Ketoconazole Research Articles

Development of ion-triggered in situ gel containing ketoconazole/hydroxypropyl-β-cyclodextrin for ocular delivery: in vitro and in vivo evaluation

The application of ketoconazole (KET) in ocular drug delivery is restricted by its poor aqueous solubility though its broad-spectrum antifungal activity. The aim of this study is to develop an ion-sensitive in situ gel (ISG) of KET to promote its ocular bioavailability in topical application. The solubility of KET in water was increased by complexation with hydroxypropyl-β-cyclodextrin (HPβCD), then KET-HPβCD inclusion complex (KET-IC) was fabricated into an ion-sensitive ISG triggered by sodium alginate (SA). The in vitro drug release and antifungal activities investigations demonstrated that the KET-IC-ISG formulation increased drug release and anti-fungal activities compared to pure KET. The ex vivo rabbit corneal permeation studied demonstrated higher permeability of KET-IC-ISG formulation (Papp of (6.34 ± 0.21) × 10−4 cm/h) than pure KET (Papp of (3.09 ± 0.09) × 10−4 cm/h). The cytotoxicity assay and the ocular irritation study in rabbits confirmed the KET-IC-ISG safety and well tolerance. The ocular pharmacokinetics of KET in rabbits was investigated and the results showed that the KET-IC-ISG increased its bioavailability in cornea by 47-fold. In conclusion, the KET-IC-ISG system promoted the precorneal retention, the ocular drug bioavailability and the developed formulation is a potential strategy to treat mycotic keratitis.

7302 Efficacy And Hepatotoxicity Of Ketoconazole In Cushing’s Syndrome

Abstract Disclosure: H. Elenius: None. R. McGlotten: None. S.T. Sharma: None. L.K. Nieman: None. Medical therapy (Rx) of Cushing’s Syndrome (CS) is complicated by variable efficacy, delays to treatment goal and adverse reactions. Ketoconazole (KTZ) use is limited by hepatotoxicity. We retrospectively reviewed records of 65 inpatients receiving KTZ for CS between 2004-2023 to assess efficacy and hepatotoxicity. 24-hour urinary free cortisol (UFC), AM serum cortisol (F), liver function tests (LFTs: alanine transaminase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP)) and daily doses of KTZ were noted. Patients were excluded if they received other medical Rx for CS or strong CYP3A4 inducers/inhibitors; baseline (base) or endpoint F/LFTs were unavailable; or if they received KTZ within 4 days prior to base labs. 35 patients (pts) were evaluated for efficacy. Treatment success was defined as F ≤12 mcg/dL. 17 pts (49%) achieved goal F at a median of 3 days (1-11, IQR 2.5-5.5). Compared to uncontrolled pts, there was no difference in Rx duration, base UFC or F, or initial or final KTZ doses, including when adjusted for base UFC, F, weight or body surface area. The absolute and percent dose increases and the F level prompting an increase did not differ between groups. Pts who reached goal had fewer days (d) between dose increases than uncontrolled pts (median 2 vs 4 d, p=0.025). Of 19 pts on a stable KTZ dose for ≥3 d after an increase, mean F decreased from d 0 to d +1 (-19%, p=0.01), +3 (-38%, p=0.0001) and +4 (-25%, p=0.04). D +3 F decreased from d +1 (-14%, p=0.03) and +2 (-13%, p=0.03). After d+3 no further reduction was seen (but likely biased by subsequent dose changes or discharge after d +3). 37 pts were evaluated for toxicity during KTZ Rx. Of 3 pts with a base LFT ≥3 times upper limit of normal (3ULN), LFTs rose ≥30% in 1, improved to <3ULN in 1 and did not change in the last pt. Of 34 pts with base LFTs <3ULN, a ≥30% rise of ≥1 LFT was seen in 27. Of these, 10/27 had ≥1 LFT rise to ≥3ULN after a minimum cumulative dose of 3400 mg and at least 4 days of Rx. Compared to the other 24, these 10 pts had higher means of base AST (75 vs 54% of ULN, p=0.046), cumulative KTZ doses (10080 vs 4071 mg, p=0.0015), and daily KTZ doses (927 vs 650 mg, p=0.004). AST and ALT increased by ≥30% before ALP (AST vs ALP: 4 vs 6 d, p=0.08). After KTZ was stopped or reduced, LFTs reached <3ULN at a median of 3 days (1-10, IQR 1.5-8.5) in 9 pts; pt 10 improved by discharge. 15/27 with an LFT rise ≥30% continued the same KTZ dose; LFTs stayed ≤ULN in 8, rose to >ULN in 5 and improved from base >ULN to ≤ULN in 2. By the end of inpt KTZ Rx (median 6 d, range 1-27, IQR 4-9), 13 pts (35%) had ≥1 LFT rise from ≤ULN to >ULN, 4 (11%) had ≥1 LFT improve from >ULN to ≤ULN. 12 stayed >ULN (32%); 8 (22%) stayed ≤ULN. Our data supports raising KTZ doses every 72 hours for rapid control. Base AST correlates with liver toxicity risk and tends to rise before ALP. An LFT rise ≥30% is seen in most pts and should not prompt Rx cessation if <3ULN. KTZ improves LFTs in a minority of pts, likely from cortisol reduction. Presentation: 6/3/2024

6570 Treatment of Cushing’s With Levoketoconazole: A Case Series

Abstract Disclosure: N. Chamorro-Pareja: None. M. Haines: None. L.E. Dichtel: Consulting Fee; Self; Lumos Pharma. Research Investigator; Self; Recordati, NovoNordisk, Perspectum Ltd, Lumos Pharma, Pfizer, Inc.. Stock Owner; Self; Marea Therapeutics. Other; Self; Third Rock Ventures. B.M. Biller: Consulting Fee; Self; Xeris Pharmaceuticals, Recordati Rare Diseases, Sparrow, Lundbeck. Background: Endogenous Cushing’s syndrome (CS) is a rare condition of excess cortisol secretion; the most common cause is a pituitary corticotroph tumor (Cushing’s disease [CD]). Medical treatment for CD is primarily used to control hypercortisolism in patients with persistent or recurrent disease after transsphenoidal surgery (TSS). Levoketoconazole (LKCZ), a steroidogenesis inhibitor, was FDA approved in January 2022 for CS treatment. This reports 3 cases of patients who were treated with LKCZ for recurrent CS. Clinical Cases: Case 1: 44-year-old (yo) male (M) with a history of CD with urinary free cortisol (UFC) >26x upper limit of normal (ULN) who was treated preoperatively with ketoconazole (KCZ) 1000 mg/day with UFC improved to 6x ULN. KCZ was discontinued at TSS, and he achieved remission post-operatively. He was lost to follow-up and re-presented after several years with worsening hypertension, muscle weakness, edema, and anxiety with UFC 28x ULN and a recurrent pituitary lesion on MRI. He declined repeat TSS and underwent radiation therapy (RT) and medical treatment. LKCZ was initiated at 150 mg twice daily (BID) and increased to 300 mg BID. At LKCZ 300 mg BID, he had a low UFC and mild nausea but an adequate serum morning cortisol (10.4 ug/dL, ref:6-18.4 ug/dL); LKCZ was reduced to 150 mg BID with resolution of symptoms (sxs) and normal UFC. Case 2: 56 yo M with a history of CD (UFC >3x ULN) who underwent 2 TSSs and RT over 10 years prior with eventual remission, but later recurred. Sxs included brain fog and mood disturbances. He achieved control with pasireotide but discontinued due to abnormal liver function tests. He was then treated with KCZ 400 mg/day but remained hypercortisolemic (LNSC 1.1x ULN) and was interested in trying a new medication, so was switched to LKCZ 150 mg BID with significant improvement of sxs and normalization of LNSC. Case 3: 54 yo F with presumed cyclic CD (negative whole-body and octreotide scans) with UFC 1.7x ULN and LNSC 3x ULN. TSS was performed with negative pathology; she had persistent hypercortisolemia and sxs including insomnia, fatigue, and mood disturbances. She was intolerant to and/or uncontrolled on 4 medications, including KCZ at 1000 mg/day that was discontinued due to a rash. She was started on LKCZ 150 mg BID and achieved normal LNSC and UFC after about 1 month. The drug was discontinued due to the development of a rash similar to that with KCZ. Conclusion: LKCZ is a new option for the treatment of CS in patients whose disease persists after TSS. These 3 patients had improvement of sxs and normalization of cortisol levels while on LKCZ, although one patient discontinued LKCZ due to a rash that was previously experienced with KCZ. The other two patients are being carefully monitored for liver function test elevation, QTc abnormalities and adrenal insufficiency with no issues to date. To our knowledge, this is the first case series of CS patients treated clinically with LKCZ. Presentation: 6/1/2024

Cocrystal screening in minutes by solution-mediated phase transformation (SMPT): Preparation and characterization of ketoconazole cocrystals with nine aliphatic dicarboxylic acids

The rapid and efficient cocrystal screening, based on solution-mediated phase transformation (SMPT), was applied to the screening of cocrystals between ketoconazole (KTZ) and nine aliphatic dicarboxylic acids. Cocrystals formed successfully, in minutes, with a change of suspension characteristics, either a cake formation or the formation of large particles. Bulk cocrystals were characterized by powder X-ray diffraction, thermal analysis, and Raman spectroscopy. Single crystals were grown, and molecular structures were determined. Three previously reported cocrystals were reproduced, and six new cocrystals were discovered, including one that was reported as a failure in literature by solution or grinding method. Two hydrogen-bonded motifs are observed in these nine cocrystals: Most cocrystals form hydrogen bonded discrete tetramer with two KTZ and two acids molecules; while two cocrystals form infinite chain. This study demonstrated the high efficacy of cocrystal generation using the slurry screening method. It should be fully utilized in future cocrystal screening.

Minor changes to circulating steroid hormones in female rats after perinatal exposure to diethylstilbestrol or ketoconazole

Current chemical test strategies lack sensitive markers for detecting female reproductive toxicity caused by endocrine disrupting chemicals (EDCs). In search of a potentially sensitive readout, the steroidogenic disrupting effects of the well-known EDCs ketoconazole (KTZ) and diethylstilbestrol (DES) were investigated in vitro and on circulating steroid hormones in perinatally exposed female Sprague-Dawley rats. Twenty-one steroid hormones were analysed using LC-MS/MS in plasma from female rat offspring at postnatal day (PD) 6, 14, 22, 42 and 90. Most circulating steroid hormone levels increased with age except for estrone (E1), estradiol (E2) and backdoor pathway androsterone (ANDROST), which decreased after PD 22. Perinatal exposure to DES did not affect circulating steroid hormone levels at any dose or age compared to controls. KTZ exposure resulted in dose-dependent increase of corticosterone (CORTICO) at PD 6 and PD 14, with statistical significance only at PD 14. In the in vitro gold standard H295R steroidogenesis assay, twenty-one steroid hormones were measured instead of only T and E2. DES had subtle effects on steroidogenesis, whereas KTZ decreased most steroid hormones, but increased CORTICO, progesterone (P4), estriol (E3) initially (around 0.1–1 µM) before decreasing. Our data suggests that circulating steroidomic profiling may not be a sensitive readout for EDC-induced female reproductive toxicity. Further studies are needed to associate H295R assay steroidomic profiles with in vivo profiles, especially in target tissues such as adrenals or gonads. Expanding the H295R steroidogenic assay to include a comprehensive steroidomic profile may enhance its regulatory applicability.

Novel therapeutic deep eutectic system for the enhancement of ketoconazole antifungal activity and transdermal permeability

In this study, we reported the investigation of a novel therapeutic deep eutectic system (THEDES) formed between capric acid (CA) and ketoconazole (KCZ) to enhance the permeability and efficacy of the antifungal drug KCZ. A THEDES was formulated by combining KCZ and CA at different molar ratios, with a 1:5 ratio (K5) representing the most stable and lowest melting point. Characterization of the interactions between CA and KCZ using NMR and FT-IR spectroscopy revealed a hydrogen bonding interaction between the amine group of KCZ’s imidazole ring and the carboxylic acid moiety of CA. This interaction resulted in converting the solid materials into liquid at room temperature, leading to a significant decrease in the melting points of the components, as confirmed by DSC. Next, the effectiveness of K5 as an antifungal agent against Candida albicans was evaluated. The results indicated a 2-fold reduction in the minimum inhibitory concentration (MIC). In addition, permeability studies conducted using a Franz diffusion cell revealed a significant enhancement in permeability with a 6.19-fold increase in flux compared to commercially available KCZ cream. The findings suggest that fatty acid-based deep eutectic systems, such as the KCZ THEDES, can serve as effective and green drug delivery systems, offering significant enhancements in drug permeability and therapeutic performance. This approach improves the efficacy of drugs and promotes the development of eco-friendly pharmaceutical formulations.

Amphiphilic disodium glycyrrhizin as a co-former for ketoconazole co-amorphous systems: Biopharmaceutical properties and underlying molecular mechanisms

Co-amorphous systems (CAMs) have been extensively investigated to improve the dissolution of hydrophobic drugs. However, drug precipitation during the storage or dissolution of CAMs has still been a major challenge. Here, disodium glycyrrhizin (Na2GA) was first used as a co-former in CAMs based on its multiple hydroxyl groups and amphiphilic structure. Ketoconazole (KTZ), a BCS class II drug, was selected as a model drug. KTZ-Na2GA CAMs at mass ratios of 1:1, 1:2.5, 1:5 and 1:10 were prepared by the spray drying method and further characterised by PXRD and DSC. The 1:2.5, 1:5 and 1:10 groups exhibited significantly enhanced Cmax (all approximately 26.67-fold) and stable maintenance of supersaturation compared to the crystalline KTZ and the corresponding physical mixtures in non-sink dissolution tests, while the 1:1 group exhibited an unstable medium Cmax (all approximately 14.67-fold). The permeability tests revealed that the permeation rate of KTZ in KTZ-Na2GA CAMs under the concentration of Na2GA in solution above the critical micelle concentration (CMC) showed a significant downwards trend compared to that below CMC. The underlying molecular mechanisms were involved in molecular miscibility, hydrogen bond interactions, solubilisation and crystallisation inhibition by Na2GA. Pharmacokinetic studies demonstrated that the AUC0-∞ of KTZ in 1:1, 1:2.5, 1:5 and 1:10 groups were significantly higher than those of the crystalline KTZ group with 2.13-, 2.30-, 2.16- and 1.86-fold, respectively (p < 0.01). In conclusion, Na2GA has proven to be a promising co-former in CAMs to enhance hydrophobic drug dissolution and bioavailability. Its effect on intestinal permeation rate of drugs also deserves attention.

Formulation Variables Influencing the Development of Ketoconazole Gastroretentive Drug Delivery System

Background: Ketoconazole (KZ) is categorized as class II according to the Biopharmaceutics Classification System (BSC) classification, which shows a strong pH-dependent solubility where its solubility is enhanced under an acidic medium (pH below 3). This strong pH dependence results in unpredictable absorption and a wide range of bioavailabilities. Objective: To prolong the gastric residence time of KZ’s tablet to enhance KZ’s solubility and hence its bioavailability for better therapeutic activity. Methods: To prepare mucoadhesive tablets, we use both direct and wet granulation methods. We employed various evaluation tests to assess the prepared tablets. These tests encompass a range of assessments, including weight variation, hardness, thickness, friability, disintegration test, swelling study, mucoadhesive strength study, and in vitro drug release studies. Results: The study found that polymer viscosity, as well as polymer concentration, have a significant effect on mucoadhesive strength and drug release, whereas diluent type has a non-significant influence on drug release. We selected Formula 7, which employs xanthan gum as a mucoadhesive polymer in a 1:1 drug polymer ratio, as the optimum formula because it provides an accepted physico-mechanical property and releases 87% of the drug over 8 hours. Conclusions: Gastric mucoadhesive tablets may be an effective method of delivering active ingredients, as they provide a favorable environment that enhances their dissolution by extending their duration in the stomach, thereby increasing their bioavailability.

Correlation of Vanillin-Induced Cytotoxicity with CYP3A-Mediated Metabolic Activation.

Vanillin (VAN) is a common flavoring agent that can cause liver damage when ingested in large amounts. Nevertheless, the precise processes responsible for its toxicity remain obscure. The present research aimed to examine the metabolic activation of VAN and establish a potential correlation between its reactive metabolites and its cytotoxicity. In rat liver microsomes incubated with VAN, reduced glutathione/N-acetylcysteine (GSH/NAC), and nicotinamide adenine dinucleotide phosphate (NADPH), two conjugates formed from GSH and one conjugate derived from NAC were identified. We also discovered one GSH conjugate in both the bile obtained from rats and the rat primary hepatocytes that were subjected to VAN exposure. Additionally, the NAC conjugate exerted in the urine of VAN-treated rats was observed. These results indicate that a quinone intermediate was produced from VAN both in vitro and in vivo. Next, we identified CYP3A as the main enzyme that initiated the bioactive pathway of VAN. After the activity of CYP3A was selectively inhibited by ketoconazole (KTZ), the generation of the GSH conjugate declined in hepatocytes exposed to VAN. Furthermore, the vulnerability to VAN-induced toxicity was alleviated by KTZ in hepatocytes. Thus, we propose that the cytotoxicity of VAN may derive from metabolic activation triggered by CYP3A.

Preclinical benefit of silymarin on ketoconazole-induced hepatotoxicity

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 (180-200g) 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

HSPiP and QbD oriented optimized stearylamine-elastic liposomes for topical delivery of ketoconazole to treat deep seated fungal infections: In vitro and ex vivo evaluations

The study explored stearylamine containing cationic elastic liposomes to improve topical delivery and efficacy of ketoconazole (KETO) to treat deeply seated fungal infections. Stearylamine was used for dual functionalities (electrostatic interaction and flexibility in lipid bilayer). Hansen solubility program (HSPiP) estimated Hansen solubility parameters (HSP) based on the SMILE file and structural properties followed by experimental solubility study to validate the predicted values. Various formulations were developed by varying phosphatidylcholine and surfactants (tween 80 and span 80) concentration. To impart cationic properties, stearylamine (1.0 %) was added into the organic phase. Using quality by design (QbD) method, we optimized the formulations and evaluated for vesicle size, polydispersity index, zeta potential, morphology (scanning electron microscopy), in vitro drug release (%), and ex vivo permeation profiles. Result showed that there is a good correlation (0.65) between HSPiP predicted and actual experimental solubility of KETO in water, chloroform, S80, and tween 80. Spherical OKEL1 showed an established correlation between the predicted and the actual formulation parameters (size, zeta potential, and polydispersity index) (259 nm vs 270 nm, +2.4 vs 0.21 mV, and 0.24 vs 0.27). OKEL1 was associated with the highest value of %EE (83.1 %) as compared to liposomes. Finally, OKEL1 exhibited the highest % cumulative permeation (49.9 %) as compared to DS (13 %) and liposomes (25 %). Moreover, OKEL1 resulted in 4-fold increase in permeation flux as compared to DS which may be attributed to vesicular mediated improved permeation and gel based compensated trans epidermal water loss in the skin. The drug deposition elicited OKEL1 and OKEL1-gel as suitable carriers for maximum therapeutic benefit to treat deeply seated fungal infections.

Reactive oxygen species sensitive nanomicelles promote the antifungal activity of ketoconazole against Candida albicans in vulvovaginal candidiasis

Excessive local accumulation of reactive oxygen species (ROS) in vulvovaginal candidiasis (VVC) leads to oxidative stress and aggravates inflammation. This study aimed to optimize and synthesize four ROS-sensitive polyethylene glycol (PEG)-boride polymers (PB, PCB, BPB, and BCPCB). A nanomicelle (BCPCB-K) was constructed using BCPCB-encapsulated ketoconazole (KTZ). Finally, the depolymerization principle and ROS-sensitive drug release of BCPCB-K as well as its anti-Candida albicans (CA) and therapeutic effects on mice with VVC were explored through in vitro and in vivo experiments. BCPCB-K exhibited low toxicity to mammalian cells in vitro and good biocompatibility in vivo. It also improved the dispersion and solubility of the hydrophobic drug KTZ. Furthermore, BCPCB-K simultaneously scavenged ROS and released the drug, thus facilitating the antifungal and VVC-treating effects of KTZ. Overall, the findings of this study broadened the application of ROS-sensitive materials in the drug-loading and antifungal fields and provided a strategy for VVC treatment.

A poly-δ-decalactone (PDL) based nanoemulgel for topical delivery of ketoconazole and eugenol against Candida albicans.

This study aimed to investigate the potential of poly-δ-decalactone (PDL) and a block copolymer (methoxy-poly(ethylene glycol)-b-poly-δ-decalactone (mPEG-b-PDL)) in the topical delivery of ketoconazole (KTZ) and eugenol (EUG) against Candida albicans. The nanoemulsion (NE) was studied for its significant factors and was optimized using the design of experiments (DOE) methodologies. A simple robust nanoprecipitation method was employed to successfully produce a nanoemulsion (KTZ-EUG-NE). The spherical globules exhibited rough surfaces, explaining the adsorption of mPEG-b-PDL onto PDL. The sustained drug release effects were governed by the amorphous nature of PDL. KTZ-EUG-NE was further used to develop a 1% w/v Carbopol-940-based nanoemulgel (KTZ-EUG-NE gel). The optimal rheological and spreadability properties of the developed nanoemulgel explain the ease of topical applications. Ex vivo permeation and retention studies confirmed the accumulation of KTZ-EUG-NE at different layers of the skin when applied topically. The cytotoxicity of the developed NE in human keratinocyte (HaCaT) cells demonstrated the utility of this newly explored nanocarrier in reducing the cell toxicity of KTZ. The higher antifungal activities of KTZ-EUG-NE at 19.23-fold lower concentrations for planktonic growth and 4-fold lower concentrations for biofilm formation than coarse drugs explain the effectiveness of the developed NE.

In vitro effects of N-acetylcysteine in combination with antifungal agents against Malassezia pachydermatis isolated from canine otitis externa.

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. 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. 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 0.02-300µg/mL, 0.04-80µg/mL, 0.16-40µg/mL and 1.25-20mg/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. The MIC90 values of M. pachydermatis were 4.6875-9.375µg/mL, 1.25µg/mL, 5-10µg/mL and 10mg/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. 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.

Microbeads produced by prilling/vibration technique: A new way to use polyvinyl alcohol in pediatric and veterinary formulations

Poly(vinyl alcohol) (PVA) is a widely used synthetic polymer and due to its hydrophilicity, biocompatibility, and biodegradability, it is considered a suitable polymer for the formulation of drug delivery systems. In this study, PVA was used in a prilling/vibration technology as a pharmaceutical grade excipient to produce microbeads for oral administration that improve class II drugs' solubility and dissolution rate according to the Biopharmaceutical Classification System (BCS). Specifically, Ibuprofen (IBU) is a weakly acidic drug with low solubility at pH 1.2 and Ketoconazole (KETO), a weakly basic drug characterized by low solubility at pH 6.8. These drugs were selected because of their requirements for specific dosing conditions in children or animals, which often differ from commercially available conventional drugs. The microbeads produced were fully characterized in terms of drug loading, encapsulation efficiency, size, morphology, and drug release experiments were also conducted in a gastric fluid for IBU-loaded microbeads and simulated intestinal fluid for KETO-loaded microbeads. Finally, PVA microbeads were compared with an amorphous solid dispersion (ASDs) of the respective APIs, showing the same increase in solubility and dissolution rate. Therefore, the use of the prilling/vibration technology to produce PVA-based microbeads containing BCS class II drugs improves solubility and dissolution profile, which represent fundamental requirements for good bioavailability. Furthermore, the manufactured microbeads provide a high degree of dosing flexibility, making them suitable for administration in pediatric or veterinary patients with swallowing difficulties and requiring customized dosing.

Design, Synthesis, and the Biological Evaluation of Some New Fused Thiazolotriazine Derivatives

Thiazolotriazine is an essential medicinal chemistry molecule due to its biological properties, particularly antifungalactivity. Antifungal drug resistance is rising worldwide, necessitating the development of innovative, safer, and more effectiveantifungals. This study intended to uncover safer and more effective thiazolotriazine antifungals. ProTox II software was employedto forecast the toxicity of the designed thiazolotriazines. The pharmacokinetic parameters were calculated using the Swiss-ADMEdatabase. The Molecular Operating Environment software (2019.0102 version) was employed for the docking studies utilizing 14-α-demethylase protein (PDB ID: 3LD6). Compounds 4c, 4d, and 4e were prepared and evaluated for in vitro antifungal activity.The computational studies revealed compounds 4a, 4b, 5b, 5c, 6b, 6c and 6d as carcinogenic; 4a, 4b, 4c, 4d and 4e demonstratedbetter pharmacokinetic behaviour; and docking results of 4c, 4d, and 4e were superior than fluconazole (FLU). The moleculardocking studies establish 4c, 4d, and 4e as SDM inhibitors, suggesting a mechanism similar to FLU and ketoconazole (KET). Theantifungal activity evaluation revealed 4d (MIC = 6.25 μg/ml) as a more potent antifungal agent than KET (MIC = 12.5 μg/ml) andFLU (MIC = 12.5 μg/ml). Compounds 4c and 4e showed equal antifungal activity to KET (MIC = 12.5 μg/ml) and FLU (MIC = 12.5μg/ml). Compounds 4c, 4d, and 4e displayed encouraging antifungal activity with a favorable safety profile. Assessing the broadspectrum of 4c, 4d, and 4e against various pathogenic fungi, including resistant forms, is recommended.

Ketoconazole Nanocrystals Fortified Gel for Improved Transdermal Applications

Ketoconazole (KTZ) is a commonly prescribed antifungal drug used to treat several tropical and systemic fungus infections. The topical bioavailability of KTZ is limited due to extremely low water solubility and high molecular weight. The present investigation aimed to develop a ketoconazole nanocrystals formulation to improve the biomimetic attributes. The ketoconazole nanocrystals were prepared using a top-down media milling technique with a size of less than 800 nm and a narrow polydispersity index (PDI) of 0.434. The simplex lattice design was used to further investigate the effect of change in the proportion of different stabilizers on critical product attributes such as particle size and PDI. The result of the in vitro drug release and anti-fungal study proved the superiority of the optimized KTZ nanocrystal in inhibiting fungal infection and suspension of pure drug. The optimized nanocrystals entrapped within Carbopol-934P gel had higher permeability through cellulose membrane compared, to the marketed product (2 % ketoconazole % w/w Ketodoc Cream®) with sustained release for 24 h. Moreover, the release profile indicated diffusion-controlled release from gel following Korsmeyer-Peppas. The present investigation successfully demonstrated the application of simplex lattice design and desirability function in optimizing ketoconazole nanocrystals to improve its transdermal application.

Ketoconazole blocks progesterone production without affecting other parameters of cumulus-oocyte complex maturation

Ketoconazole (KTZ) is widely used as a fungicide, but it is also known to target steroid hormone formation which may affect female reproductive health. Our study aims to investigate the effects of KTZ on in vitro matured bovine cumulus-oocyte complexes (COCs), as a model for female reproductive toxicity. Cumulus cells of in vitro maturing COCs produce progesterone and pregnenolone, but exposure to 10−6 M KTZ effectively blocked the synthesis of these hormones. Exposure to lower concentrations of KTZ (i.e. 10−7 M and 10−8 M) had no such effect on steroidogenesis compared to the 0.1 % v/v DMSO vehicle control. Classical parameters of in vitro COC maturation, such as oocyte nuclear maturation to the metaphase II stage and expansion of the cumulus investment, were not affected by any KTZ concentration tested. Apoptosis and necrosis levels were also not altered in cumulus cells or oocytes exposed to KTZ. Moreover, oocytes exposed to KTZ during maturation showed normal cleavage and early embryo development up to day 8 post fertilization; albeit a statistically significant decrease was observed in day 8 blastocysts produced from oocytes exposed to the lowest concentration of 10−8 M KTZ. When unexposed mature oocytes were fertilized, followed by embryo culture for 8 days under KTZ exposure, no adverse effects in embryo cleavage and blastocyst formation were observed. In conclusion, KTZ has no major impact on in vitro bovine oocyte maturation and blastocyst formation in our study, even at concentrations blocking steroidogenesis.

Machine learning-assisted SERS approach enables the biochemical discrimination in Bcl-2 and Mcl-1 expressing yeast cells treated with ketoconazole and fluconazole antifungals

Antifungal medications are important due to their potential application in cancer treatment either on their own or with traditional treatments. The mechanisms that prevent the effects of these medications and restrict their usage in cancer treatment are not completely understood. The evaluation and discrimination of the possible protective effects of the anti-apoptotic members of the Bcl-2 family of proteins, critical regulators of mitochondrial apoptosis, against antifungal drug-induced cell death has still scientific uncertainties that must be considered. Novel, simple, and reliable strategies are highly demanded to identify the biochemical signature of this phenomenon. However, the complex nature of cells poses challenges for the analysis of cellular biochemical changes or classification. In this study, for the first time, we investigated the probable protective activities of Bcl-2 and Mcl-1 proteins against cell damage induced by ketoconazole (KET) and fluconazole (FLU) antifungal drugs in a yeast model through surface-enhanced Raman spectroscopy (SERS) approach. The proposed SERS platform created robust Raman spectra with a high signal-to-noise ratio. The analysis of SERS spectral data via advanced unsupervised and supervised machine learning methods enabled unquestionable differentiation (100 %) in samples and biomolecular identification. Various SERS bands related to lipids and proteins observed in the analyses suggest that the expression of these anti-apoptotic proteins reduces oxidative biomolecule damage induced by the antifungals. Also, cell viability assay, Annexin V-FITC/PI double staining, and total oxidant and antioxidant status analyses were performed to support Raman measurements. We strongly believe that the proposed approach paves the way for the evaluation of various biochemical structures/changes in various cells.

Effectiveness of luliconazole vs ketoconazole topical formulation in reversing damaged hair cuticle

Azole antifungal agents are effective agents for treating scalp ailments such as seborrheic dermatitis. Luliconazole (LZ) is a new azole with unique effects against clinically important dermatomycotic fungi. This study examines the impact of different topical formulation of Luliconazole vs Ketoconazole (KZ) on damaged hair cuticle repair after 5 and 10 washes, using SEM images and sensory Analysis.In this in-vitro study,twelve damaged hair tresses were divided into two groups, and treated with LZ and KZ formulations. Both groups underwent pretreatment with 20% Sodium Laureth sulfate (SLES) and damage induction using 9% HO and 20% ammonium solution, followed by respective LZ (Lupizol ZS, manufactured by Lupin Ltd, India) and KZ therapies. SEM imaging and expert sensory analysis were conducted at baseline, after 5, and 10 washes to evaluate surface characterization like cuticle upliftment, smoothness, and softness.After five washes, LZ-treated hair exhibited smooth, intact cuticles with no upliftment, improving to grade 1 cuticle damage. In contrast, KZ-treated hair continued to show substantial upliftment without damage grade improvement. After ten washes, LZ maintained grade 1 damage and 0 µm upliftment, while KZ-treated strands persisted in showing considerable cuticular distress. Sensory analysis supported these results, with LZ improving hair smoothness and softness by 2.42x and 2.72x respectively, after ten washes, significantly outperforming KZ. Visually, LZ-treated hair appeared smoother and healthier, indicating its greater effectiveness in enhancing hair integrity post-washing.The botanical conditioner-based formulation of LZ is more efficacious in enhancing hair integrity post-washing compared to the Ketoconazole formulation. Well-controlled human studies are required to further establish the clinical effects on human participants.