Experimental Solubility of Ketoconazole, Validation Models, and In vivo Prediction in Human Based on GastroPlus.

The study aimed to identify a suitable cosolvent + water mixture for subcutaneous (sub-Q) delivery of ketoconazole (KETO). The solubility was assessed for several dimethyl acetamide (DMA) + water mixtures at T = 293.2 to 318.2 K and pressure P = 0.1 MPa. The experimental solubility (xe) was validated using the Van 't Hoff and Yalkowsky models and functional thermodynamic parameters (enthalpy ΔsolH°, entropy ΔsolS°, and Gibbs free energy ΔsolG°). The in vitro drug release study was performed at physiological pH, and the data served as the input to GastroPlus, which predicted the in vivo performance of KETO dissolved in a DMA + water cosolvent mixture for sub-Q delivery in human. The maximum solubility (mole fraction) of KETO (9.81 × 10-1) was obtained for neat DMA at 318.2 K whereas the lowest value (1.7 × 10-5) was for pure water at 293.2 K. An apparent thermodynamic analysis based on xe gave positive values for the functional parameters. KETO dissolution requires energy, as evidenced by the high positive values of ΔsolH° and ΔsolG°. Interestingly, ΔsolG° progressively decreased with increasing concentration of DMA in the DMA + water mixture, suggesting that the DMA-based molecular interaction improved the solubilization. Positive values of ΔsolG° and ΔsolS° for each DMA + water cosolvent mixture corroborated the endothermic and entropy-driven dissolution. GastroPlus predicted better absorption of KETO through sub-Q delivery than oral delivery. Hence, the DMA + water mixture may be a promising system for sub-Q delivery of KETO to control topical and systemic fungal infections.

Taxifolin binds with LXR (α & ß) to attenuate DMBA-induced mammary carcinogenesis through mTOR/Maf-1/PTEN pathway.

AIM: 7,12-dimethylbenz(a)anthracene(DMBA), a PAH derivative initializes cascades of signaling events that alters a variety of enzymes responsible for lipid and glucose homeostasis resulting in enhanced availability and consumption of energy producing molecules for the development of carcinogenesis. 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoAR) is a key enzyme regulating the pathway of synthesis of cholesterol whereas liver-X-receptor (LXR) regulates lipid, carbohydrate metabolism in various malignancies including mammary carcinogenesis (MC). In this study Taxifolin (TAX), a potential flavanoid has been subjected to evaluate its anti-cancer potential on (MC). METHODS: We designed to screen the molecular docking analysis of TAX on LXRα, LXRß, HMG-CoAR, mTOR and PTEN using MAESTRO tool comparing with their reference ligands. MC was developed by the administration of DMBA in the air pouch (under the mammary fat pad) of the female Sprague-Dawley rats (55 days old). After 90 days of cancer induction, the chemotherapeutic potential of TAX was evaluated by administering TAX at different doses (10, 20 and 40 mg/kg b.w./day). Then western blot and RT-qPCR analysis were performed for determination of the protein and mRNA expressions respectively. RESULTS: The docking analysis revealed significant interaction with LXR (α&ß), HMG-CoAR, mTOR and PTEN. The docking results were validated with the enzyme inhibition assay using HMG-CoAR (EC 1.1.1.34). TAX inhibited the HMG-CoAR activity with an IC50 value of 97.54 ±â€¯2.5 nM whereas the reference molecule pavastatin revealed an IC50 value of 84.35 ±â€¯1.2 nM. Moreover, TAX modulated the energy regulation on DMBA-induced MC in SD-rats by significantly restoring the cancer-induced alterations in body weight, tumor growth and lipid, lipoproteins, lipid metabolizing enzymes and glycolytic enzymes. TAX interacted with LXRs, HMG-CoAR, metabolic enzymes and restored the altered metabolism that accelerates uncontrolled cell proliferation in MC. Moreover, TAX also altered the mRNA and protein expressions of HMG-CoAR, LXR (α,ß), Maf1, PTEN, phosphoinositide 3-kinase (PI3K), Akt, mTOR, fatty acid synthase (FASN) and acetyl-CoA carboxylase 1 (ACC1) in a dose dependent manner. CONCLUSION: These results validate the anti-cancer potential of TAX in DMBA-induced MC through LXR-mTOR/Maf1/PTEN axis.

Taxifolin Inhibits 7,12-Dimethylbenz(a)anthracene-induced Breast Carcinogenesis by Regulating AhR/CYP1A1 Signaling Pathway.

BACKGROUND: Breast cancer (BC), because of its invasive characteristics, is one of the most common and deadliest cancers among the female population around the world. Research has demonstrated that AhR signaling also plays a vital role in BC initiation and development as well. Therefore, blocking this pathway to natural interferences paves a new channel for the prevention of BC. Several natural compounds such as flavonoids possess the anticancer activities against different cancers. OBJECTIVE: The present study has been designed to estimate the chemotherapeutic potential of taxifolin (TAX) against 7,12-dimethylbenz(a)anthracene (DMBA)-induced mammary carcinoma in Sprague-Dawley rats. MATERIALS AND METHODS: Initially, the molecular docking analysis of AhR and cytochrome P450s (CYPs) (CYP1A1 and CYP1B1) was performed using MAESTRO tool, in an attempt to rationalize the activity of TAX, based on their CYP1-binding potential. The in vitro CYP1A1 activity was determined by luciferase assay with CYP1A1 substrate luciferin CEE. The in vivo analysis was performed by administrating TAX at 10, 20, 40 mg/kg BW for 28 days intragastrically in DMBA induced (25 mg/animal dose) at 55 days of age Sprague-Dawley (SD) rats. BC initiates after 90 days of tumor induction phase. The molecular mechanism of TAX on Ahr and CYPs was also examined through the mRNA and protein expressions using reverse transcription-quantitative polymerase chain reaction and Western blotting analysis. RESULTS: Furthermore, TAX altered the energy regulation on DMBA-induced BC in SD rats by considerably restoring the cancer-induced modulations in tumor growth. Our results showed that TAX reduced the expressions of CYP1A1 and CYP1B1 in DMBA-induced mammary carcinoma by downregulating the AhR signaling pathway. CONCLUSION: This study revealed that TAX might be able to act as a chemotherapeutic agent against CYP1A1- and CYP1B1-mediated cancer and the inhibition of the DMBA-induced mammary carcinogenesis in a rat model.Abbreviations used: CYPs: Cytochrome P450s; PAH: polycyclic aromatic hydrocarbons; HRP- Horseradish peroxidase; BSA: Bovine serum albumin; DTTP: Deoxythymidine Triphosphate (nucleotide); RT-qPCR: Real Time quantitative polymerase chain reaction; CADD: Computer Aided Drug Drafting.

Optimized permeation enhancer for topical delivery of 5-fluorouracil-loaded elastic liposome using Design Expert: part II.

OBJECTIVE: To prepare and optimize the topical elastic liposome (EL)-loaded carbopol-980 gel of 5-Fluorouracil (5-FU) containing permeation enhancers (azone, propylene glycol (PG) and lauryl alcohol (LA)) and further evaluation for permeation flux of 5-FU, the activation energy and irritation in the rat skin. METHODS: EL formulations were prepared using phosphatidylcholine and varied surfactants (Span 60, Span 80 and Tween-80) by rotator evaporation method and optimized by experimental design. In vitro characterizations dictated the EL containing Span 80 (lipid:surfactant = 7:3) (EL3-S80) for further optimization of gel. Different gel formulations (5% w/w) with varying concentration (1-3%) of permeation enhancers were prepared and evaluated for viscosity, spreadability, the 5-FU permeation and deposition. The activation energy using the Franz diffusion cell and the plausible irritation using the Draize test were assessed on the albino rat and rabbit, respectively. RESULTS AND DISCUSSION: EL3-S80 was selected as an optimized EL owing to maximum desirability (0.99) and enhanced 5-FU flux (187.86 ± 14.1 µg/cm(2)/h). EL3-S80 suspension loaded gels (0.5%) revealed reduced viscosity leading to higher spreadability than blank gel. EL containing 3% azone in gel, EL containing 3% LA in gel and EL containing 3% PG in gel portrayed 187.86 ± 14.1, 117.7 ± 13.4 and 106.7 ± 7.3 µg/cm(2)/h as enhanced 5-FU flux values, respectively as compared to drug solution (8.8 ± 0.76 µg/cm(2)/h). Furthermore, reduced value of activation energy (2.63-folds) and the non-irritancy of gel could be effective and safe. CONCLUSION: ELA-3 gel formulation could be used as an effective and economic gel in cutaneous cancer and skin-related keratoses.