX-HPCH NL on the membrane pre-covered with cosmetic polish exhibited the same permeation profile as daily application of the medicated lacquer directly on the nail as well as the same microbiological activity. CONCLUSIONS: The breathable cosmetic nail polish can be applied on the nail affected by onychomycosis in association with CPX-HPCH NL to mask the imperfections. The application of CPX-HPCH NL twice a day appears to be a good solution to obtain the same results as for a daily application without the presence of the cosmetic layer.