Ketoconazole Research Articles

DNA binding study of antifungal drug Ketoconazole by molecular docking and spectroscopic analysis.

The pregnaneXreceptor is a novel host target for dengue virus infection that reprograms lipid metabolism and suppresses the immune response.

Three-color triple platform for point-of-care detection of three antifungal azoles in livestock wastewater and sludge.

N(14)-phenyl-substituted evodiamine derivatives for the treatment of superficial fungal infections by inhibiting xanthine dehydrogenase.

Abstract Breast cancer brain metastasis (BCBM) accounts for 10-30% of the breast cancer metastatic burden and is associated with dismal prognoses, having a median survival time of 7.9 months. The poor outcomes stem from limited understanding of BCBM and the lack of blood-brain barrier (BBB) and blood-tumor barrier (BTB) penetrant drugs. This highlights the imperative to develop new therapies for BCBM. Truncated GLI1 (tGLI1), a tumor-specific GLI1 variant and terminal effector of the SHH pathway, has been identified as a key driver of breast cancer stem cells (CSCs) and a promoter of BCBM. The FDA-approved antifungal ketoconazole (KCZ) was discovered to selectively target tGLI1-positive breast cancer cells in vitro and inhibit tGLI1-driven brain metastases in vivo. However, the use of KCZ raises safety concerns due to its potent inhibition of the CYP3A4 enzyme, thereby leading to liver toxicity, adrenal insufficiency, and drug interactions. To address these issues, we modified the structure of KCZ and developed KCZ-analog, a novel tGLI1 inhibitor candidate. KCZ-analog was found to selectively target tGLI1-positive breast CSCs, while it lost the ability to inhibit CYP3A4 activity in vitro. Characterization of KCZ-analog revealed that it binds directly and specifically to tGLI1 but does not inhibit DNA binding. Through an in vivo maximum tolerated dose (MTD) study, we found that KCZ-analog showed no liver toxicity (normal serum ALT) or adrenal insufficiency (normal serum ACTH) levels. Toxicological analyses confirmed no toxic effects on other vital organs, and neither KCZ-analog nor KCZ affected blood cell count. Moreover, a perfusion study showed that KCZ-analog has enhanced bioavailability and can cross the BBB and BTB. Furthermore, a mouse metastasis model demonstrated that systemic administration of KCZ-analog suppressed the progression of tGLI1-positive BCBM. Our study supports further characterization of the pharmacological properties of KCZ-analog and its potential in the prevention of BCBM in vivo.

In vitro effects of polycyclic aromatic hydrocarbons on sex steroid production by Arabian sea bream Acanthopagrus arabicus ovarian cells.

Ketoconazole (KTZ) and metyrapone (MET) are used to normalize cortisol in Cushing syndrome (CS). Available recommendations can delay time to control. This work aimed to identify predictors of treatment success and hepatotoxicity during rapid titration of KTZ and MET and to assess differences in blood pressure or potassium. A retrospective evaluation was conducted at a tertiary referral center. Participants included 52 patients receiving treatment for adrenocorticotropin (ACTH)-dependent CS from 2004 to 2023. Interventions included KTZ or MET. The main outcome measures included the number of patients achieving target morning serum cortisol (AM F), defined as 12 mcg/dL or less (≤331 nmol/L), or increased liver function tests (LFTs) suggesting drug-induced liver injury (alanine/aspartate transaminase and alkaline phosphatase ≥3-fold upper limit of normal [≥3ULN], total bilirubin [Bili] ≥2ULN). KTZ achieved target AM F in 39% (95% CI 24%-56%) of patients, compared to 74% (95% CI 49%-90%) on MET. Lower baseline AM F predicted success only with MET. Among KTZ responders, maximal effect occurred by 2 days after a dose increase. LFTs worsened with KTZ and improved with MET. A similar proportion of patients had an LFT reach or exceed 3ULN with KTZ (22%; 95% CI 10%-39%) and MET (25%; 95% CI 4%-64%). Higher doses of KTZ, but not MET, predicted this. Bili reached or exceeded 2ULN in 3% (95% CI 0%-15%) of patients receiving KTZ and none receiving MET. Blood pressure and hypokalemia improved with KTZ but did not change with MET. Hypercortisolism can likely be controlled faster with rapid titration of KTZ or MET. LFT abnormalities increased with KTZ but were common with MET treatment, likely reflecting underlying liver pathology in CS.

The goal of the current research was to identify a safe and effective non-oncology drug combination as a substitute to existing toxic chemotherapeutics for the treatment melanoma. Further intend was to develop an oral solid self-emulsifying drug delivery system (S-SEDDS) for concurrent delivery of identified combination. The drug containing S-SEDDS was prepared and characterized for flowability, compressibility, drug content, particle size and zeta potential, and in vitro cytotoxicity against melanoma cells. In silico molecular docking for drug with excipients interaction shows compatibility with each other. Moreover, the formulations were characterized in vivo for hepatotoxicity and pharmacokinetic study in rats. The S-SEDDS showed good flowability and compressibility. The particle size of S-SEDDS upon dilution was found in nanometer range. Furthermore, the in vitro cytotoxicity of S-SEDDS containing non-oncology drug (NOD) combination [ketoconazole (KCZ), tadalafil (TLF), disulfiram (DSR)] and docetaxel (DTX) was observed to be higher than S-SEDDS containing only NOD combination against mouse melanoma cells. No significant change in the hematological parameters, animal vital organs weights, and body weights were observed after oral administration of S SEDDS containing non-oncology drug combination with DTX indicating their safety. In addition, significant (p< 0.05) improvement in the oral bioavailability of DTX was observed following its administration in the form of S-SEDDS when compared to the Taxotere in the rats. The developed S-SEDDS containing non-oncology drug combination alone and in combination with docetaxel could be a promising and safe approach in the effective treatment of melanoma.

Ketoconazole alleviates UVB-induced photoaging by suppressing ROS generation and mitochondrial dysfunction in dermal fibroblasts and ex vivo porcine skin models.

ABSTRACTA novel series of compounds was designed and synthesized by combining the distal piperazine nitrogen of the antifungal ketoconazole (KTZ) with primary arylsulfonamides. The aim of this study is to present the basis for a new generation of Malassezia antifungal agents able to inhibit the enzyme lanosterol‐14α‐demethylase (CYP51; EC 1.14.13.70) as well as a newly emergent therapeutic target: carbonic anhydrases (CAs; EC 4.2.1.1). The final compounds showed effective interactions with the intended targets in vitro, as well as KTZ comparable minimum inhibitory concentrations on yeast strains of the Malassezia genus: Malassezia furfur ATCC 14521; Malassezia globosa ATCC MYA 4612; and Malassezia pachydermatis DSM 6172. Overall, the data obtained account for the reported compounds as promising antifungal candidates with high safety profiles for the management of fungal infections.

This study investigates the co-amorphization of ketoconazole (KTZ) with fumaric acid (FA) and tartaric acid (TA) through co-milling, aiming to enhance the solubility, stability, and dissolution properties of this poorly water-soluble antifungal. Phase diagrams obtained via Hot Stage Microscopy (HSM) showed eutectic-like behavior at equimolar ratios for both KTZ-FA and KTZ-TA systems, with a more pronounced melting point depression in KTZ-FA, indicative of stronger molecular interactions fostering stable amorphous formation. Solid-state characterization using Powder X-ray Diffraction, Fourier Transform Infrared Spectroscopy, and Differential Scanning Calorimetry confirmed amorphization and showed significant hydrogen bonding in KTZ-FA. Further analyses with Thermogravimetric Analysis and Scanning Electron Microscopy demonstrated reduced thermal stability and particle size, accompanied by homogenous amorphous morphologies. Solubility and dissolution studies highlighted remarkable improvements: solubilities of KTZ-FA and KTZ-TA were 11.652 mg/mL and 8.750 mg/mL, respectively, compared to 0.060 mg/mL for pure KTZ. Dissolution profiles indicated superior performance of KTZ-FA at neutral pH, attributed to enhanced hydrogen bonding. Taken together, these findings position the co-amorphous KTZ–FA and KTZ–TA systems as promising candidates for developing rapid-acting oral antifungal dosage forms with improved bioavailability and patient compliance.

Ketoconazole-loaded microspone film coating agent for superficial fungal infection: design, preparation and characterization.

Seborrheic dermatitis (SD) is the most common superficial fungal skin infection affecting large number of the population worldwide. Prevalence of this disease has been increased. The present study aimed to formulate topical gel loaded with Ketoconazole (KTZ) as an antifungal agent and black seed oil with anti-inflammatory or antifungal activity to effectively treat seborrheic dermatitis (SD). The dispersion method was used to formulate gel preparations using gelling agents (Carbopol 934, Methylcellulose, and Xanthan gum). The prepared gels were evaluated for organoleptic properties, pH, spreadability, rheology, and drug content. The antifungal assay was performed using Malassezia furfur. In vitro permeation studies were performed on Franz diffusion cells. For drug-excipients compatibility studies, FTIR was performed. According to ICH guidelines, three months of stability studies were performed. The results indicated that gel formulations follow non-Newtonian shear-thinning pseudo-plastic type flow; F2 has high drug content (92.22 ± 0.32%), and the zone of inhibition (22 ± 1.25 mm), and highest drug release (91.88 ± 0.11%). No physicochemical interactions were found between the drug and polymer. Stability studies revealed that the formulations were stable at 25 °C. In conclusion, a gel of KTZ with oil exhibited a synergetic effect and offered a potential SD treatment strategy, suggesting it may be an alternative treatment for SD.

Carvedilol (CAR) is commonly administered in the treatment of essential hypertension. Current reports suggest that CAR therapy may elevate the risk of hepatotoxicity, occasionally progressing to liver injury. However, the underlying mechanisms of the toxicity remain poor understood. This study investigated CAR-associated hepatotoxicity through reactive metabolites formation. In the microsomal incubation mixture containing CAR (50μM), four phase I metabolites (M1-M4) were detected. Upon the addition of glutathione (GSH), N-acetylcysteine (NAC), or cysteine as trapping agents, four GSH conjugates (M5-M8), four NAC conjugates (M9-M12), and four cysteine conjugates (M13-M16) were also detected. Chemical synthesis of 8-hydroxy CAR identified M1 as the primary oxidative metabolite of CAR. Following the administration of CAR (25mg/kg), we detected GSH conjugate (M5) in bile, NAC conjugate (M9) in urine, and cysteine adduct (M13) in proteolytic mixture of liver tissues of rat. Furthermore, it was found that CYP3A4 dominated the metabolic activation of CAR. Additionally, CAR exhibited time-course changes and dose-dependent (0, 25, 50, and 100mg/kg) protein adduction in rat liver tissues, as well as time- and concentration-dependent (0, 10, 25, 50 and 100μM) inhibition of hepatocyte viability. Ketoconazole (KTZ) significantly decreased the susceptibility of hepatocytes to CAR-induced cytotoxicity. Collectively, these findings offer new insight into the hepatotoxicity mechanism associated with the metabolic activation of CAR.

Abstract This study was focused to formulate and optimize transferosomes encapsulating ketoconazole (KTZ) for its repurposed use as a hair growth promoting agent. Ketoconazole exerts trichogenic effect in patients with androgenic alopecia androgen by acting on receptors present in keratinocytes and sebocytes of the scalp. This necessitates the penetration of ketoconazole into deep epidermal and dermal layers for exerting trichogenic effect. Transferosomes have been reported to improve drug penetration owing to their deformable vesicular structure. Thus, in the present work, transferosomal gel loaded with ketoconazole was developed with the intention to enhance drug permeation and improved hair proliferation activity. Solvent evaporation method has been adopted for the formulation of transferosomes and then optimized by quality by design approach. KTZ‐TF (ketoconazole‐transferosomes) were assessed for particle size, entrapment efficiency (%EE), surface charge, and morphology. The optimized KTZ‐TF formulation demonstrated particle size of 151.22 ± 1.3 nm, PDI index of 0.191 ± 0.034, and ζ potential of –33.05 ± 01.3 mV, respectively. The developed formulation was further added into gel and compared with commercially available product. It was concluded that KTZ‐TF gels showed control drug release (89.1 ± 2.12%) for 9 h. The in vivo skin irritation test demonstrated that the gel formulation caused minimal irritation and was well accepted by the scalp. In vivo qualitative hair growth activity demonstrated improved hair growth with the developed formulation in comparison to marketed KTZ. Histopathological studies also corroborated the findings through demonstrating increase in number of hair follicles. Hence, this study concluded that ketoconazole‐loaded transferosomes are efficacious in hair growth activity.

This study was designed to evaluate the effects of Melaleuca alternifolia essential oil for its antifungal activity as mono-therapeutic agent, and in combination with current antifungal agents, like itraconazole and ketoconazole. To assess the significance of TTO (Tea Tree Oil), ITZ (Itraconazole) and KTZ (Ketoconazole), for in vitro susceptibility pattern of dermatophyte, which was obtained from the cases of clinically examined dermatophytosis, attending the dermatology outpatient department of Sheikh Zayed Hospital. The tea tree essential oil was extracted through steam distillation method using 500g of fresh Melaleuca alternifolia leaves from Lawrence Garden and obtained the yield of 3mL that comes to be 0.6%. Trichophyton violaceum grown on SDA Sabouraud dextrose agar ager plates for 48h were tested for fungicidal activity using equal quantity of TTO employing well method technique. In a comparative study assessing the minimum fungicidal concentration (MFC) of ITZ and KTZ, the MFC of KTZ was found to be greater than the MFC of ITZ because the solution of same concentration produced lesser inhibition zones in case of ITZ as compared to KTZ. In another study to ascertain the synergistic effects of TTO with ITZ, it was established that TTO significantly potentiated the effect of azoles in combination therapy reducing the MFC of ITZ up to 8 folds from 4 to 0.07 ug/mL. In yet another study to cross check the synergistic effects of TTO with KTZ in combination therapy. It was positively found that TTO potentiated the fungicidal activity of KTZ, reducing the MFC of KTZ up to 8 folds from 0.25 to 0.03μg/mL. Comparing the synergistic effects of TTO with ITZ and TTO with KTZ in combination therapies the inhibition zones produced by TTO with KTZ are found to be prominently biggest. Hence Synergy of TTO with KTZ is most proficient because it reduces the MFC of azole maximally while potentiating the fungicidal activity of KTZ.

Ketoconazole (KET), an imidazole derivative with well-known antifungal properties, with poor aqueous solubility, therefore its topical clinical use has practical disadvantages. Bilosome plays an important role in topical drug delivery as they can reduce toxicity and modify dermal drug targeting by acting as a drug reservoir that can adjust the drug release rate. This research aimed to formulate and optimize KET bilosomes to enhance its dissolution and topical antifungal activity. Ten KET bilosomes formulas were prepared by probe sonication method using two types of non-ionic surfactants (Span 40 or Span 60) along with cholesterol and sodium deoxycholate (SDC) as lipid strengthen and bile salt stabilizer, respectively. The formulations were evaluated for vesicles size, PDI, entrapment efficiency and in vitro drug release. The optimum were investigated its morphological property, zeta-potential, FTIR spectrum and antifungal activity. All prepared bilosomes showed nanosize vesicles of (189.27 ± 2.75 - 251.87 ± 1.74 nm) and entrapment efficiency was found in the range of 32.07 ± 0.67 and 92.33± 0.76. The optimum formula that contained span 60: cholesterol: SDC at weight (350:60:15) of spherical shape appearance without aggregation and its zeta potential was – 54.45 mV. The optimum formula was found to provide significant antifungal activity. Its % cumulative KET released was 97% at 8 hours. According to obtained result, it was concluded that bilosomes loaded with KET can be developed successfully to improve dissolution and the antifungal activity.

This study aimed to elucidate the drug absorption mechanisms after oral administration of lipid-based formulations (LBFs), emphasizing the impact of their composition on first-pass drug metabolism. Ketoconazole (KTZ), a CYP3A substrate, was loaded into two types of LBFs: a long-chain LBF (type II-LC) and a lipid-free formulation (type IV). Following oral administration of type II-LC, the systemic exposure of KTZ was lower compared to that for the type IV and a control suspension. However, pretreatment with 1-aminobenzotriazole, a nonspecific CYP inhibitor, revealed equivalent in vivo exposure among the formulations tested. The absorption of KTZ from type II-LC in the early period was slower than that from the suspension and type IV. Experiments on in vitro digestion in sequence with in vitro permeation across a dialysis membrane showed that the drug permeation rate for type II-LC was extremely low. This was probably due to the reduction in free drug molecules in the donor compartment via the incorporation of KTZ into mixed micelles comprising digestion products derived from type II-LC and bile components. Furthermore, luminal concentration measurements revealed that gastric emptying was delayed when a type II-LC was administered. The reduced free drug concentration and transient delay in gastric emptying of KTZ resulted in the slower absorption of KTZ for type II-LC. The product of the fraction of drug absorbed and fraction of the drug not metabolized in the gut wall (Fa × Fg) calculated from the systemic and portal plasma concentration-time courses of KTZ was 0.185 for type II-LC and 0.327 for suspension. Since the luminal concentration measurement demonstrated complete absorption of KTZ from the gastrointestinal tract (Fa ≅ 1), the Fa × Fg values can be regarded as Fg. In conclusion, the lower in vivo exposure following oral administration of type II-LC was attributed to reduced Fg, that is, slower drug absorption from the jejunum resulted in low KTZ concentration in enterocytes, leading to enhanced metabolic efficiency. Our findings can be valuable when selecting excipients for designing LBFs with the preferred in vivo performance for highly metabolized drugs.

BackgroundMalassezia pachydermatis (MP) is implicated in severe dermatitis and otitis externa (OE) of companion animals and recently gained attention for its increasing resistance to azole compounds. For this reason, developing novel therapeutic strategies is of great interest. In a previous work, we used reference yeast isolates to evaluate several compounds bearing acyl/selenoureido moieties and primary/secondary sulfonamide groups for antifungal activity through organic selenium and carbonic anhydrase inhibition.ObjectivesThis work aimed to evaluate the antifungal efficacy of eight selenoureido compounds on 36 clinical MP isolates from dogs, compared to selected azoles, notably ketoconazole (KCZ), miconazole (MCZ) and fluconazole (FCZ).Materials and MethodsMIC assays of 5g, 7a, 7c, 7k, 8c, 10c, 11b, 11f, KCZ, MCZ and FCZ were performed on 36 MP field isolates isolated from dogs affected by dermatitis and/or OE in which yeast aetiology was suspected. Minimum 50% and 90% inhibitory concentrations (MIC50 and MIC90) were calculated. MP identification was confirmed with a nested PCR for the internal transcribed spacer region of the rRNA gene.ResultsOverall, the MIC50 of the tested compounds on MP field isolates was higher than the MICs obtained on reference MP DSM 6172. Although KCZ showed the lowest MIC50 value, compounds 5g, 7a and 7k showed lower MIC50s than MCZ and FCZ. Five clinical isolates showed a MIC on azoles >MIC90. Compounds 7a (four of five), 10c (three of five) and 8c (three of five) showed lower MIC values on these isolates compared to the tested azoles, suggesting good activity in phenotypically azole‐resistant MP.Conclusions and Clinical RelevanceConsidering the increasing azole resistance of the Malassezia genus, selenoureido compounds could represent a potential topical treatment for dog skin and ear mycotic infections.

Aim: The present study was done to formulate ketoconazole (KET) nanosponges (NSs) using ethyl cellulose polymer using the solvent evaporation method. Materials and Methods: The prepared NSs were subjected to a drug-polymer incompatibility study using Fourier transform infrared analysis. In addition, formulations F1-F6 were evaluated for various parameters such as percentage yield, % entrapment efficiency (EE), % drug content, in vitro release study, and particle size determination using scanning electron microscopy analysis. Results and Discussion: KET-loaded EC nanosponges F6 optimized formulation showed superior % drug content, % yield, and EE, showing extended drug release of drug (84.48%) at the end of 240 minutes. Optimized formulation was loaded into HPMC gel and evaluated for pH, viscosity, extrudability, and % drug content. KET-NSs-loaded HPMC gel (GK5) showed optimal pH (4.24), good spreadibility (23.76 g.cm/sec), extrudability (96.14%), and viscosity (3567 cp). In vitro antifungal study revealed that KET-loaded NSs showed potent antifungal activity against C. albicans. GK5 formulation loaded with HPMC effectively targets fungal infection and is effective for topical delivery. Conclusion: The findings revealed that the nanosponges-loaded gel was effective for antifungal delivery.