Pharmaceutical Sciences
Volume:30 Issue: 2, Apr 2024

 Drugs containing the 4-anilinoquinazolines scaffold play a critical role in cancer treatment by inhibiting protein kinases, especially tyrosine kinases. In this study, a novel series of 4-anilinoquinazoline derivatives were synthesized and evaluated as cytotoxic agents.

 All final compounds were synthesized using two methods, including a conventional approach using potassium iodide and dimethylformamide as well as a green method using a deep eutectic solvent (DES) comprising choline chloride:urea. The cytotoxicity was tested on the A431, HUVEC, and HU02 cell lines. To evaluate the binding pattern of the compounds with EGFR and VEGFR-2, a molecular docking investigation was performed. Finally, the wound healing assay was carried out to assess the potency of compounds in inhibiting cell migration.

 The final reaction time was approximately 15-20 min with yields of 60-72% using DES, while the conventional method took 3 to 4 h to complete, with yields between 30% and 42%. Compounds 8k and 8l showed better cytotoxicity against both cell lines compared to vandetanib (IC50=0.11 µM and 0.26 µM on A431 and IC50=5.01 µM and 5.24 µM on HUVEC, respectively). Molecular docking studies revealed that compound 8k, which contained 3-methylaniline at the 4-position of the quinazoline core, showed efficient binding affinity to both EGFR and VEGFR-2. An essential hydrogen bond was formed between quinazoline N1 of 8k and the Met796 residue of EGFR with a docking score of -8.76 kcal/mol. The imidazole N3 of 8k interacted with the Cyc919 residue of VEGFR-2, forming a hydrogen bond with a docking score of -9.03 kcal/mol. Moreover, compound 8k exhibited the best inhibitory activity on cell migration and wound healing.

 Tocilizumab may be the most efficient remission-inducing and relapse-lowering biological agent for patients with GCA, and TNF inhibitors pose the highest risk of infection among the biologics studied.

Cancer is widely recognized as the second leading cause of death on a global scale. In recent years, nanotechnology has emerged as a promising strategy in the field of cancer therapy. Nanoscale drug delivery systems, a category of innovative technologies, harness the potential of various nanoparticles and nanomaterials to efficiently transport chemotherapeutic drugs, revolutionizing cancer treatment. The use of natural products has shown substantial promise in both the prevention and therapy of cancer. Herbal medicines, in particular, have gained widespread use due to their inherent therapeutic advantages and notably fewer adverse effects compared to modern drugs. However, their hydrophobic nature has presented a challenge, limiting their bioavailability and therapeutic efficacy. To overcome these limitations, researchers have developed nanocarriers tailored for the delivery of therapeutic agents to specific target cells. The combination of nanocarriers with herbal remedies results in improved bioavailability, enhanced pharmacological activity, and increased stability, all while minimizing systemic toxicity in cancer treatment. This review provides a comprehensive discussion of novel nanocarriers that find application in cancer treatment, with a specific focus on herbal medicine. The amalgamation of these innovative approaches offers promising prospects for the future of cancer therapy.

Emulsion-based formulations have gained attention in food and pharmaceutical products due to their unique properties. However, their use in food product formulation faces problems because of phase separation and fat oxidation, which seriously reduces the quality of the product. Therefore, finding ways to increase the physical and oxidative stability of emulsions is valuable. This work aimed to assess of physicochemical properties of sodium caseinate (SC)-tannic acid (TA) complex treated with heating and ultrasonication as well as their efficiency in physical and oxidative stability of high internal phase Pickering emulsion (HIPPEs) as antioxidant colloidal particles.

SC 1% (w/v) was mixed with a different concentration of TA (0.1, 0.3, 0.5, 0.7, 1% w/v) and the pH of solutions was adjusted to 9. The unheated, heat-treated, and ultrasonicated SC-TA complexes were analyzed to elucidate possible interaction using FTIR, fluorescence spectroscopy, and DSC. Finally, HIPPEs were prepared by mixing the prepared samples and soybean oil at a volume ratio of 25:75 v/v respectively. The microstructure of the most stable HIPPEs was assessed using SEM.

Based on the FTIR results the covalent bond in heat-treated SC-TA was formed via the Maillard reaction. In addition, the reduction of free amino groups confirms Schiff base formation. All treated SC-TA samples showed a superior ability to stabilize emulsion in comparison with native SC when used as an aqueous phase of HIPPEs. The long-term physical was observed in heat-treated SC-TA HIPPEs for over two months. In PEs stabilized by SC-TA complex nanoparticles, primary and secondary oxidation product levels were significantly lower than in SC alone.

The fabricating antioxidant emulsions using heat-treated SC-TA are a good guarantee for the physical and oxidative stability of food formulations due to TA's intrinsic antioxidant properties and the protective role of SC-TA colloidal particles against coalescence.

 Dry powder inhalers (DPIs) are dosage forms that are used via the pulmonary route. Their formulations include two major parts; drug substance and carrier. For many years, DPIs have been made with lactose, a particularly popular carrier. Leucine has drawn more attention in recent years when it comes to DPI formulations made using the spray drying technique. Leucine was utilized in conjunction with carriers like lactose to enhance physicochemical and aerosolization properties.

 In this investigation, when lactose and leucine were co-spray dried, the color of powders around the cyclone separators of the spray dryer turned brown while the produced powder in the collector was white. Both the white powder inside the collector and the brown powder around the cyclone separators were investigated by differential scanning calorimetry (DSC), Fourier transform-infrared spectroscopy (FT-IR), scanning electron microscopy (SEM), x-ray diffraction (XRD), and liquid chromatography with tandem mass spectrometry (LC-MS-MS) to determine the identity of the degraded chemicals and to look for any potential interactions.

 A new peak at 177 ºC in DSC analysis is a sign of interaction. Also, FT-IR analysis shows the new peak at 1627 cm-1 which is related to the carbonyl group. According to SEM and XRD analysis co spray dried leucine-lactose is amorphous. Obtained data from LC-MS analysis indicates the adduct compound of leucine-lactose that resulted from the Maillard reaction was detected in both white and brown powder. Also, the reaction proceeded to form n-formyl compound.

 There is a possibility of lactose and leucine incompatibility during DPIs manufacturing, especially in elevated temperature and humidity.

 Chemotherapy-induced premature ovarian failure is a prevalent issue for cancer patients, and current treatment options are associated with limitations. Platelet-rich plasma (PRP) has emerged as a safe and straightforward treatment option for various medical conditions, including infertility. The study aims to assess the impact of PRP on the follicular function of granulosa cells damaged with Cyclophosphamide (CTX).

 The study evaluated the biological characteristics of Human Granulosa Cells (HGrC1) that were damaged with 4 hydroxy-cyclophosphamide (4-HC) as the active form of CTX. Then, cells were treated with different concentrations of platelet-rich plasma (PRP), and the expression of PI3K, K-RAS, BCL-2, P27, and Caspase 3 genes were analyzed. Cell viability and apoptosis were also assessed.

 In the MTT assay, it was observed that cells treated with Cyclophosphamide had a faster growth rate when exposed to high concentrations of PRP. The results of the apoptosis assay using Annexin-V and propidium iodide (PI) revealed that PRP effectively inhibited apoptosis and enhanced cell proliferation across all incubation periods (24, 48, and 72 hours). Compared to untreated cells, those treated with different concentrations of PRP showed significantly lower levels of apoptosis, indicating higher cell viability. Real-time PCR results demonstrated that PRP treatment decreased the expression of apoptotic factors P27 and caspase 3 while increasing the expression of genes that promote cell survival and proliferation, such as BCL-2, PI3K, and K-RAS. These findings are consistent with previous research, which suggests that the growth factors present in platelets have anti-apoptotic effects and promote high rates of cell proliferation.

 The study suggests that PRP therapy may have potential benefits in promoting follicular growth and repairing ovarian tissue. However, further research is necessary to establish novel therapeutic strategies based on PRP therapy for treating infertility.

 Drugs containing the 4-anilinoquinazolines scaffold play a critical role in cancer treatment by inhibiting protein kinases, especially tyrosine kinases. In this study, a novel series of 4-anilinoquinazoline derivatives were synthesized and evaluated as cytotoxic agents.

 All final compounds were synthesized using two methods, including a conventional approach using potassium iodide and dimethylformamide as well as a green method using a deep eutectic solvent (DES) comprising choline chloride: urea. The cytotoxicity was tested on the A431, HUVEC, and HU02 cell lines. To evaluate the binding pattern of the compounds with EGFR and VEGFR-2, a molecular docking investigation was performed. Finally, the wound healing assay was carried out to assess the potency of compounds in inhibiting cell migration.

 The final reaction time was approximately 15-20 min with yields of 60-72% using DES, while the conventional method took 3 to 4 h to complete, with yields between 30% and 42%. Compounds 8k and 8l showed better cytotoxicity against both cell lines compared to vandetanib (IC50=0.11 µM and 0.26 µM on A431 and IC50=5.01 µM and 5.24 µM on HUVEC, respectively). Molecular docking studies revealed that compound 8k, which contained 3-methylaniline at the 4-position of the quinazoline core, showed efficient binding affinity to both EGFR and VEGFR-2. An essential hydrogen bond was formed between quinazoline N1 of 8k and the Met796 residue of EGFR with a docking score of -8.76 kcal/mol. The imidazole N3 of 8k interacted with the Cyc919 residue of VEGFR-2, forming a hydrogen bond with a docking score of -9.03 kcal/mol. Moreover, compound 8k exhibited the best inhibitory activity on cell migration and wound healing.

 DES significantly improved the time and yield of the final reactions. Compound 8k, which showed the best cytotoxicity and inhibitory activity on cell migration, could be a suitable candidate for further structural optimization.

 Administering Cinacalcet HCl (CINA) can be challenging because of its low oral bioavailability (20 to 25%) due mainly to its high first-pass metabolism and poor aqueous solubility. However, nanosuspensions are an effective way of enhancing solubility by reducing size. Furthermore, pulmonary delivery of the drug as a promising alternative route can bypass the hepatic first-pass metabolism.

 A CINA nanosuspension was produced by sonoprecipitation and optimized to achieve minimum particle size and polydispersity index (PDI). These nanosuspensions were then spray-dried with different types of sugars to form nano-in-micro composite particles. The particles were then analyzed by scanning electron microscopy (SEM), X-ray diffraction (XRD), Fourier transform infrared (FTIR), and differential scanning calorimetry (DSC), and the dissolution rate, solubility, and in vitro aerosol deposition behavior were determined.

 The particle size of nanosuspensions was in the range of 239.5 to 1281.8 nm and the size was dependent on the process parameters. The spray-dried microparticles had a smooth and spherical surface morphology. The particle size of the composite particles was in the range of 2 to 10 µm and the dissolution rate of processed powders was significantly higher than raw CINA powder. Its crystallinity was partially diminished and no polymorphic conversion were observed. The in vitro deposition study, using a twin-stage impinger (TSI), presented fine particle fractions up to 76.7 percent.

 The utilization of nano-in-micro composite particles as a pulmonary delivery system for CINA has shown great potential in enabling a more efficient drug delivery.

 Colistin use is primarily associated with nephrotoxicity, which has been shown to be reversible with a low incidence of long-term kidney impairment. This study aimed to investigate the risk factors for acute kidney injury (AKI) in patients receiving intravenous colistin.

 A retrospective cohort study was conducted at Nakornping Hospital in northern Thailand from 2015 to 2020. Adult patients who received intravenous colistin were included, while those with chronic kidney disease or prior renal replacement therapy were excluded. The study assessed potential AKI risk factors, including demographics, comorbidities, and concurrent use of medications. Cases of AKI are identified among the cohort, while the control group includes individuals not experiencing AKI during the follow-up but similar to the cases in terms of the exposure. Univariate and multivariable logistic regression analyses were performed to identify risk factors associated with AKI.

 Among the 206 patients included in the study, a majority were admitted to the intensive care unit, required mechanical ventilation, and experienced septic shock. Univariate analysis revealed diabetes (odd ratio (OR)=2.82, 95% CI: 1.21–6.59, p=0.016), malignancy (OR=2.06, 95% CI:1.12–3.77, p=0.020), and baseline Scr (OR=0.71, 95% CI: 0.51–0.99, p=0.048) as significant risk factors for AKI. Multivariate analysis confirmed the association of diabetes (adjusted odd ratio(aOR)= 3.09, 95% CI: 1.20–7.96, p=0.019), malignancy (aOR= 2.31, 95% CI: 1.18–4.52, p=0.015), septic shock (aOR = 2.80, 95% CI: 1.02–7.69, p=0.045), and vasopressor use (aOR = 2.85, 95% CI: 1.12–7.23, p=0.028) with an increased risk of AKI. Conversely, baseline Scr (aOR = 0.54, 95% CI: 0.36–0.82, p=0.004) were associated with a decreased risk of AKI. Other factors, including concomitant use of aminoglycosides, vancomycin, rifampin, combination therapy, nephrotoxins, hypertension, and intensive care unit admission, did not show significant associations.

 This study identified diabetes, malignancy, septic shock, and vasopressor use as significant risk factors for AKI in patients receiving colistin. Baseline Scr levels were found to be inversely associated with the risk of AKI. These findings contribute to a better understanding of colistin-related nephrotoxicity and can guide clinical management to mitigate the risk of AKI in this patient population.

 The N-terminal domain of the myelin oligodendrocyte glycoprotein (MOG) has been shown to generate experimental autoimmune encephalomyelitis (EAE), an animal model of MS. A considerable amount of MOG must be accessible for EAE induction. Here, for the first time, Response Surface Methodology-Box-Behnken (RSM-BBD) was employed to identify the ideal culture conditions for causing Escherichia coli (E. coli) BL21 to overproduce the Thioredoxin-MOG (Trx-MOG) fusion protein. The RSM method is a powerful, efficient, and reliable alternative to the One-Factor-At-A-Time (OFAT) method in optimizing process variables, allowing for a smaller number of experimental runs, investigating variable interaction, and being cheaper and less time-consuming.

 Here, using the 29 experimental assays, the direct and indirect effects of factors including post-induction time, IPTGinducer concentration, pre-induction optical density, and post-induction temperature on the protein expression level content were evaluated.

 The proposed quadratic model demonstrated a significant effect of the two variables A (time) and C (temperature) on protein synthesis. An inducer concentration of 0.491 mM, the pre-induction optical density (OD600) of 0.8, and a temperature of 23 °C for 23.878 hours were found to be the best growth conditions for high yield Trx-MOG synthesis. The optimum protein concentration was attained (163.96 µg/mL) and was within the range of (200.04 µg/mL), which was the value predicted.

 The study concluded that RSM optimization effectively increased the production of Trx-MOG in E. coli, which could have the potential for large-scale fermentation.

 The most prevalent pediatric cancer is acute lymphoblastic leukemia (ALL). It is exceedingly challenging to treat recurrent diseases, and there aren’t many new medications available for children with disease resistance. The size-dependent anticancer effect of zinc oxide nanoparticles (ZnONPs) on T-cell acute lymphoblastic leukemia (T-ALL) cell line MOLT 3 is the central theme of this study.

 The leaf and bark extracts of Diospyros montana were subjected to nanoparticle (NPs) synthesis and characterized analytically to acquire ZnONPs. The ZnONPs were characterized using UV-Vis spectra, DLS, XRD, EDX, SEM, and TEM analysis. Then the ZnONPs were separated into two groups having <50 nm and 50-100 nm NPs sizes. In addition, MTT assay, dual staining, autophagy, DNA damage, and oxidative damage measurement were done to find out the anti-cancer effect of the ZnONPs on MOLT 3 cells.

 The ZnONPs exhibited a size-dependent anticancer effect against MOLT 3 cells. The IC50 of ZnONPs of < 50 nm was found to be ~75 µg/mL while the IC50 of ZnONPs of 50-100 nm size was found to be ~102 µg/mL. Treatment with ZnONPs of <50 nm size decreased mitochondrial membrane potential, more than that with 50-100 nm ZnONPs. On the other hand, autophagy was found to be more prevalent in 50-100 nm treated ZnONPs when compared with < 50 nm size. However, treatment with both sizes of ZnONPs reduced cell proliferation markers such as ki67 positive cells while increasing 8-OHG and HDCF-DA positive cells.

 The obtained results portrayed that different-sized ZnONPs induce different modes of T-ALL cell death. Small-sized ZnONPs revealed higher efficacy, highlighting the size-dependent property. Further, this finding denotes that ZnONPs could be an effective anticancer agent against dreadful diseases like T-ALL, warranting further investigation.

In the current work, the performance of the shake-flask and laser monitoring-based techniques for the determination of the solubility is described as a video file. The video is prepared in three parts. The first part is a general explanation of solubility and its manual and automatic measurement methods. The second part is about how to perform the shake-flask method to measure drug solubility, and the third part is about how the laser monitoring -based automatic device works to measure drug solubility.