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Aldehyde oxidase (AO) contributes to the clearance of many approved and investigational small molecule drugs, which are often dual substrates of AO and drug‐metabolizing enzymes such as cytochrome P450s (CYPs). As such, the lack of established framework for quantitative translation of the clinical pharmacologic correlates of AO‐mediated clearance represents an unmet need. This study aimed to evaluate the utility of physiologically based pharmacokinetic (PBPK) modeling in the development of AO and dual AO‐CYP substrates. PBPK models were developed for capmatinib, idelalisib, lenvatinib, zaleplon, ziprasidone, and zoniporide, incorporating in vitro functional data from human liver subcellular fractions and human hepatocytes. Prediction of metabolic elimination with/without the additional empirical scaling factors (ESFs) was assessed. Clinical pharmacokinetics, human mass balance, and drug–drug interaction (DDI) studies with CYP3A4 modulators, where available, were used to refine/verify the models. Due to the lack of clinically significant AO‐DDIs with known AO inhibitors, the fraction metabolized by AO (fmAO) was verified indirectly. Clearance predictions were improved by using ESFs (GMFE ≤1.4‐fold versus up to fivefold with physiologically‐based scaling only). Observed fmi from mass balance studies were crucial for model verification/refinement, as illustrated by capmatinib, where the fmAO (40%) was otherwise underpredicted up to fourfold. Subsequently, independent DDI studies with ketoconazole, itraconazole, rifampicin, and carbamazepine verified the fmCYP3A4, with predicted ratios of the area under the concentration–time curve (AUCR) within 1.5‐fold of the observations. In conclusion, this study provides a novel PBPK‐based framework for predicting AO‐mediated pharmacokinetics and quantitative assessment of clinical DDI risks for dual AO‐CYP substrates within a totality‐of‐evidence approach. [ABSTRACT FROM AUTHOR]

Background/objectives Methods Results Conclusion Topically applied antifungal agents can induce adverse effects, such as pain and irritation. The transient receptor potential (TRP) channels—TRPA1 and TRPV1—mainly expressed in sensory neurons, act as sensors for detecting irritants. This study aims to evaluate the involvement of nociceptive channels in topical antifungal‐induced pain and irritation. We tested nine topical antifungals belonging five classes: isoconazole, econazole, miconazole, clotrimazole, and ketoconazole as imidazoles; liranaftate as a thiocarbamate; terbinafine as an allylamine; amorolfine as a morpholine; and butenafine as a benzylamine.Intracellular calcium concentrations ([Ca2+]i) and membrane currents in response to antifungals were measured to estimate channel activity using heterologously expressing cells and isolated mouse sensory neurons.In mouse TRPA1‐expressing cells, all the tested drugs induced an increase in [Ca2+]i, which was abrogated or reduced by a TRPA1 blocker. Although many drugs evoked the TRPA1‐nonspecific [Ca2+]i response at high concentrations, responses to clotrimazole, ketoconazole, and liranaftate were TRPA1 specific and elicited current responses in TRPA1‐expressing cells. In mouse TRPV1‐expressing cells, clotrimazole and ketoconazole elicited [Ca2+]i and current responses. In mouse sensory neurons, liranaftate‐induced increase in [Ca2+]i was abrogated by a TRPA1 blocker and Trpa1 deletion. Responses to ketoconazole were inhibited by TRPA1 and TRPV1 blockers and by the genetic deletion of either channel.These results suggest that topical antifungal‐induced pain and irritation are attributable to the activation of nociceptive TRPA1 and/or TRPV1 channel/s. Consequently, caution should be exercised in the use of topical antifungals with symptoms of pain. [ABSTRACT FROM AUTHOR]

Amide bioisoterism is a widely used strategy in drug development to fine‐tune physicochemical, pharmacokinetic, and metabolic properties, eliminate toxicity and gain intellectual property rights in uncharted chemical space. Of these, oxetane‐amines offer particularly exciting possibilities as bioisosteres, although they are less frequently investigated than warranted due to the lack of simple and widely applicable synthetic methods. Herein, we report a two‐step, practical, modular, robust, and scalable method for the construction of oxetane‐containing amide bioisosteres that relies on the readily available oxetan‐3‐one. This operationally simple procedure exploits the enhanced reactivity of the keto group of the commercially available oxetan‐3‐one to form amine‐benzotriazole intermediates, which springloaded adducts are then reacted with various aliphatic and aromatic organometallic reagents under mild conditions to afford various amino‐oxetanes in good to high yields. The simplicity and broad applicability of the method greatly facilitates the synthesis of derivatives that were previously difficult or impossible to produce. The usefulness of this method in the field medicinal chemistry was also demonstrated by eliminating the well‐known metabolic problem of ketoconazole. [ABSTRACT FROM AUTHOR]

Mollusks are the second most diverse animal phylum, yet little is known about their endocrinology or how they respond to endocrine disrupting compound (EDC) pollution. Characteristic effects of endocrine disruption are reproductive impairment, skewed sex ratios, development of opposite sex characteristics, and population decline. However, whether classical vertebrate EDCs, such as steroid hormone-like chemicals and inhibitors of steroidogenesis, exert effects on mollusks is controversial. In the blue mussel, Mytilus edulis, EDC exposure is correlated with feminized sex ratios in wild and laboratory mussels, but sex reversal has not been confirmed. Here, we describe a non-destructive qPCR assay to identify the sex of M. edulis allowing identification of males and females prior to experimentation. We exposed male mussels to 17α-ethinylestradiol and female mussels to ketoconazole, EDCs that mimic vertebrate steroid hormones or inhibit their biosynthesis. Both chemicals changed the sex of individual mussels, interfered with gonadal development, and disrupted gene expression of the sex differentiation pathway. Impacts from ketoconazole treatment, including changes in steroid levels, confirmed a role for steroidogenesis and steroid-like hormones in mollusk endocrinology. The present study expands the possibilities for laboratory and field monitoring of mollusk species and provides key insights into endocrine disruption and sexual differentiation in bivalves. [ABSTRACT FROM AUTHOR]

A highly sensitive voltametric technique has been developed for the electrochemical oxidation of ketoconazole (KTZ), a member of the azole antifungal drug class renowned for its inhibitory effect on fungal growth. Employing a tailored glassy carbon electrode TiO2-HNC/GCE, this method exhibits exceptional sensitivity and specificity in KTZ determination. Characterization of the electrode was meticulously conducted through XRD and SEM–EDS analyses. The well-established cyclic voltammetry (CV) and square wave voltammetry (SWV) were utilized to explore KTZ analysis. Optimal oxidation of KTZ was noticed at a pH of 7.0. The process displayed an irreversible and diffusion-controlled nature. A linear detection range spanning from 1.0 to 10.0 μM was delineated through concentration variance assessments. Notably, the detection limit was determined to be 1.67 nM and the quantification limit was calculated to be 5.58 nM, which was found to be surpassing most of the previous findings. The applicability of the developed sensor was tested for KTZ concentration detection in biological samples and pharmaceutical samples. Evaluation of vital parameters underscores the ability of the sensor in terms of stability and sensitivity, rendering it conducive for employment in pharmacokinetics and quality control laboratories. [ABSTRACT FROM AUTHOR]

Environmental sampling around a landfill site in the UK previously identified the methylimidazolium ionic liquid, 1-octyl-3-methylimidazolium (M8OI), in the soil. More recently, M8OI was shown to be detectable in sera from 5/20 PBC patients and 1/10 controls and to be oxidised on the alkyl chain in the human liver. The objective of this study was to examine the metabolism of M8OI in humans in more detail. In human hepatocytes, M8OI was mono-oxygenated to 1-(8-Hydroxyoctyl)-3-methyl-imidazolium (HO8IM) then further oxidised to 1-(7-carboxyheptyl)-3-methyl-1H-imidazol-3-ium (COOH7IM). The addition of ketoconazole—in contrast to a range of other cytochrome P450 inhibitors—blocked M8OI metabolism, suggesting primarily CYP3A-dependent mono-oxygenation of M8OI. Hepatocytes from one donor produced negligible and low levels of HO8IM and COOH7IM, respectively, on incubation with M8OI, when compared to hepatocytes from other donors. This donor had undetectable levels of CYP3A4 protein and low CYP3A enzyme activity. Transcript expression levels for other adult CYP3A isoforms—CYP3A5 and CYP3A43—suggest that a lack of CYP3A4 accounted primarily for this donor's low rate of M8OI oxidation. Insect cell (supersome) expression of various human CYPs identified CYP3A4 as the most active CYP mediating M8OI mono-oxygenation, followed by CYP3A5. HO8IM and COOH7IM were not toxic to human hepatocytes, in contrast to M8OI, and using a pooled preparation of human hepatocytes from five donors, ketoconazole potentiated M8OI toxicity. These data demonstrate that CYP3A initiates the mono-oxygenation and detoxification of M8OI in adult human livers and that CYP3A4 likely plays a major role in this process. [ABSTRACT FROM AUTHOR]

Background: Many clinicians prescribe antifungal agents to treat canine otitis externa (OE). However, studies evaluating the antifungal effects of N‐acetylcysteine (NAC) and its combinations are limited. Hypothesis/objectives: The aim of this study was to evaluate the antifungal effects of NAC alone and in combination with other antifungal agents against Malassezia pachydermatis isolated from canine OE. Materials and methods: M. pachydermatis samples were collected from 13 dogs with OE. The final concentration of the inoculum suspensions of M. pachydermatis was 1–5 × 106 colony forming units/mL. The concentrations of the test compounds ketoconazole (KTZ), terbinafine (TER), nystatin (NYS) and NAC were 0.02–300 µg/mL, 0.04–80 µg/mL, 0.16–40 µg/mL and 1.25–20 mg/mL, respectively. The minimum inhibitory concentration (MIC) was measured to evaluate the susceptibility of the M. pachydermatis to KTZ, TER, NYS and NAC. The checkerboard testing method and fractional inhibitory concentration index were used to evaluate the effect of NAC in combination with KTZ, TER and NYS against M. pachydermatis. Results: The MIC90 values of M. pachydermatis were 4.6875–9.375 µg/mL, 1.25 µg/mL, 5–10 µg/mL and 10 mg/mL for KTZ, TER, NYS and NAC, respectively. The synergistic effects of KTZ, TER and NYS with NAC were identified in 0/13, 2/13 and 0/13 isolates, respectively. Conclusions and clinical relevance: NAC had an antifungal effect against M. pachydermatis but did not exert synergistic effects when used with KTZ, TER and NYS. Thus, the use of NAC alone as a topical solution could be considered an effective treatment option for canine OE involving M. pachydermatis. [ABSTRACT FROM AUTHOR]

Background & Objectives: Genotypic identification of the etiologic agents of vaginal candidiasis (VC) is of significance in epidemiologic studies and in the establishment of adequate treatment protocol. The aim of this study was to determine the antifungal susceptibility and gene diversity of C. albicans isolated from a group of Jordanian women with VC. Methods: A total of 312 isolates of candida species, recovered from women with vaginal candidiasis who attended gynecology clinics affiliated to three major private hospitals in Amman over a period of five months (July 2020 to December 2020) were included in this study. The isolated Candida were characterized by phenotypic and genotypic means. Genotypic studies were performed using specific PCR primers of the rDNA and RPS genes. Susceptibility testing of all C. albicans isolates was conducted following the National Committee for Clinical Laboratory Standards and E-test strips. Results: Candida albicans was the most dominant Candida spp. that caused VC among the studied population. C. albicans isolates were found to be of three different subtypes at the 25S rDNA gene. All isolates belonged to genotypes A, B and C while genotypes D and E were not detected. The diversity of C. albicans was higher on the basis of RPS region where the use of two markers (P-I and P-II) resulted in the identification of nine distinct C. albicans subtypes. The sensitivity testing revealed variations in the susceptibility of various genotypes to different antifungal drugs. Genotype A isolates were more susceptible to fluconazole, flucytosine and ketoconazole than genotypes B and C. Conclusion: Candida albicans incriminated as etiologic agents of vaginitis among Jordanian women exhibited relationship between various genotypes and antifungal drugs. [ABSTRACT FROM AUTHOR]

Background: The emergence of tolerance to antifungal agents in Candida albicans complicates the treatment of fungal infections. Understanding the mechanisms underlying this tolerance is crucial for developing effective therapeutic strategies. Objective: This study aims to elucidate the genetic and molecular basis of ketoconazole tolerance in C. albicans, focusing on the roles of chromosomal aneuploidy, Hsp90, and calcineurin. Methods: The wild-type C. albicans strain SC5314 was exposed to increasing concentrations of ketoconazole (0.015-32 µg/mL) to select for tolerant adaptors. Disk diffusion and spot assays were used to assess tolerance. Wholegenome sequencing identified chromosomal changes in the adaptors. The roles of Hsp90 and calcineurin in maintaining and developing ketoconazole tolerance were investigated using specific inhibitors and knockout strains. Results: Adaptors exhibited tolerance to ketoconazole concentrations up to 16 µg/mL, a significant increase from the parent strain's inhibition at 0.015 µg/mL. All tolerant adaptors showed amplification of chromosome R, with 29 adaptors having trisomy and one having tetrasomy. This aneuploidy was unstable, reverting to euploidy and losing tolerance in drug-free conditions. Both Hsp90 and calcineurin were essential for maintaining and developing ketoconazole tolerance. Inhibition of these proteins resulted in loss of tolerance. The efflux gene CDR1 was not required for the development of tolerance. Chromosome R trisomy and tetrasomy induce cross-tolerance to other azole antifungal agents, including clotrimazole and miconazole, but not to other antifungal classes, such as echinocandins and pyrimidines, exemplified by caspofungin and 5-flucytosine. Conclusion: Ketoconazole tolerance in C. albicans is mediated by chromosomal aneuploidy, specifically chromosome R amplification, and requires Hsp90 and calcineurin. These findings highlight potential targets for therapeutic intervention to combat antifungal tolerance and improve treatment outcomes. [ABSTRACT FROM AUTHOR]

Background: Perianal fistulas are painful ulcers or sinus tracts that disproportionately affect German shepherd dogs and are proposed as a spontaneous animal model of fistulising Crohn's disease. Objectives: To characterise the rectal and cutaneous microbiota in German shepherd dogs with perianal fistulas and to investigate longitudinal shifts with lesion resolution during immunomodulatory therapy. Animals: Eleven German shepherd dogs with perianal fistulas and 15 healthy German shepherd dogs. Materials and Methods: Affected dogs were evaluated and swabbed at three visits, 30 days apart, while undergoing treatment with ciclosporin and ketoconazole. Healthy German shepherd dogs were contemporaneously sampled. Sites included the rectum, perianal skin and axilla. The microbiome was evaluated following sequencing of the V4 hypervariable region of the 16S ribosomal RNA (rRNA) gene. Results: Alpha diversity was not significantly different between healthy and affected dogs at each of the three body sites (p > 0.5), yet rectal and perianal beta diversities from affected dogs differed significantly from those of healthy dogs at Day 0 (p = 0.004). Rectal and perianal relative abundance of Prevotella spp. increased and perianal Staphylococcus spp. relative abundance decreased in affected dogs over time, coincident with lesion resolution. Conclusions and Clinical Relevance: Changes in lesional cutaneous and rectal microbiota occur in German shepherd dogs with perianal fistulas and shift over time with lesion resolution during immunomodulatory therapy. Further investigations of the role of cutaneous and enteric microbiota in the pathogenesis of perianal fistulas, and whether manipulation of microbial populations may ameliorate disease, are needed. [ABSTRACT FROM AUTHOR]

Background: Cutibacterium (C. acnes) lipase activity can be reduced by topical antifungal cream called ketoconazole (KTZ). Additionally, it contains anti-inflammatory and anti-androgenic properties. The aim of this study was to evaluate the efficacy of topical ketoconazole 2% cream versus placebo in the treatment of mild and moderate acne vulgaris. Patients & Methods: 40 patients presented by mild and moderate acne were instructed to apply ketoconazole 2 % cream to the right half of the face and placebo to the left half of the face twice daily for 8 weeks Results: The mean percent reduction of inflammatory lesions (papules and pustules) and Total lesions count from baseline was significantly higher in ketoconazole than placebo. There was a statistically significant decrease in acne severity assessed by IGA score in both sides. The success rate of ketoconazole was significantly higher than placebo. In ketoconazole side, 17.5% of patients considered clear versus12.5%in control side and 52.5% almost clear versus 35% in control side. There was a statistically significant negative relationship between the therapeutic response and number of pustules in each side. Conclusion: Topical ketoconazole 2% can be an effective and safe treatment option for mild and moderate acne vulgaris. [ABSTRACT FROM AUTHOR]

The structures of three multicomponent crystals formed with imidazole‐based drugs, namely metronidazole, ketoconazole and miconazole, in conjunction with trithiocyanuric acid are characterized. Each of the obtained adducts represents a different category of crystalline molecular forms: a cocrystal, a salt and a cocrystal of salt. The structural analysis revealed that in all cases, the N—H...N hydrogen bond is responsible for the formation of acid–base pairs, regardless of whether proton transfer occurs or not, and these molecular pairs are combined to form unique supramolecular motifs by centrosymmetric N—H...S interactions between acid molecules. The complex intermolecular forces acting in characteristic patterns are discussed from the geometric and energetic perspectives, involving Hirshfeld surface analysis, pairwise energy estimation, and natural bond orbital calculations. [ABSTRACT FROM AUTHOR]

Background: Ketoconazole (KT) use has raised safety concern regarding hepatotoxicity. Silymarin (SL) is a natural bioactive substance with activities on a wide range of human pathologies. The protective activity of SL against KT-induced hepatotoxicity in rats was determined in this study. Methods: Thirty adult Wistar rats of both sexes (220-300g) of n= 5/group were used. Groups I (Control) and II were orally administered with normal saline (0.2mL/day) and SL (200 mg/kg/day), respectively, whereas group III was orally administered with KT (200 mg/kg/day) for 28 days. Groups IV-VI were orally supplemented with SL (50 mg/kg/day, 100 mg/kg/day, and 200 mg/kg/day) before the administration of KT (200 mg/kg/day) for 28 days, respectively. On day 29, the rats were anesthetized and blood samples were collected and examined for biochemical markers. Liver tissues were collected and assessed for oxidative stress markers and histology. Results: KT significantly (p<0.01) increased liver weight, and significantly (p<0.001) increased serum bilirubin, amino transferases, lactate dehydrogenase, gamma-glutamyl transferase, alkaline phosphatase, and liver malondialdehyde levels when compared to the control. KT significantly (p<0.01) decreased body weight, and significantly (p<0.001) decreased liver catalase, glutathione peroxidase, superoxide dismutase, and glutathione levels when compared to the control. KT caused hepatocellular necrosis. However, body, and liver weights and the aforementioned biochemical and oxidative stress markers were significantly restored in a dose-related fashion by SL supplementation at 50 mg/kg (p<0.05), 100 mg/kg (p<0.01), and 200 mg/kg (p<0.001) when compared to KT. The various doses of SL restored liver histology. Conclusion: SL may have clinical benefit in KT-induced hepatotoxicity. [ABSTRACT FROM AUTHOR]

Abstract Mollusks are the second most diverse animal phylum, yet little is known about their endocrinology or how they respond to endocrine disrupting compound (EDC) pollution. Characteristic effects of endocrine disruption are reproductive impairment, skewed sex ratios, development of opposite sex characteristics, and population decline. However, whether classical vertebrate EDCs, such as steroid hormone-like chemicals and inhibitors of steroidogenesis, exert effects on mollusks is controversial. In the blue mussel, Mytilus edulis, EDC exposure is correlated with feminized sex ratios in wild and laboratory mussels, but sex reversal has not been confirmed. Here, we describe a non-destructive qPCR assay to identify the sex of M. edulis allowing identification of males and females prior to experimentation. We exposed male mussels to 17α-ethinylestradiol and female mussels to ketoconazole, EDCs that mimic vertebrate steroid hormones or inhibit their biosynthesis. Both chemicals changed the sex of individual mussels, interfered with gonadal development, and disrupted gene expression of the sex differentiation pathway. Impacts from ketoconazole treatment, including changes in steroid levels, confirmed a role for steroidogenesis and steroid-like hormones in mollusk endocrinology. The present study expands the possibilities for laboratory and field monitoring of mollusk species and provides key insights into endocrine disruption and sexual differentiation in bivalves.

Ketoconazole and Minocycline based ointment for Combating Fungal and bacterial infections. As the global burden of infectious diseases continues to rise, innovative therapeutic approaches are essential. The proposed based ointment offers a promising solution, capitalizing on the synergistic antimicrobial properties of ketoconazole and minocycline.The development process involves a comprehensive exploration of various pharmaceutical parameters, including formulation strategies, physicochemical characterization, stability assessment, and biopharmaceutical considerations. By integrating these components, this review provide potential overview of ketoconazole,minocycline based ointment as a versatile therapeutic option.Formulation Strategies the article discusses the formulation techniques used to create a stable and efficacious ointment, taking into account factors such as excipient selection, particle size, and compatibility of active ingredients.Physicochemical Characterization an in-depth analysis of the physical and chemical properties of the based ointment is presented, including particle size distribution, morphology, crystallinity, and drug release profiles.Stability assessment the long-term stability of the powder is critically evaluated, examining factors like moisture sensitivity, photostability, and shelf-life considerations, ensuring its suitability for clinical use.Biopharmaceutical Considerationsthe pharmacokinetic and pharmacodynamic aspects of ketoconazole and minocycline in the ointment formulation are discussed, highlighting their bioavailability and potential drug-drug interactions.Antimicrobial Efficacy the antimicrobial activity of the powder against fungal and bacterial pathogens is assessed, shedding light on its potential as a broad-spectrum therapeutic agent.clinical relevance: The article explores the clinical implications of this novel formulation, including its applicability in treating various infectious diseases and potential to minimize drug resistance.Future perspectives a forward-looking perspective discusses the future directions and challenges in the development of ointment for infectious diseases, emphasizing the need for further research and clinical trials. [ABSTRACT FROM AUTHOR]

Objective: This study aims to formulate a ketoconazole patch containing electrospun nanofibres and enhance the solubility due to the increased particle surface using the electrospinning method. Methods: The Design-Expert version13 software was used in experimental designing, to ensure an efficient nanofiber preparation process. Several nanofiber formulations were prepared with different concentrations of drug and polymers. In this study, Ketoconazole was selected as the model drug, ketoconazole is widely used as an antifungal drug in the treatment of fungal infections. Eudragit and Polyethylene glycol polymers were used with ketoconazole to formulate electrospun nanofibers. Then Ketoconazole nanofibers were investigated and evaluated chemically and morphologically by Fourier transform infrared spectroscopy (FTIR) and scanning electron microscopy (SEM). Results: Utilizing the electrospinning method, Ketoconazole electrospun nanofiber was successfully fabricated. The produced ketoconazole-loaded nanofibers mat was formulated as a dermal patch. The Eudragit and polyethylene glycol polymers revealed good characteristics that led to the production of uniform ketoconazole nanofibers. The prepared patch showed good physical and mechanical properties. The SEM results Images for the produced nanofiber mat showed good nanofiber distribution and no beads formation with several fiber diameter sizes, while Fourier Transform Infrared Spectroscopy findings revealed the conjugation between polymers and ketoconazole pure powder, the major characteristic peaks of ketoconazole appeared in the FTIR spectrum. Formula 7 showed minimum nanofibers diameter with maximum entrapment efficiency. Conclusions: In this study, the use of the electrospinning method completed the formulation of a dermal patch containing antifungal nanofibers successfully. Using design expert software to ensure maximum optimization, two biocompatible polymers were used, Eudragit E100 and PEG 600 to formulate ketoconazole nanofibers. The formulated dermal patch could be promising for pharmaceutical antifungal applications. [ABSTRACT FROM AUTHOR]

The antifungal agent, ketoconazole, and the anti-inflammatory drug, piroxicam, were incorporated into matrices of xanthan or oleic acid-esterified xanthan (Xn) and polyurethane (PU), to develop topical drug delivery systems. Compared to matrices without bioactive compounds, which only showed a nominal compressive stress of 32.18 kPa (sample xanthan–polyurethane) at a strain of 71.26%, the compressive resilience of the biomaterials increased to nearly 50.04 kPa (sample xanthan–polyurethane–ketoconazole) at a strain of 71.34%. The compressive strength decreased to around 30.67 kPa upon encapsulating a second drug within the xanthan–polyurethane framework (sample xanthan–polyurethane–piroxicam/ketoconazole), while the peak sustainable strain increased to 87.21%. The Weibull model provided the most suitable fit for the drug release kinetics. Unlike the materials based on xanthan–polyurethane, those made with oleic acid-esterified xanthan–polyurethane released the active ingredients more slowly (the release rate constant showed lower values). All the materials demonstrated antimicrobial effectiveness. Furthermore, a higher volume of piroxicam was released from oleic acid-esterified xanthan–polyurethane–piroxicam (64%) as compared to xanthan–polyurethane–piroxicam (44%). Considering these results, materials that include polyurethane and either modified or unmodified xanthan showed promise as topical drug delivery systems for releasing piroxicam and ketoconazole. [ABSTRACT FROM AUTHOR]

Neutral conditions are conducive for the yeast to mycelium transformation of C. albicans and inducing biofilm formation. Alternatively, an acidic environment can promote the growth of C. albicans yeast and phospholipase expression, and obviously affect the antifungal activity of ketoconazole (KET). In this study, KET-loaded nanostructure hybrid lipid capsules (KET-nHLCs) comprised of soybean lecithin, HS15 and ethyl α-linolenate were prepared using the thin film hydration method. Additionally, the effect of pH on the release and antifungal activity of KET-nHLCs was investigated. The encapsulation efficiency of KET-nHLCs was determined to be 91.53% ± 1.24%, and the water solubility of KET in the KET-nHLC group was enhanced by 158-fold compared to the crude KET. KET-nHLCs could control the in vitro drug release at pH 4.5/7.4, while its slow-release effect on KET was more obvious at pH 4.5. The MIC50 values of KET-nHLCs and KET were 0.5 and 0.25 μg mL−1 at pH 7.4 and 2 and 4 μg mL−1 pH 4.5, respectively. Interestingly, KET-nHLCs more effectively inhibited the yeast-hyphae transformation and had better antibiofilm activity than crude KET. Thus, the -nHLC delivery system containing soybean lecithin has potential application in the field of fungal infection treatment. [ABSTRACT FROM AUTHOR]

Objectives: Malassezia species are common, clinically relevant, and lipid‐dependent yeasts of humans. They are also the leading causes of the dandruff problem of humans, and the azoles are used primarily in their topical and systemic treatment. Resistance to azoles is an emerging problem among Malassezia sp., which indicates the need of new drug assessments that will be effective against dandruff and limit the use of azoles and other agents in treatment. Among them, the efficacy of various combinations of piroctone olamine and climbazole against Malassezia sp. is highly important. Here, we assessed the efficacies of various piroctone olamine and climbazole formulations against Malassezia sp. in comparison with ketoconazole. Methods: A total of nine formulations were included in the study, where each formulation was prepared from different concentrations of piroctone olamine and climbazole and both. All formulations contained the same ingredients as water, surfactants, hair conditioning agents, and preservatives. Malassezia furfur CBS1878, Malassezia globosa CBS7874, and Malassezia sympodialis CBS9570 were tested for antifungal susceptibility of each formulation by agar diffusion method. Sizes of the inhibition zones were compared with standard medical shampoo containing 2% ketoconazole, and the data were analyzed by Dunnett's multiple‐comparison test. Results: For all Malassezia sp. strains, climbazole 0.5% and piroctone olamine/climbazole (0.1%/0.1% and 0.1%/0.5%) combinations were found to have the same effect as the medical shampoo containing 2% ketoconazole. Piroctone olamine/climbazole 1.0%/0.1% formulation showed the same efficacy as 2% ketoconazole on M. furfur and M. sympodialis, while 0.1%/0.5% formulation to only M. furfur. For M. globosa, none of the formulations tested were as effective as ketoconazole. Conclusion: The species distribution of Malassezia sp. varies depending on the anatomical location on the host. According to the results of this study, climbazole and piroctone olamine combinations seem to be promising options against the dandruff problem with their high antifungal/anti dandruff efficacy. [ABSTRACT FROM AUTHOR]

Antifungal azole drugs like fluconazole, itaconazole and ketoconazole are widely used for treatment of fungal related diseases including aspergillosis and mucormycosis. This study aimed at biosynthesis of fluconazole, itaconazole and ketoconazole containing oil/water (O/W) nanoemulsions (NE) using Eucalyptus essential oil and its effect against aspergillosis and mucormycosis. Nanoemulsions were synthesized having eucalyptus essential oil, surfactants: tween 80, and co-surfactant: ethanol. Zeta potential, pH, conductivity and droplet size of nano-formulations were studied by using Zeta sizer. Nanoemulsions were analyzed by UV–VIS, FT-IR and fluorescent techniques. Stability studies were conducted by storing the nanoemulsions at different conditions for 60 days. Anti-aspergillosis, anti-mucormycosis and drug release pharmokinetics were evaluated. Average size of nanoemulsions ranged from 245 to 415 nm along with zeta potential from − 9.20 to − 25.4 mV. Encapsulation efficiency of drug loaded nanoemulsions was ranged from 40 to 50%. Nano-droplets displayed stability after 60 days of storage. Considerable anti-aspergillosis and anti-mucormycosis activities were detected. Among all formulations, F1NEs depicted high antifungal activity against Aspergillus strains MTCC 277, MTCC 343 as observed by zone of inhibition (ZOI) values. Against Mucor spp strain MTCC 3373, visual pictures clearly showed substantial inhibition in fungal growth. Pharmokinetic study shown that all nanoformulations showed Korsmeyer–Peppas model. [ABSTRACT FROM AUTHOR]

Introduction: Candidiasis is a fungal infection caused by Candida yeasts in immunocompromised patients. This study aimed to assess antifungal susceptibility of clinical isolates of Candida species to ketoconazole and nystatin by broth microdilution. Material & Methods: In this descriptive-analytical study, 377 clinical isolates of Candida species were collected from different regions of Iran. The species were identified using polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) method. The antifungal susceptibility testing of clinical isolates of Candida species to ketoconazole and nystatin was performed using broth microdilution according to standard protocol CLSI (M27-A3 and M27-S4). The standard strain of Candida parapsilosis was used as the quality of control. The minimum inhibitory of concentrations was determined after 24h at 37 ºC. Results: Based on molecular identification, Candida albicans 266 (70.7%), C. krusei 64 (17%), C. parapsilosis 40 (10.7%), and C. tropicalis 6 (1.6%) were identified. The MIC90 and MIC50 values of ketoconazole and nystatin for all isolates were 0.063 µg/ml, 0.031 µg/ml, 2 µg/ml, and 4 µg/ml, respectively. Discussion & Conclusion: As evidenced by the results of this study, antifungal susceptibility testing along with the identification of fungi at the species level would certainly be very useful in selecting primary antifungal agents for treatment, especially in invasive fungal infections. According to our findings, ketoconazole was much more effective on Candida spp. than nystatin. [ABSTRACT FROM AUTHOR]

The aim of the current study was to fabricate and optimize lipid polymer hybrid nanoparticles (LPNPs) of ketoconazole (KTZ) through ionic gelation method with chitosan as a polymer having high biocompatibility, biodegradability, and intrinsic antifungal property. Topical hydrogels have the potential to overcome the risk of hepatotoxicity associated with conventional oral dosage forms by targeting infection sites. Hence, these hybrid structures were loaded into Carbopol hydrogel for topical treatment of superficial fungal skin infections. Particle size, zeta potential, surface morphology, entrapment efficiency, and molecular interaction were the characteristics of the optimal nanoformulation. In addition, the physical characteristics, rheology, pH, safety, and stability profile of transdermal hydrogel were described. Assays for antifungals, in vitro and ex vivo, were used to determine whether PLNPs could be used topically. The optimized nanoparticles were found to have a mean particle size of 173 nm and a polydispersity index (PDI) of 0.177. An investigation using Fourier transform infrared (FTIR) did not show any molecular interactions. The Higuchi model describes the anomalous non-Fickian drug release from the matrix system, and this is also explained by the in vitro release model. Higher zones of inhibition were obtained from an in vitro antifungal experiment on Aspergillus niger in comparison to the commercially available ketoconazole gel. Hydrogel is essential for managing the pH-sensitive release at the targeted location. [ABSTRACT FROM AUTHOR]

Idiosyncratic drug-induced liver injury (DILI) is a rare and unpredictable form of hepatotoxicity. While its clinical course is usually benign, cases leading to liver transplantation or death can occur. Based on modern prospective registries, antimicrobials including antibiotics and antifungals are frequently implicated as common causes. Amoxicillin–clavulanate ranks as the most common cause for DILI in the Western World. Although the absolute risk of hepatotoxicity of these agents is low, as their usage is quite high, it is not uncommon for practitioners to encounter liver injury following the initiation of antibiotic or antifungal therapy. In this review article, mechanisms of hepatoxicity are presented. The adverse hepatic effects of well-established antibiotic and antifungal agents are described, including their frequency, severity, and pattern of injury and their HLA risks. We also review the drug labeling and prescription guidance from regulatory bodies, with a focus on individuals with hepatic impairment. [ABSTRACT FROM AUTHOR]

As a powerful imidazole antifungal drug, ketoconazole's low solubility (0.017 mg/mL), together with its odor and irritation, limited its clinical applications. The inclusion complex of ketoconazole with randomly methylated β-cyclodextrin was prepared by using an aqueous solution method after cyclodextrin selection through phase solubility studies, complexation methods, and condition selection through single factor and orthogonal strategies. The complex was confirmed by FTIR (Fourier-transform infrared spectroscopy), DSC (differential scanning calorimetry), TGA (thermogravimetric analysis), SEM (scanning electron microscope images), and NMR (Nuclear magnetic resonance) studies. Through complexation, the water solubility of ketoconazole in the complex was increased 17,000 times compared with that of ketoconazole alone, which is the best result so far for the ketoconazole water solubility study. In in vitro pharmacokinetic studies, ketoconazole in the complex can be 100% released in 75 min, and in in vivo pharmacokinetic studies in dogs, through the complexation, the Cmax was increased from 7.56 μg/mL to 13.58 µg/mL, and the AUC0~72 was increased from 22.69 μgh/mL to 50.19 μgh/mL, indicating that this ketoconazole complex can be used as a more efficient potential new anti-fungal drug. [ABSTRACT FROM AUTHOR]

Athelia rolfsii induces severe Sclerotium rots on 500 plantspecies, thus efficient field and post-harvest management strategies for this disease exist. A completely randomized design with three replications was used to set up two sub-trials. Sub-trial 1: Interaction of Mancozeb (all concentrations) x Trichoderma species caused 29.3-100% inhibition and all Ketoconazole x Trichoderma species caused 95.8-100% inhibition of A. rolfsii. Ketoconazole and Mancozeb (main effects) ranged between 23.3-100% inhibition of A. rolfsii. T. virens, T. harzianum, and T. viride (main effects) ranged from 60.3-96.7% inhibition of A. rolfsii. Unfortunately, Ketoconazole inhibited Trichoderma species more than Mancozeb. The chemical fungicides and Trichoderma species were highly positively correlated (0.522**, P≤0.05). Sub-trial 2: The Plant extracts (Ricinus and Eucalyptus species: 100% concentration) x Trichoderma species interactions caused 95-100% inhibition of A. rolfsii. Botanicals (50% concentration) x Trichoderma species caused above 80% inhibition of A. rolfsii. Trichoderma species (main effects) (in environs of 50% botanicals) caused 57-84% inhibition. The results revealed that at 100% concentration, plant extracts completely inhibited A. rolfsii. [ABSTRACT FROM AUTHOR]

Androgenetic alopecia (AGA) presents a significant challenge in clinical practice due to its prevalence and impact on patients’ quality of life. With a diverse array of available treatment options, selecting the most appropriate therapy demands careful consideration of factors such as efficacy, safety, practicality, and cost. This review aims to evaluate the efficacy and safety profiles of various topical treatments for AGA, investigating their potential advantages in limiting systemic side effects compared to oral medications. This article explores the pharmacology, mechanisms of action, clinical efficacy, and adverse events associated with topical medications like minoxidil, finasteride, ketoconazole shampoo, clascoterone, latanoprost, spironolactone, flutamide, cetirizine, pyrilutamide, and GT20029. [ABSTRACT FROM AUTHOR]

Abstract Background Many clinicians prescribe antifungal agents to treat canine otitis externa (OE). However, studies evaluating the antifungal effects of N‐acetylcysteine (NAC) and its combinations are limited. Hypothesis/objectives The aim of this study was to evaluate the antifungal effects of NAC alone and in combination with other antifungal agents against Malassezia pachydermatis isolated from canine OE. Materials and methods M. pachydermatis samples were collected from 13 dogs with OE. The final concentration of the inoculum suspensions of M. pachydermatis was 1–5 × 106 colony forming units/mL. The concentrations of the test compounds ketoconazole (KTZ), terbinafine (TER), nystatin (NYS) and NAC were 0.02–300 µg/mL, 0.04–80 µg/mL, 0.16–40 µg/mL and 1.25–20 mg/mL, respectively. The minimum inhibitory concentration (MIC) was measured to evaluate the susceptibility of the M. pachydermatis to KTZ, TER, NYS and NAC. The checkerboard testing method and fractional inhibitory concentration index were used to evaluate the effect of NAC in combination with KTZ, TER and NYS against M. pachydermatis. Results The MIC90 values of M. pachydermatis were 4.6875–9.375 µg/mL, 1.25 µg/mL, 5–10 µg/mL and 10 mg/mL for KTZ, TER, NYS and NAC, respectively. The synergistic effects of KTZ, TER and NYS with NAC were identified in 0/13, 2/13 and 0/13 isolates, respectively. Conclusions and clinical relevance NAC had an antifungal effect against M. pachydermatis but did not exert synergistic effects when used with KTZ, TER and NYS. Thus, the use of NAC alone as a topical solution could be considered an effective treatment option for canine OE involving M. pachydermatis.

Over the past decade, abiraterone and enzalutamide have largely replaced ketoconazole as oral treatments for castration-resistant prostate cancer (CRPC). We investigated the differential adoption of abiraterone and enzalutamide across facilities in a national healthcare system to understand the impact a facility has on the receipt of these novel therapies. Using data from the VA Corporate Data Warehouse, we identified a cohort of men with CRPC who received the most common first-line therapies: abiraterone, enzalutamide, docetaxel, or ketoconazole between 2010 and 2017. We described variability in the adoption of abiraterone and enzalutamide across facilities by time period (2010-2013 or 2014-2017). We categorized facilities depending on the timing of adoption of abiraterone and enzalutamide relative to other facilities and described facility characteristics associated with early and late adoption. We identified 4998 men treated with ketoconazole, docetaxel, abiraterone, or enzalutamide as first-line CRPC therapy between 2010 and 2017 at 125 national facilities. When limiting the cohort to oral therapies, most patients treated earlier in the study period (2010-2013) received ketoconazole. A dramatic shift was seen by the second half of the study period (2014-2017) with most men treated with first-line abiraterone (61%). Despite this shift and a new standard of care, some facilities persisted in the widespread use of ketoconazole in the later period, so-called late adopting facilities. After multivariable adjustment, patients who received treatment at a late adopting facility were more likely receiving care at a lower complexity, rural facility, with less urology and hematology/oncology workforce (all p

Hepatocellular carcinoma (HCC) is a form of malignancy with limited curative options available. To improve therapeutic outcomes, it is imperative to develop novel, potent therapeutic modalities. Ketoconazole (KET) has shown excellent therapeutic efficacy against HCC by eliciting apoptosis. However, its limited water solubility hampers its application in clinical treatment. Herein, a mitochondria‐targeted chemo‐photodynamic nanoplatform, CS@KET/P780 NPs, is designed using a nanoprecipitation strategy by integrating a newly synthesized mitochondria‐targeted photosensitizer (P780) and chemotherapeutic agent KET coated with chondroitin sulfate (CS) to amplify HCC therapy. In this nanoplatform, CS confers tumor‐targeted and subsequently pH‐responsive drug delivery behavior by binding to glycoprotein CD44, leading to the release of P780 and KET. Mechanistically, following laser irradiation, P780 targets and destroys mitochondrial integrity, thus inducing apoptosis through the enhancement of reactive oxygen species (ROS) buildup. Meanwhile, KET‐induced apoptosis synergistically enhances the anticancer effect of P780. In addition, tumor cells undergoing apoptosis can trigger immunogenic cell death (ICD) and a longer‐term antitumor response by releasing tumor‐associated antigens (TAAs) and damage‐associated molecular patterns (DAMPs), which together contribute to improved therapeutic outcomes in HCC. Taken together, CS@KET/P780 NPs improve the bioavailability of KET and exhibit excellent therapeutic efficacy against HCC by exerting chemophototherapy and antitumor immunity. [ABSTRACT FROM AUTHOR]

The gas anti-solvent (GAS) process utilizing compressed carbon dioxide as an anti-solvent was applied to prepare coprecipitated particles between ketoconazole (KET), a poorly water-soluble drug substance, and nicotinamide (NIC), a water-soluble carrier. KET-NIC solid dispersion was also prepared by solvent evaporation and compared with the coprecipitated particles obtained from GAS process. DSC results indicated that KET formed eutectic with NIC at a weight ratio of 7:3. The results showed that the KET-NIC coprecipitated particles prepared by the GAS process, at an initial weight ratio of 1:1.5 in ethanolic solution, had suitable particle morphology and exhibited a remarkably higher dissolution than solid dispersion, physical mixture, and unprocessed KET. The formation of a simple eutectic mixture between KET and NIC in the coprecipitates prepared by both processes was confirmed by DSC, FTIR spectroscopy and powder X-ray diffraction. The enhanced dissolution of the GAS coprecipitated particles might be attributed to the eutectic formation, the improved wettability and hydrophilic microenvironment by the water-soluble carrier, the lower crystallinity, and the smaller size of the drug crystals. [ABSTRACT FROM AUTHOR]

Pregnancy is a period in which the anatomy and physiology of the pituitary gland change significantly. Normal pituitary gland functions are necessary for fertility and the continuation of pregnancy. The presence of a pituitary disease requires management with a multidisciplinary approach to protect the health of the mother and fetus, and it is recommended that these patients become pregnant in a planned manner. Treatment should be considered before pregnancy for pituitary adenomas with a risk of growth. Non-contrast magnetic resonance imaging (MRI) may be performed safely during pregnancy, but the ideal approach is to postpone the MRI until after the birth if possible, and if it is not possible, to take it without contrast. If there are no signs of compression in pituitary adenomas, no treatment is necessary during pregnancy. However, due to increased fetal and maternal morbidity and mortality in Cushing’s disease, treatment is necessary even if there is no compression. In the presence of compression findings, dopamine agonists can be used in all types of pituitary adenomas. Surgery may be performed in the second trimester for pituitary adenomas that cause compression unresponsive to medical treatment and for Cushing’s disease. In pregnant women with pituitary insufficiency, replacement doses should be adjusted according to the gestational week. The diagnosis and treatment of pituitary diseases in this period is more complex and specific than in the nonpregnant period and require a multidisciplinary approach. [ABSTRACT FROM AUTHOR]

Castration resistant prostate cancer (CRPC) is a challenging subset of prostate cancer associated with an extensive metastatic profile and high mortality. Ketoconazole is a nonselective steroid 17 a-hydroxylase/17,20 lyase (CYP17A1) inhibitor and is employed as a second line treatment option for CRPC with an established efficacy profile in patients. The aim of this study is to assess the efficacy of ketoconazole containing regimens for CRPC in terms of prostate specific antigen (PSA) decline rate using a systematic review and meta-analysis. In this review, an electronic search was carried out on PubMed, Cochrane CENTRAL, Scopus, and Google Scholar to find relevant literature. Random effects model was used to assess pooled PSA decline rate and 95% CIs. Publication bias was assessed using the funnel plot symmetry and one-tailed Egger's and Begg's test. In all cases, P -value < .05 was indicative of significant results. The review is registered with PROSPERO: CRD42023466536. A total of 483 articles were retrieved after database searching, out of which 23 studies (having a total of 1315 patients) were included in the review based on prespecified cr iter ia. The PSA decline rate was reported in the 14 observational studies (having 964 patients) and 9 experimental studies (having 351 patients). Pooled results revealed that 48.6% (95% CI 43.1-54.2; P -value < .001; I2 = 73.24%) of participants achieved more than 50% decline in PSA (602/1315 participants). Sensitivity analysis using the leave-one-out method revealed no substantial change in pooled effect estimates; (Risk Ratio) RR 47.2% to RR 49.8% demonstrating the robustness of our results. There was no evidence of publication bias as assessed from the funnel plot symmetry. Ketoconazole containing regimens have shown moderate efficacy in high risk CRPC patients as demonstrated by the pooled results. Hence, a ketoconazole based chemotherapy can be added to patients' regimen if there is a persistent rise in PSA levels after androgen deprivation therapy. [ABSTRACT FROM AUTHOR]

This study aimed to determine the antibiotic and antifungal susceptibility profiles of animal clinical bacterial and fungal isolates and to evaluate the antimicrobial activities of essential oils (EOs) in both the agar disc diffusion method and the broth dilution assay. The minimum inhibitory concentration (MIC), minimum bactericidal concentration (MBC) and minimum fungicidal concentration (MFC) of thyme, mint, and lavender EOs were evaluated. The results of the antibiotic and antifungal susceptibility profiles tests showed differences in the bacterial sensitivities to the studied antibiotics and antimycotics with the emerging of multidrug-resistant bacteria and dermatophytes. Ciprofloxacin was the most effective antibiotic and the tested fungal isolates were much more sensitive to ketoconazole than other antifungals. Thyme essential oil exhibited potent antibacterial activity against every tested strains of bacteria with MICs of less than 9µl/ml (0.9%) for the majority of the tested pathogens. The tested EOs effectively inhibited the growth of dermatophytes. Thyme oil presents itself as a promising antibacterial and anti-fungal agent against veterinary pathogens, being a natural product that can represent an interesting antimicrobial in the efforts to combat bacterial and fungal infections in veterinary medicine. [ABSTRACT FROM AUTHOR]

Background and Purpose: Fraction metabolized (fm) and fraction transported (ft) are important for understanding drug–drug interactions (DDIs) in drug discovery and development. However, current in vitro systems cannot accurately estimate in vivo fm due to inability to reflect the ft by efflux transporters (ft,efflux). This study demonstrates how CYP3A‐mediated DDI for CYP3A/P‐gp substrates can be predicted using Hu‐PXB mice as human liver chimeric mice. Experimental Approach: For estimating human in vitro fm by CYP3A enzyme (fm,CYP3A,in vitro), six drugs, including CYP3A/P‐gp substrates (alprazolam, cyclosporine, docetaxel, midazolam, prednisolone, and theophylline) and human hepatocytes were incubated with or without ketoconazole as a CYP3A inhibitor. We calculated fm,CYP3A,in vitro based on hepatic intrinsic clearance. To estimate human in vivo fm,CYP3A (fm,CYP3A,in vivo), we collected information on clinical DDI caused by ketoconazole for these six drugs. We calculated fm,CYP3A,in vivo using the change of total clearance (CLtotal). For evaluating the human DDI predictability, the six drugs were administered intravenously to Hu‐PXB and SCID mice with or without ketoconazole. We calculated the change of CLtotal caused by ketoconazole. We compared the CLtotal change in humans with that in Hu‐PXB and SCID mice. Key Results: The fm,CYP3A,in vitro was overestimated compared to the fm,CYP3A,in vivo. Hu‐PXB mice showed much better correlation in the change of CLtotal with humans (R2 = 0.95) compared to SCID mice (R2 = 0.0058). Conclusions and Implications: CYP3A‐mediated DDI can be predicted by correctly estimating human fm,CYP3A,in vivo using Hu‐PXB mice. These mice could be useful predicting hepatic fm and ft,efflux. [ABSTRACT FROM AUTHOR]