Nanostructured Lipid Carriers to Enhance the Bioavailability and Solubility of Ranolazine: Statistical Optimization and Pharmacological Evaluations.

Chronic stable angina pectoris is the primary indication for ranolazine (RZ), an anti-anginal drug. The drug has an anti-ischemic action that is unaffected by either blood pressure or heart rate. Due to the first-pass effect, the drug has a reduced bioavailability of 35 to 50%. The study emphasized developing a novel transdermal drug delivery system of nanostructured lipid carriers (NLCs) for delivering RZ. Many pharmaceutical companies employ lipid nanoparticles as biocompatible carriers for medicinal, cosmetic, and biochemical uses. These carriers are appropriate for many applications, such as topical, transdermal, parenteral, pulmonary, and oral administration, because of the large variety of lipids and surfactants that are readily available for manufacturing. RZ NLCs were made using high-pressure homogenization. Statistical analysis was utilized to find the best formula by varying the concentrations of Precirol ATO 5 (X1), oleic acid (X2), and Tween 80 (X3). Variables such as entrapment effectiveness (EE) (Y1), particle size (Y2), polydispersity index (PDI) (Y3), and zeta potential (Y4) were tested. A variety of tests were performed on the new formulation to ascertain how well it would be absorbed in the body. These tests included in vivo absorption studies, skin permeability assessments, in vitro drug release assessments, and physicochemical analyses. The particle size of RZ-NLCs was shown to be very small (118.4 ± 5.94 nm), with improved EE (88.39 ± 3.1%) and low ZP and PDI (-41.91 ± 0.38 and 0.118 ± 0.028). SEM and TEM analysis confirmed the structure of the NLCs and showed a smooth, spherical surface. Improved RZ-NLCs were used to create NLC gel, which was then tested for elasticity both physically and rheologically. The formulation's elasticity was investigated. Optimized RZ-NLCs and NLCG were found to have transdermal fluxes of 48.369 g/cm2/h and 38.383 g/cm2/h, respectively. These results showed that the transdermal delivery of RZ distribution through NLC's transdermal gel had more significant potential. According to in vivo experiments, the drug's bioavailability in Wistar rats increased when it was delivered through NLCs. The findings demonstrated that NLCs loaded with RZ successfully transported the RZ to the designated site with no interruptions and that a quadratic connection existed between the independent and dependent variables.

Biomedical Applications of Zirconia-Based Nanomaterials: Challenges and Future Perspectives.

ZrO2 nanoparticles have received substantially increased attention in every field of life owing to their wide range of applications. Zirconium oxide is a commercially economical, non-hazardous, and sustainable metal oxide having diversified potential applications. ZrO2 NPs play a vast role in the domain of medicine and pharmacy such as anticancer, antibacterial, and antioxidant agents and tissue engineering owing to their reliable curative biomedical applications. In this review article, we address all of the medical and biomedical applications of ZrO2 NPs prepared through various approaches in a critical way. ZrO2 is a bio-ceramic substance that has received increased attention in biomimetic scaffolds owing to its high mechanical strength, excellent biocompatibility, and high chemical stability. ZrO2 NPs have demonstrated potential anticancer activity against various cancer cells. ZrO2-based nanomaterials have exhibited potential antibacterial activity against various bacterial strains and have also demonstrated excellent antioxidant activity. The ZrO2 nanocomposite also exhibits highly sensitive biosensing activity toward the sensing of glucose and other biological species.

Lopinavir-Loaded Self-Nanoemulsifying Drug Delivery System for Enhanced Solubility: Development, Characterisation and Caco-2 Cell Uptake.

BACKGROUND: The antiretroviral protease inhibitor drug, lopinavir (LPV), is used to treat HIV-1 infection. LPV is known to have limited oral bioavailability, which may be attributed to its poor aqueous solubility, low efficacy and high first-pass metabolism. Self-nanoemulsifying drug delivery systems (SNEDDS) for LPV have been developed and optimised to counter the current issues. METHODS: The titration method was used to prepare LPV-loaded SNEDDS (LPV-SNEDDS). Six different pseudo-ternary phase diagrams were constructed to identify the nanoemulsifying region. The developed formulations were chosen in terms of globule size < 100 nm, dispersity ≤ 0.5, dispersibility (Grade A) and% transmittance > 85. Heating-cooling cycle, freeze-thaw cycle, and centrifugation studies were performed to confirm the stability of the developed SNEDDS. RESULTS: The final LPV-SNEDDS (L-14) droplet size was 58.18 ± 0.62 nm, with polydispersity index, zeta potential, and entrapment efficiency (EE%) values of 0.326 ± 0.005, -22.08 ± 1.2 mV, and 98.93 ± 1.18%, respectively. According to high-resolution transmission electron microscopy (HRTEM) analysis, the droplets in the optimised formulation were < 60 nm in size. The selected SNEDDS released nearly 99% of the LPV within 30 min, which was significantly (p < 0.05) higher than the LPV-suspension in methylcellulose (0.5% w/v). It indicates the potential use of SNEDDS to enhance the solubility of LPV, which eventually could help improve the oral bioavailability of LPV. The Caco-2 cellular uptake study showed a significantly (p < 0.05) higher LPV uptake from the SNEEDS (LPV-SNEDDS-L-14) than the free LPV (LPV-suspension). CONCLUSION: The LPV-SNEDDS could be a potential carrier for LPV oral delivery.

Insulinotropic Potential of Moxifloxacin and Gemifloxacin: An In Vivo Rabbits Model Study Followed by Randomized Phase I Clinical Trial.

Fluoroquinolones (FQs) have been reported to cause dysglycemia in both diabetic and non-diabetic patients. However, diabetic patients are usually on polypharmacy, so we cannot attribute the dysglycemia specifically to FQs. To answer the question as to whether Moxifloxacin and Gemifloxacin influence blood glucose levels and serum insulin levels or otherwise, rabbits were used as experimental animals in an in vivo model followed by a phase I randomized clinical trial in euglycemic healthy volunteers. The effects on the serum insulin and blood glucose levels in the Moxifloxacin and Gemifloxacin treated groups were, respectively, determined on the fifth day in both the in-vivo rabbits model and in the test subjects of the phase I clinical trial. The effects of these drugs were also checked on the histomorphology of the pancreas in the rabbits. The findings of our study suggest that Moxifloxacin and Gemifloxacin significantly (p < 0.05) reduced the blood glucose levels via a subsequent significant shift in the serum insulin levels both in the in vivo animal model and in the test subjects of the phase I clinical trial. No prominent effects on the beta cells histomorphology were noted in this study. Moxifloxacin showed a more significant effect than Gemifloxacin. The insulinotropic effect was comparable to the effect of Glibenclamide. It is concluded that Moxifloxacin and Gemifloxacin have a significant blood glucose lowering effect mediated through insulinotropic action. (Clinical Trials.gov identifier: NCT04692623).

Ibuprofen-Loaded Chitosan-Lipid Nanoconjugate Hydrogel with Gum Arabic: Green Synthesis, Characterisation, In Vitro Kinetics Mechanistic Release Study and PGE2 Production Test.

Ibuprofen is a well-known non-steroidal anti-inflammatory (NSAID) medicine that is often used to treat inflammation in general. When given orally, it produces gastrointestinal issues which lead to lower patient compliance. Ibuprofen transdermal administration improves both patient compliance and the efficacy of the drug. Nanoconjugation hydrogels were proposed as a controlled transdermal delivery tool for ibuprofen. Six formulations were prepared using different compositions including chitosan, lipids, gum arabic, and polyvinyl alcohol, through ionic interaction, maturation, and freeze-thaw methods. The formulations were characterised by size, drug conjugation efficiency, differential scanning calorimetry (DSC), and Fourier transform infrared spectroscopy (FTIR). Further analysis of optimised hydrogels was performed, including X-ray diffraction (XRD), rheology, gel fraction and swelling ability, in vitro drug release, and in vitro macrophage prostaglandin E2 (PGE2) production testing. The effects of ibuprofen's electrostatic interaction with a lipid or polymer on the physicochemical and dissolution characterisation of ibuprofen hydrogels were evaluated. The results showed that the S3 (with lipid conjugation) hydrogel provided higher conjugation efficiency and prolonged drug release compared with the S6 hydrogel.

Synthesis of Capsaicin Loaded Silver Nanoparticles Using Green Approach and Its Anti-Bacterial Activity Against Human Pathogens.

Nanotechnology is drawing attention nowadays due to its ability to regulate metals into nanosize, ultimately changing metal's physical, chemical, and optical properties. Silver nanoparticles are known for their potential impact as antimicrobial agents due to their inherent property penetrating the cell wall. The present study aimed to develop and statistically optimise using a novel combination of capsaicin loaded silver nanoparticles (AgCNPs) as an effective anti-bacterial agent to treat psoriasis using a green approach. Ascorbic acid was used as a reducing agent to fabricate silver nanoparticles. The formulation parameters optimisation was conducted using Box-Behnken Design (3×3 factorial design). The loading of capsaicin was confirmed by attenuated total reflectance-fourier transform infrared spectroscopy. Energy-dispersive X-ray spectroscopy-scanning electron microscopy (EDX-SEM) confirmed the existence of silver; net-like structure revealed in SEM and high-resolution transmission electron microscopy further confirmed the nano size of the formulation. Differential scanning calorimetry and X-ray diffraction demonstrated the capsaicin transformed into amorphous after encapsulated. An in-vitro microbial study showed that the 0.10 M formulation of AgCNPs exerted potent anti-bacterial activity, which can be considered an alternative anti-bacterial agent. It also displayed that the zone of inhibition was significantly high in gram-negative bacteria (E. coli) than gram-positive bacteria (S. aureus). Green synthesised AgCNPs showed highly significant anti-bacterial activity, which indicates that this formulation can be very promising for treating psoriasis.

Synthesis of New Naphthyl Aceto Hydrazone-Based Metal Complexes: Micellar Interactions, DNA Binding, Antimicrobial, and Cancer Inhibition Studies.

In the present study, naphthyl acetohydrazide (HL) ligand was prepared and used for the synthesis of new six amorphous transition metal (Co(II), Ni(II), Cu(II), Zn(II), Pb(II), Cd(II)) complexes. All the compounds were characterized by elemental analysis, UV-vis, FT-IR, 1H- and 13C-NMR, and Matrix-Assisted Laser Desorption Ionization (MALDI). The solubilization study was carried out by estimating the interaction between the metal complexes with surfactants viz. sodium stearate (SS) and Cetyltrimethylammonium bromide (CTAB). UV-Visible spectroscopy was employed to determine partitioning and binding parameters, whereas electrical conductivity measurements were employed to estimate critical micellar concentration (CMC), the extent of dissociation, and free energy of micellization. The CT-DNA interaction of synthesized compounds with DNA represents the major groove binding. The synthesized ligand and metal complexes were also tested against bacterial and fungal strains and it has been observed that Cu(II) complex is active against all the strains except Candida albicans, while Cd(II) complex is active against all bacterial and fungal strains except Pseudomonas. Among all compounds, only the Pd(II) complex shows reasonable activity against cervical cancer HeLa cell lines, representing 97% inhibition.

lnc-HOTAIR predicts hepatocellular carcinoma in chronic hepatitis C genotype 4 following direct-acting antivirals therapy.

Emerging hepatocellular carcinoma (HCC) has been sequentially reported in chronic hepatitis C virus (HCV) treated with direct-acting antivirals (DAAs). Homeobox transcript antisense RNA (HOTAIR), an oncogene, has been reported to be associated with cancer. We investigated the predictive value of lnc-HOTAIR for HCC surveillance in chronic HCV patients following DAAs therapy. The expression levels of lnc-HOTAIR and ATG-7 genes were measured in 220 with chronic HCV, following a DAAs based therapy for 12 weeks, the patients were followed-up for attentive surveillance of HCC for 12 months after starting DAAs. In terms of lnc-HOTAIR, patients with HCC and high viral load had significantly higher median expression levels of HOTAIR of (68 vs. 24; p = .001) and (94 vs. 52; p = .001), respectively. Moreover, the median expression level of ATG-7 was higher in those who developed HCC (114 vs. 51; p = .001). The expression of lnc-HOTAIR and ATG-7 are significant predictors of the development of HCC in HCV-4 infected patients treated with DAAs, with a cut-off value of 37 and 86, respectively. The increased expression levels of lnc-HOTAIR more than 68 in HCC patients following DAAs were correlated with poorer disease outcomes compared to those with lower expression levels; however, ATG-7 expression levels more than 114 were correlated with worse overall survival but not the progression-free one. We suggest that high expression levels of lnc-HOTAIR could serve as a risk assessment biomarker for HCC before and during DAAs course therapy in Chronic HCV-4 patients, and should be rigorously taken into consideration before DAAs.

Tissue-based long non-coding RNAs "PVT1, TUG1 and MEG3" signature predicts Cisplatin resistance in ovarian Cancer.

OBJECTIVES: The current study aimed to investigate the potentiality of three lncRNAs "Plasmacytoma variant translocation 1(lnc-PVT1), Taurine upregulated gene type 1(lnc-TUG1) and Maternally expressed gene 3 (lnc-MEG-3)", to predict Cisplatin resistance in ovarian cancer (OC), in addition, to access their prognostic significance. METHODS: The expression level of lncRNAs were measured in 100 formalin-fixed paraffin-embedded tissue (FFET) samples of OC patients who were treated by Cisplatin-based chemotherapy using qPCR. RESULTS: The results showed that lnc_PVT1 was significantly upregulated by 2.3 folds in Cisplatin resistant tissues, while, lnc-TUG1 and lnc-MEG3 were downregulated by 1.2 and 3 folds, respectively. In addition, the three lncRNAs exhibited high sensitivity and specificity in predicting chemo-resistance and they were negatively associated with OS and progression-free survival (p < 0.001). CONCLUSION: The lnc-PVT1, lnc-TUG1, and lnc-MEG3 transcriptome signatures could be used for predicting resistance to Cisplatin in OC patients.

Mechanisms of nanoparticle internalization and transport across an intestinal epithelial cell model: effect of size and surface charge.

This study investigated the effect of nanoparticle size (50 and 100 nm) and surface charge on their interaction with Caco-2 monolayers as a model of the intestinal epithelium, including cell internalization pathways and the level of transepithelial transport. Initially, toxicity assays showed that cell viability and cell membrane integrity were dependent on the surface charge and applied mass, number, and total surface area of nanoparticles, as tested in two epithelial cell lines, colon carcinoma Caco-2 and airway Calu-3. This also identified suitable nanoparticle concentrations for subsequent cell uptake experiments. Nanoparticle application at doses below half maximal effective concentration (EC50) revealed that the transport efficiency (ratio of transport to cell uptake) across Caco-2 cell monolayers is significantly higher for negatively charged nanoparticles compared to their positively charged counterparts (of similar size), despite the higher level of internalization of positively charged systems. Cell internalization pathways were hence probed using a panel of pharmacological inhibitors aiming to establish whether the discrepancy in transport efficiency is due to different uptake and transport pathways. Vesicular trans-monolayer transport for both positively and negatively charged nanoparticles was confirmed via inhibition of dynamin (by dynasore) and microtubule network (via nocodazole), which significantly reduced the transport of both nanoparticle systems. For positively charged nanoparticles a significant decrease in internalization and transport (46% and 37%, respectively) occurred in the presence of a clathrin pathway inhibitor (chlorpromazine), macropinocytosis inhibition (42%; achieved by 5-(N-ethyl-N-isopropyi)-amiloride), and under cholesterol depletion (38%; via methyl-ß-cyclodextrin), but remained unaffected by the inhibition of lipid raft associated uptake (caveolae) by genistein. On the contrary, the most prominent reduction in internalization and transport of negatively charged nanoparticles (51% and 48%, respectively) followed the inhibition of lipid raft-associated pathway (caveolae inhibition by genistein) but was not significantly affected by the inhibition of clathrin pathway.