Nintedanib in Combination With Chemotherapy in the Treatment of Non-small Cell Lung Cancer: A Systematic Review and Meta-Analysis.

Lung cancer remains a major global health challenge, contributing to substantial morbidity and mortality rates. Nintedanib, a tyrosine kinase inhibitor, has demonstrated potential as a treatment for lung cancer. We aim to evaluate nintedanib's efficacy in treating patients with non-small cell lung cancer (NSCLC), depending on the available evidence. Our search for relevant articles was conducted on PubMed, Cochrane Library, Scopus, and Web of Science for randomized controlled trials (RCTs) that involved adult patients with NSCLC up to August 15, 2023. These trials compared the combination of nintedanib and chemotherapy to either placebo plus chemotherapy or chemotherapy alone. Our main outcomes include progression-free survival (PFS) and overall survival (OS). We utilized the Review Manager Software V.5.4 (The Cochrane Collaboration) to analyze all relevant data. Three identified trials, which included 2270 patients, fulfilled the inclusion criteria. Our analysis showed significantly improved PFS (hazard ratio (HR) = 0.79; 95% confidence interval (CI) 0.71-0.88, P < 0.0001) in patients receiving nintedanib compared to placebo. However, OS was not statistically significant (HR = 0.96; 95% CI 0.88-1.05, P = 0.35). In conclusion, a combination of nintedanib and chemotherapy in treating patients with NSCLC was associated with improved PFS than chemotherapy alone but not with improved OS. Further clinical trials assessing nintedanib in the setting of NSCLC are necessary before any further recommendations can be made.

Safety and Efficacy of Proprotein Convertase Subtilisin-Kexin Type 9 Inhibitors After Acute Coronary Syndrome: A Meta-analysis of Randomized Controlled Trials.

BACKGROUND: Elevated circulating cholesterol levels in patients with acute coronary syndrome (ACS) increase morbidity and mortality. Recent studies reported that PCSK9 inhibitors (PCSK9i) have a beneficial effect on various domains of patients' lipid profiles and cardiovascular and mortality outcomes. Here, we aim to further investigate the efficacy and safety of PCSK9i in patients with ACS or who experienced recent episodes. METHODS: We comprehensively searched PubMed, Scopus, Web of Science and Cochrane CENTRAL to identify all randomized controlled trials comparing PCSK9i versus placebo. Data were extracted and analysed using Stata/MP version 17.0. RESULTS: Eleven studies (n = 24,732) were included in this meta-analysis. In terms of efficacy outcomes, compared with the control group, PCSK9i significantly decreased levels of LDL-C, TC, TG, Lp (a) and Apo-B, with the following values, respectively: Cohen's d of - 1.25, 95% confidence interval (CI - 1.64 to - 0.87); Cohen's d of - 1.32, 95% CI (- 1.83 to - 0.81); Cohen's d of - 0.26, 95% CI (- 0.37 to - 0.14); Cohen's d of - 0.70, 95% CI (- 1.15 to - 0.26); and Cohen's d of - 1.46, 95% CI (- 1.97 to - 0.94). The levels of HDL-C and Apo-A1 increased by: Cohen's d 0.27, 95% CI (0.16-0.39) and Cohen's d of 0.30, 95% CI (0.17-0.42), respectively. Regarding safety outcomes, PCSK9i was associated with lower odds of myocardial infarction (MI) and cerebrovascular events with the following values, respectively: OR = 0.87, 95% CI (0.78-0.97) and OR = 0.71, 95% CI (0.52-0.98). CONCLUSIONS: PCSK9i was associated with better lipid profile and quality of life of patients and can be recommended as an optimal treatment strategy. Further trials should study combinations of PCSK9i with other lipid-lowering drugs.

Does fully closed-loop automated insulin delivery improve glycaemic control in patients with type 2 diabetes? A meta-analysis of randomized controlled trials.

AIMS: This meta-analysis investigated the efficacy and safety of fully closed-loop automated insulin delivery (AID) in patients with type 2 diabetes. MATERIALS AND METHODS: We systemically searched PubMed, Scopus, Web of Science, and Cochrane Central from inception until April 26, 2023. We included randomized controlled trials (RCTs) comparing fully closed-loop AID versus conventional insulin therapy. The outcomes were pooled as the mean difference (MD) and risk ratio with 95% confidence interval (CI) in the random effect model. Our primary outcome was the proportion of time in the target glucose range (5.6-10 mmol/L, 3.9-10 mmol/L, or 3.9-8 mmol/L, depending on the study). Key secondary outcomes included the proportion of time spent in hyperglycaemia or hypoglycaemia. RESULTS: We included seven RCTs (three crossover and four parallel design), compromising 390 patients. Our analysis showed that compared to the control group, fully closed-loop AID increased the proportion of time spent within the target glucose range by additional 337 min per 24 h (MD = 23.39%, 95% CI [16.64%, 30.14%], p < 0.01), additional 108 min overnight (MD = 22.40%, 95% CI [12.88%, 31.91%], p < 0.01), and additional 258 min during the daytime period (MD = 26.85%, 95% CI [21.06%, 32.63%], p < 0.01). Compared to the control group, the overall time in hyperglycaemia was shortened by 326 min per 24 h (MD = -22.67%, 95% CI [-30.87%, -14.46%], p < 0.01). There was no significant difference between the two groups in terms of overall, overnight, and daytime periods spent in hypoglycaemia. CONCLUSIONS: Our meta-analysis suggests that fully closed-loop AID may improve glycaemic control in patients with type 2 diabetes, particularly for those with more challenging diabetes management. Further research is required to establish the feasibility of implementing these systems in clinical practice. [Correction added on 26 August 2023 after first online publication: Under Results, the first sentence "We included seven RCTs (three crossover and one parallel designs)" has been changed to "We included seven RCTs (three crossover and four parallel designs)".].

Formulation and Evaluation of Prednisolone Sodium Metazoate-Loaded Mucoadhesive Quatsomal Gel for Local Treatment of Recurrent Aphthous Ulcers: Optimization, In Vitro, Ex Vivo, and In Vivo Studies.

This study aims to formulate a buccal mucoadhesive gel containing prednisolone sodium metazoate-loaded quatsomes for efficient localized therapy of recurrent aphthous ulcers. Quatsomes were prepared using a varied concentration of quaternary ammonium surfactants (QAS) and cholesterol (CHO). A 23 factorial design was conducted to address the impact of independent variables QAS type (X1), QAS to CHO molar ratio (X2), and sonication time (X3). The dependent variables were particle size (PS; Y1), polydispersity index (PDI; Y2), zeta potential (ZP; Y3), entrapment efficiency percent (EE%; Y4) and percent of drug released after 6 h (Q6%: Y5). Then, the selected quatsomes formula was incorporated into different gel bases to prepare an optimized mucoadhesive gel to be evaluated via in vivo study. The PS of the developed quatsomes ranged from 69.47 ± 0.41 to 113.28 ± 0.79 nm, the PDI from 0.207 ± 0.004 to 0.328 ± 0.004, ZP from 45.15 ± 0.19 to 68.1 ± 0.54 mV, EE% from 79.62 ± 1.44 to 98.60% ± 1.22 and Q6% from 58.39 ± 1.75 to 94.42% ± 2.15. The quatsomal mucoadhesive gel showed rapid recovery of ulcers, which was confirmed by the histological study and the evaluation of inflammatory biomarkers. These results assured the capability of the developed quatsomal mucoadhesive gel to be a promising formulation for treating buccal diseases.

Anticholinesterases activity of Murraya koenigii (L.) Spreng. and Murraya paniculata (L.) Jacq. essential oils with GC/MS analysis and molecular docking.

GC/MS analysis of Murraya koenigii (L.) Spreng. and Murraya paniculata (L.) Jacq. leaves revealed the identification of 73 components, with an evident greater contribution of monoterpenes hydrocarbons to their total volatiles. α-Pinene (37.5%) and ß-caryophyllene (27.4%) were the most abundant compounds in M. koenigii leaves and ß-phellandrene (40.7%) in M. paniculata leaves, using headspace. ß-Phellandrene (33.7%) was the major constituent by M. koenigii leaves where germacrene D (23.8%), and δ-elemene (22.0%) were predominant in M. paniculata leaves, using steam distillation. M. koenigii leaves oil showed quite remarkable cholinesterase inhibitory activity, where oil of M. paniculata leaves showed strong inhibitory activity against AChE (IC50=13.2 ± 0.9 µg/mL) and BChE (IC50=5.1 ± 0.3 µg/mL). Germacrene D, α-zingiberene, and δ-elemene showed higher affinity to BChE than AChE as revealed from docking scores (S = -5.65 to -6.03 Kcal/mol) for BChE and (S = -5.56 to -6.25 Kcal/mol) for AChE.

Design, synthesis, and biological evaluation of furan-bearing pyrazolo[3,4-b]pyridines as novel inhibitors of CDK2 and P53-MDM2 protein-protein interaction.

The novel series of furan-bearing pyrazolo[3,4-b]pyridines were designed as cyclin-dependent kinase 2 (CDK2) inhibitors and as p53-murine double minute 2 (MDM2) inhibitors. The newly synthesized compounds were screened for their antiproliferative activity toward hepatocellular carcinoma (HepG2) and breast cancer (MCF7) cell lines. The most active compounds on both cell lines were additionally evaluated for their in vitro CDK2 inhibitory activity. Compounds 7b and 12f displayed enhanced activity (half-maximal inhibitory concentration [IC50 ] = 0.46 and 0.27 µM, respectively) in comparison to the standard roscovitine (IC50 = 1.41 ± 0.03 µM), in addition to, cell cycle arrest at S phase and G1/S transition phase in MCF7 cells treated with both compounds, respectively. Moreover, the most active spiro-oxindole derivative against MCF7 cell line, 16a, exhibited enhanced inhibitory activity against p53-MDM2 interaction in vitro (IC50 = 3.09 ± 0.12 µM) compared to nutlin, and increased the levels of both p53 and p21 by nearly fourfold in comparison to the negative control. Molecular docking studies demonstrated the plausible interaction patterns of the most potent derivatives 17b and 12f in the CDK2 binding pocket and the spiro-oxindole 16a with p53-MDM2 complex, respectively. Consequently, the new chemotypes 7b, 12f, and 16a can be presented as promising antitumor hits for further studies and optimization.

Discovery of new pyridine heterocyclic hybrids; design, synthesis, dynamic simulations, and in vitro and in vivo breast cancer biological assays.

Pyridine is a nitrogen bearing heterocyclic scaffold that shows a wide range of biological activities. The pyridine nucleus has become an interesting target for medicinal chemistry researchers worldwide. Several pyridine derivatives exhibited good anticancer effects against diverse cell lines. Therefore, to explore new anticancer pyridine entities, novel pyridine derivatives were designed and synthesized and evaluated for their anticancer abilities in vitro and in vivo. All of the target compounds were evaluated against three different human cancer cell lines (Huh-7, A549 and MCF-7) via MTT assay. Most of the compounds exhibited significant cytotoxic activities. Compounds 3a, 3b, 5a and 5b showed superior antiproliferative activities to Taxol. Where, compound 3b showed IC50 values of 6.54, 15.54 and 6.13 µM compared to Taxol (6.68, 38.05, 12.32 µM) against Huh-7, A549 and MCF-7, respectively. Also, tubulin polymerization assay was carried out. The most potent compounds 3a, 3b, 5a and 5b could significantly inhibit tubulin polymerization with IC50 values of 15.6, 4.03, 6.06 and 12.61 µM, respectively. Compound 3b exhibited the highest tubulin polymerization inhibitory effect with an IC50 value of 4.03 µM compared to combretastatin (A-4) (1.64 µM). Molecular modeling studies of the designed compounds confirmed that most of the compounds made the essential binding interactions compared to the reference compound which assisted in the prediction of the structure requirements for the detected anticancer activity. Finally, in vivo studies showed that compound 3b could significantly inhibit breast cancer.

Sertaconazole-Nitrate-Loaded Leciplex for Treating Keratomycosis: Optimization Using D-Optimal Design and In Vitro, Ex Vivo, and In Vivo Studies.

This study aims to develop efficient topical therapy for keratomycosis using sertaconazolenitrate (STZN)-loaded leciplex (LP). The D-optimal design was used to optimize STZN-loaded LP by utilizing soy phosphatidylcholine (SPC) molar ratio (X1), cationic surfactant molar ratio (X2), and cationic surfactant type (X3) as the independent variables, whereas their impact was studied for entrapment efficiency percent (EE; Y1), particle size (PS; Y2), polydispersity index (PDI; Y3), zeta potential (ZP; Y4), and permeability coefficient (Kp; Y5). The optimized formula was evaluated regarding morphology, ex vivo permeation, mucoadhesion, stability, and in vivo studies. The optimized formula was spherical and showed EE of 84.87 ± 1.71%, PS of 39.70 ± 1.35 nm, PDI of 0.242 ± 0.006, ZP of +54.60 ± 0.24 mV, and Kp of 0.0577 ± 0.0001 cm/h. The ex vivo permeation study revealed that the optimized formula enhanced the Kp and corneal deposition by 2.78 and 12.49 folds, respectively, compared to the aqueous drug dispersion. Furthermore, the optimized formula was stable and revealed promising mucoadhesion properties. Finally, the in vivo studies showed that the optimized formula was superior to the drug dispersion in treating rats with induced keratomycosis. These results confirmed the capabilities of LP as a promising nanocarrier for treating ocular diseases topically.

Silica-Coated Magnetic Nanoparticles for Vancomycin Conjugation.

Drug resistance is a global health challenge with thousands of deaths annually caused by bacterial multidrug resistance (MDR). Efforts to develop new antibacterial molecules do not meet the mounting needs imposed by the evolution of MDR. An alternative approach to overcome this challenge is developing targeted formulations that can enhance the therapeutic efficiency and limit side effects. In this aspect, vancomycin is a potent antibacterial agent that has inherent bacterial targeting properties by binding to the D-Ala-D-Ala moiety of the bacterial peptidoglycan. However, the use of vancomycin is associated with serious side effects that limit its clinical use. Herein, we report the development of vancomycin-conjugated magnetic nanoparticles using a simple conjugation method for targeted antibacterial activity. The nanoparticles were synthesized using a multistep process that starts by coating the nanoparticles with a silica layer, followed by binding an amide linker and then binding the vancomycin glycopeptide. The developed vancomycin-conjugated magnetic nanoparticles were observed to exhibit a spherical morphology and a particle size of 16.3 ± 2.6 nm, with a silica coating thickness of 5 nm and a total coating thickness of 8 nm. The vancomycin conjugation efficiency on the nanoparticles was measured spectrophotometrically to be 25.1%. Additionally, the developed formulation retained the magnetic activity of the nanoparticles, where it showed a saturation magnetization value of 51 emu/g, compared to 60 emu/g for bare magnetic nanoparticles. The in vitro cell biocompatibility demonstrated improved safety where vancomycin-conjugated nanoparticles showed IC50 of 183.43 µg/mL, compared to a much lower value of 54.11 µg/mL for free vancomycin. While the antibacterial studies showed a comparable activity of the developed formulation, the minimum inhibitory concentration was 25 µg/mL, compared to 20 µg/mL for free vancomycin. Accordingly, the reported formulation can be used as a platform for the targeted and efficient delivery of other drugs.

Utilization of propranolol hydrochloride mucoadhesive invasomes as a locally acting contraceptive: in-vitro, ex-vivo, and in-vivo evaluation.

It was found that propranolol hydrochloride (PNL), which is a beta-blocker used for hypertension treatment, has a potent spermicidal activity through local anesthetic activity or beta-blocking effect on sperm cells subsequently it could be used as a contraceptive remedy. This study aimed to entrap PNL into invasomes (INVs) and then formulate it as a locally acting contraceptive gel. PNL-loaded mucoadhesive INVs were prepared via the thin-film hydration technique. The D-optimal design was utilized to fabricate INVs employing lipid concentration (X1), terpenes concentration (X2), terpenes type (X3), and chitosan concentration (X4) as independent variables, while their impact was observed for entrapment efficiency percent (Y1; EE%), particle size (Y2; PS), zeta potential (Y3; ZP), and amount of drug released after 6 h (Y4; Q6h). Design Expert® was bestowed to nominate the desired formula. The selected INV was subjected to further studies and formulated into a mucoadhesive gel for ex-vivo and in-vivo investigations. The optimum INV showed a spherical shape with EE% of 65.01 ± 1.24%, PS of 243.75 ± 8.13 nm, PDI of 0.203 ± 0.01, ZP of 49.80 ± 0.42 mV, and Q6h of 53.16 ± 0.73%. Differential scanning calorimetry study asserted the capability of INVs to entrap PNL. Permeation studies confirmed the desired sustained effect of PNL-loaded INVs-gel compared to PNL-gel, INVs, and PNL solution. Sperm motility assay proved the potency of INVs-gel to inhibit sperm motility. Besides, the histopathological investigation verified the tolerability of the prepared INVs-gel. Taken together, the gained data justified the efficacy of PNL-loaded INVs-gel as a potential locally acting contraceptive.

An alternative, low-dissolution counter electrode to prevent deceptive enhancement of HER overpotential.

Electrochemical hydrogen evolution reaction (HER) is typically studied in three-electrode system. In this system, several counter electrodes are commonly used to ensure fast kinetics, including Pt, gold, and glassy carbon. However, the extensive application of such electrodes has raised caveats on the contribution of the redox-active species dissolving from such electrodes and redepositing on the surface of the working electrode to the measured overpotential. Consequently, this has been frequently confused with the actual electrochemical signature of the working electrode catalyst, resulting in a deceptive enhancement in the recorded overpotential. This issue becomes more critical when the electrolysis measurements involve an activation step, necessitating the need for alternative counter electrodes that are stable, especially in acidic medium, which is commonly used as the electrolyte in HER studies. Herein, while we systematically unveil such problems, an alternative counter electrode that overcomes those problems is demonstrated. Specifically, the correlation between the working electrode area to that of the counter electrode, the dissolution rate of the counter electrode, and the potential range used in the activation/cleaning of the surface on accelerating the dissolution rate is explored and discussed in detail. Finally, commercial Ti mesh is demonstrated as an alternative emerging counter electrode, which is proven to be very stable and convenient to study the HER in acidic media.

Molecularly-imprinted polymer-base bulk optode for the determination of ivabradine hydrochloride in Procoralan®.

IVH may be administered orally twice per day for treating heart failure, sinus rhythm, heart-related chest pain and angina pectoris, and its overdose may cause problems such as blurred vision, uncontrolled blood pressure, prolonged bradycardia, and others. A molecularly imprinted polymer-based bulk optode, miptode, was constructed for the determination of ivabradine hydrochloride (IVH) in its pharmaceutical preparation Procoralan®. The molecularly-imprinted polymers (MIPs) were prepared in different ratios, and MIP3 had the highest imprinting factor (1.6) as an ionophore in the miptode preparation. The miptode was prepared using weight ratios of 30% PVC polymer, 62% nitrophenyl octyl ether (NPOE) plasticizer, 6% MIP3 ionophore, 1% tetraphenyl borate derivative (TPB) ion-exchanger, and 1% ETH7075 chromoionophore; this miptode exhibited an absorbance increase at 530 nm in the concentration range of 10-2-10-5 M with a detection limit of 3.1 µM using Tris-HCl buffer of pH 7.2. The miptode was imaged using AFM, and showed the dissolution of all components except MIP particles which exhibited restricted solubility. However, the incorporation of MIP3 as an ionophore improved the selectivity coefficient over the interfering species that may exist in the pharmaceutical formulation to an extent that was not reported before; e.g. coefficients of IVH over sodium, magnesium, and glucose were improved by 5, 4 and 2 orders, when compared to the previous sensor that operated with the molecular interaction mechanism. The selectivity improvement in miptode is due to the Key-Lock fitting (host-guest molecular recognition) between the MIP particles and the template IVH molecule which is transduced with the ion-exchange process of the chromoionophore. The miptode has a response time of 1-2 minutes, and a reliable lifetime of two months. The miptode was applied successfully for the determination of IVH in the pharmaceutical preparation Procoralan® with recovery values of 89-99.8% with low standard deviations of <1.2.

Respirable spray dried vancomycin coated magnetic nanoparticles for localized lung delivery.

Bacterial pneumonia is a common pulmonary infection responsible for premature death. Biomaterials based-carriers loaded with antibiotics enhance drug potency through localizing the therapy, minimizing the associated adverse effects, and improving patient compliance. Herein, this study reports the preparation of an inhalable dry powder formulation composed of a nano-in-microparticles. Vancomycin was adsorbed on the core of magnetic nanoparticles followed by spray drying into lactose/dextran to optimize the aerodynamic performance and allow the local delivery of the drug into the bacterial pneumonia infection site. Lactose and Dextran are polysaccharides commonly used for pulmonary delivery due to their optimum aerodynamic performance and biocompatibility. The preparation of the nano-in-micro particles with optimum properties was confirmed using FTIR, TEM, SEM, Laser-diffraction, ICP-AES and TGA. The TEM micrographs confirmed the formation of spherical magnetic nanoparticles with a diameter 14.7 ± 5.9 nm and a coating thickness 3 - 16 nm, while laser diffraction showed that outer microparticles exhibited a mean diameter < 5 µm. The formulations demonstrated a promising activity against S. aureus and MRSA and better biocompatibility using MTT assay. In vivo safety and pharmacokinetic studies confirmed the localization of VAN in lung tissue and minimized adverse effects compared to free VAN. Therefore, the developed nano-in-microparticles confers a good potential for eradication of lung infections.

Formulation and characterization of propolis and tea tree oil nanoemulsion loaded with clindamycin hydrochloride for wound healing: In-vitro and in-vivo wound healing assessment.

This study aimed to develop propolis and tea tree oil nanoemulsion loaded with clindamycin hydrochloride to heal wound effectively. Nanoemulsion formulae were prepared and characterized by droplet size analysis, zeta potential, viscosity, ex-vivo permeation, and skin deposition. The optimal formula was evaluated in terms of morphology, cytotoxicity, and in-vitro wound healing assay. Also, the efficacy of the optimal formula was evaluated by in-vivo wound healing and histopathological studies. The optimal formula (F3) was composed of 9% tea tree oil and 0.4% propolis extracts with mean droplet size 19.42 ± 1.7 nm, zeta potential value -24.5 ± 0.2 mV, and viscosity 69.4 ± 1.8 mP. Furthermore, the optimal formula showed the highest skin deposition value 550.00 ± 4.9 µg/cm2 compared to other formulae. The TEM micrograph of the optimal formula showed that the nanoemulsion droplet has an almost spherical shape. Also, the optimal formula did not show noticeable toxicity to the human skin fibroblast cells. The in-vitro and in-vivo wound healing assay showed unexpected results that the un-loaded drug nanoemulsion formula had a comparable wound healing efficacy to the drug-loaded nanoemulsion formula. These results were confirmed with histopathological studies. Our results showed that the propolis and tea tree oil nanoemulsion, whether loaded or unloaded with an antibiotic, is an efficient local therapy for wound healing.

Formulation and Evaluation of Baclofen-Meloxicam Orally Disintegrating Tablets (ODTs) Using Co-Processed Excipients and Improvement of ODTs Performance Using Six Sigma Method.

PURPOSE: This study aimed to formulate an orally disintegrating tablet (ODT) containing both baclofen and meloxicam together for treating osteoarthritis. METHODS: Direct compression method was used to prepare ODTs using three types of co-processed excipients (Prosolv ODT G2®, F-melt®, and Pharmaburst®500). ODTs were evaluated according to weight variation, thickness, friability, hardness, drug content, wetting time, in-vitro disintegration time, in-vitro dissolution test, and palatability. To enhance the in-vitro dissolution of meloxicam and palatability of ODT, a six sigma methodology was used, and an improvement phase was established where ODTs were prepared using lyophilization and levigation techniques. Finally, a pharmacokinetic study of the improved ODT was accomplished in comparison to the conventional oral tablet. RESULTS: Pharmaburst-based formula (F4) showed the shortest wetting time and, consequently, the shortest disintegration time and the highest percentage of drug dissolved within 3 min compared to the other formulae. All the improved ODTs had a bitterness taste score vary from (0) palatable and (+1) tasteless. The current sigma level was 3.628 σ and 3.33 σ for palatability and solubility of ODT, respectively, which indicated the process was successfully improved compared with the previous sigma level of 2.342 σ of both processes. Pharmacokinetic study of the improved ODTs showed a significant decrease of Tmax to 120 and 30 min instead of 180 and 120 min for meloxicam and baclofen, respectively. CONCLUSION: ODTs were successfully improved using the six sigma methodology, the pharmacokinetic parameters of both drugs were enhanced due to rapid absorption through the oral mucosa.

Design and synthesis of novel furan, furo[2,3-d]pyrimidine and furo[3,2-e][1,2,4]triazolo[1,5-c]pyrimidine derivatives as potential VEGFR-2 inhibitors.

Novel furan 6a-c, furo[2,3-d]pyrimidine 7a-f, 9, 10a-f, 12a,b, 14a-d and furo[3,2-e][1,2,4]triazolo[1,5-c]pyrimidine 8a-f derivatives were designed based on their structural similarity to a previously described oxazole VEGFR-2 back pocket binding fragment. The designed compounds were synthesized and screened for their in vitro VEGFR-2 inhibitory activity where they exhibited good to moderate nanomolar inhibition with improved ligand efficiencies. 8b and 10c (IC50 = 38.72 ± 1.7 and 41.40 ± 1.8 nM, respectively) were equipotent to sorafenib and 6a, 6c, 7f, 8a, 8c, 10b, 10f, 12b, 14c and 14d showed good activity (IC50 = 43.31-98.31 nM). The furotriazolopyrimidines 8a-c and furopyrimidine derivative 10c were further evaluated for their in vitro antiproliferative activity against human umbilical vein endothelial cells (HUVECs) where 8b showed higher potency than sorafenib and resulted in cell cycle arrest at G2/M phase whereas 8c revealed good antiproliferative activity with cell cycle arrest at G1 phase. Moreover, 8a-c and 10c showed significant inhibitory effects on the invasion and migration of HUVECs. Molecular docking study was conducted to gain insight about the potential binding mode. The furo[3,2-e][1,2,4]triazolo[1,5-c]pyrimidine derivatives 8b and 8c represent interesting starting point for antiangiogenic compounds based on their activity and favorable drug likeness profiles.

Ultra-deformable liposomes containing terpenes (terpesomes) loaded fenticonazole nitrate for treatment of vaginal candidiasis: Box-Behnken design optimization, comparative ex vivo and in vivo studies.

Fenticonazole nitrate (FTN) is a potent antifungal drug adopted in the treatment of vaginal candidiasis. It has inadequate aqueous solubility hence, novel ultra-deformable liposomes 'Terpesomes' (TPs) were developed that might prevail over FTN poor solubility besides TPs might abstain the obstacles of mucus invasion. TPs were assembled by thin-film hydration then optimized by Box Behnken design utilizing terpenes ratio (X1), sodium deoxycholate amount (X2), and ethanol concentration (X3) as independent variable, whereas their impact was inspected for entrapment efficiency (Y1), particle size (Y2), and polydispersity index (Y3). Design Expert® was bestowed to select the optimal TP for more studies. The optimal TP had entrapment efficiency of 62.18 ± 1.39%, particle size of 310.00 ± 8.16 nm, polydispersity index of 0.20 ± 0.10, and zeta potential of -10.19 ± 0.2.00 mV. Elasticity results were greater in the optimal TP related to classical bilosomes. Further, ex vivo permeation illustrated tremendous permeability from the optimal TP correlated to classical bilosomes, and FTN suspension. Besides, in vivo assessment displayed significant inhibition effect in rats from FTN-TPs gel compared to FTN gel. The antifungal potency with undermost histopathological variation was detected in rats treated with FTN-TPs gel. Overall, the acquired findings verified the potency of utilizing FTN-TPs gel for treatment of vaginal candidiasis.

Formulation and Characterization of Sertaconazole Nitrate Mucoadhesive Liposomes for Vaginal Candidiasis.

PURPOSE: The aim of this study is to develop efficient localized therapy of sertaconazole nitrate for the treatment of vaginal candidiasis. METHODS: Sertaconazole nitrate-loaded cationic liposomes were prepared by thin-film hydration method and coated with different concentrations of pectin (0.05%, 0.1% and 0.2%) to develop mucoadhesive liposomes. The formulated mucoadhesive vesicles were characterized in terms of morphology, entrapment efficiency, particle size, zeta value, mucoadhesive properties and drug release. The selected formula was incorporated into a gel base and further characterized by an ex vivo permeation study in comparison with conventional sertaconazole gel. Also, the in vivo study was performed to assess the efficacy of sertaconazole mucoadhesive liposomal gel in treating rats with vaginal candidiasis. RESULTS: The mucoadhesive liposomes were spherical. Coating liposomes with pectin results in increased entrapment efficiency and particle size compared with uncoated vesicles. On the contrary, zeta values were reduced upon coating liposomes with pectin indicating efficient coating of liposomes with pectin. Mucoadhesive liposomes showed a more prolonged and sustained drug release compared with uncoated liposomes. Ex vivo study results showed that mucoadhesive liposomal gel increased sertaconazole tissue retention and reduced drug tissue penetration. In the invivo study, the mucoadhesive liposomal gel showed a significant reduction in the microbial count with a subsequent reduction in inflammatory responses with the lowest histopathological change compared with conventional gel. CONCLUSION: The study confirmed the potentiality of employing mucoadhesive liposomes as a successful carrier for the vaginal delivery of antifungal drugs.

Neurobehavioral investigation and acetylcholinesterase inhibitory activity study for some new coumarin derivatives.

Twenty four 6-aminocoumarin based derivatives were synthesized according to two schemes. All the compounds were screened for their acetylcholinesterase inhibitory activity where compound 5b proved to be the most potent AChE inhibitor with (IC50 = 37 nM) compared to tacrine and donepezil (IC50 = 55.0 and 59.0 nM, respectively). Six compounds 2f, 2g, 4b, 5b, 8b and 9b revealed superior activity over donepezil and a conclusive structure activity relationship study was conducted explaining the obtained results. Furthermore, compounds 2f, 4b and 5b were investigated for their neurobehavioral effect in vivo. All the tested compounds showed improvement of neurobehavioral experiments using donepezil as reference drug. In addition, compounds 2f, 4b and 5b were able to reduce extracellular deposition of amyloid beta 42 in a comparable manner to donepezil. The binding modes of the synthesized compounds were evaluated in silico via molecular docking in the active site of AChE, as well as molecular dynamics simulation study. A pharmacophore model was generated for the newly synthesized compounds.