Recent developments in targeting breast cancer stem cells (BCSCs): a descriptive review of therapeutic strategies and emerging therapies.

Despite recent advancements in the diagnosis and treatment of breast cancer (BC), patient outcomes in terms of survival, recurrence, and disease progression remain suboptimal. A significant factor contributing to these challenges is the cellular heterogeneity within BC, particularly the presence of breast cancer stem cells (BCSCs). These cells are thought to serve as the clonogenic nexus for new tumor growth, owing to their hierarchical organization within the tumor. This descriptive review focuses on the evolving strategies to target BCSCs, which have become a pivotal aspect of therapeutic development. We explore a variety of approaches, including targeting specific tumor surface markers (CD133 and CD44), transporters, heat shock proteins, and critical signaling pathways like Notch, Akt, Hedgehog, KLF4, and Wnt/ß-catenin. Additionally, we discuss the modulation of the tumor microenvironment through the CXCR-12/CXCR4 axis, manipulation of pH levels, and targeting hypoxia-inducible factors, vascular endothelial growth factor, and CXCR1/2 receptors. Further, this review focuses on the roles of microRNA expression, strategies to induce apoptosis and differentiation in BCSCs, dietary interventions, dendritic cell vaccination, oncolytic viruses, nanotechnology, immunotherapy, and gene therapy. We particularly focused on studies reporting identification of BCSCs, their unique properties and the efficacy of various therapeutic modalities in targeting these cells. By dissecting these approaches, we aim to provide insights into the complex landscape of BC treatment and the potential pathways for improving patient outcomes through targeted BCSC therapies.

Levofloxacin loaded chitosan and poly-lactic-co-glycolic acid nano-particles against resistant bacteria: Synthesis, characterization and antibacterial activity.

BACKGROUND: With the global increase in antibacterial resistance, the challenge faced by developing countries is to utilize the available antibiotics, alone or in combination, against resistant bacterial strains. We aimed to encapsulate the levofloxacin (LVX) into polymeric nanoparticles using biodegradable polymers i.e. Chitosan and PLGA, estimating their physicochemical characteristics followed by functional assessment as nanocarriers of levofloxacin against the different resistant strains of bacteria isolated from biological samples collected from tertiary care hospital in Lahore, Pakistan. METHODS: LVX-NPs were synthesized using ion gelation and double emulsion solvent-evaporation method employing chitosan (CS) and poly-lactic-co-glycolic acid (PLGA), characterized via FTIR, XRD, SEM, and invitro drug release studies, while antibacterial activity was assessed using Kirby-Bauer disc-diffusion method. RESULTS: Data revealed that the levofloxacin-loaded chitosan nanoparticles showed entrapment efficiency of 57.14% ± 0.03 (CS-I), 77.30% ± 0.08(CS-II) and 87.47% ± 0.08 (CS-III). The drug content, particle size, and polydispersity index of CS-I were 52.22% ± 0.2, 559 nm ± 31 nm, and 0.030, respectively, whereas it was 66.86% ± 0.17, 595 nm ± 52.3 nm and 0.057, respectively for CS-II and 82.65% ± 0.36, 758 nm ± 24 nm and 0.1, respectively for CS-III. The PLGA-levofloxacin nanoparticles showed an entrapment efficiency of 42.80% ± 0.4 (PLGA I) and 23.80% ± 0.4 (PLGA II). The drug content, particle size and polydispersity index of PLGA-I were 86% ± 0.21, 92 nm ± 10 nm, and 0.058, respectively, whereas it was 52.41% ± 0.45, 313 nm ± 32 nm and 0.076, respectively for PLGA-II. The XRD patterns of both polymeric nanoparticles showed an amorphous nature. SEM analysis reflects the circular-shaped agglomerated nanoparticles with PLGA polymer and dense spherical nanoparticles with chitosan polymer. The in-vitro release profile of PLGA-I nanoparticles showed a sustained release of 82% in 120 h and it was 58.40% for CS-III. Both types of polymeric nanoparticles were found to be stable for up to 6 months without losing any major drug content. Among the selected formulations, CS-III and PLGA-I, CS-III had better antibacterial potency against gram+ve and gram-ve bacteria, except for K. pneumonia, yet, PLGA-I demonstrated efficacy against K. pneumonia as per CSLI guidelines. All formulations did not exhibit any signs of hemotoxicity, nonetheless, the CS-NPs tend to bind on the surface of RBCs. CONCLUSION: These data suggested that available antibiotics can effectively be utilized as nano-antibiotics against resistant bacterial strains, causing severe infections, for improved antibiotic sensitivity without compromising patient safety.

Exploring the pharmacokinetics of second-generation cephalosporin, cefaclor: a systematic review in healthy and diseased populations.

Cefaclor is a bactericidal antibiotic recommended for treating diverse types of infections. This review aims to comprehensively assess the pharmacokinetic (PK) data on cefaclor in humans.Google Scholar, PubMed, Cochrane Library, and EBSCO databases were systematically performed to identify all the relevant studies containing at least one reported PK parameter of cefaclor.Cefaclor shows the linear PK profile as the area under the plasma concentration-time curve from 0 to t (AUC0-t) and maximum plasma concentration (Cmax) increase in a dose-dependent manner. The AUC0-t of cefaclor in the rice diet was found to be higher than that of bread food, i.e. 19.9 ± 2.6 ug/ml.hr vs 15.4 ± 4 ug/ml.hr. The AUC in paediatrics during the fed state was significantly higher compared to that in adults. Patients with renal impairments showed a Cmax 2.2 times higher than that of normal subjects. A significant increase in Cmax was depicted among individuals following a vegetarian diet in comparison with the non-vegetarian diet. Moreover, cefaclor exhibits time-dependent killing above the minimum inhibitory concentration (MIC < 2 ug), favouring its use in treating infections caused by specific pathogens.This systematic review summarises all the reported PK parameters of cefaclor in healthy and diseased subjects in the literature. This data can help practitioners in adjusting cefaclor doses among different diseases and populations to avoid drug interactions and adverse effects.

Design, synthesis, in-vitro biological profiling and molecular docking of some novel oxazolones and imidazolones exhibiting good inhibitory potential against acetylcholine esterase.

Heterocyclic compounds with oxazole and imidazole rings in their structure have disclosed momentous biological aptitudes. Taking into account their superlative attributes, the present study was designed to introduce a new synthetic scheme to make new derivatives with tremendous futuristic pharmacological potentialities. Series of Oxazolones were synthesized by using substituted benzaldehyde with benzyl halides to produce respective benzaldehyde derivatives 1 (a-d) which further reacted with hippuric acid to yield oxazolones 2 (a-e). Newly synthesized oxazolones then reacted with 4-chloroaniline to yield corresponding imidazolones 3 (a-e). All the compounds were characterized by using FTIR and NMR spectroscopic techniques. Docking studies of Compounds were conducted using AutoDock Vina and analyzed with PYMOL. All synthesized oxazolone and imidazolone derivatives exhibited antioxidant potential, demonstrated by their IC50 values compared to ascorbic acid standard. Oxazolone derivatives (2a-2e) exhibited good acetyl cholinesterase inhibitory potential whereas Imidazolone series did not show significant inhibition as shown by their IC50 values compared to donepezil as a standard. Docking studies of all compounds against acetylcholinesterase demonstrated favorable binding affinity, indicating their potential for further in-vivo studies. It is notable that novel compounds of both oxazolones and Imidazolone series exhibited antioxidant potential with maximum percentage inhibition of 75.9 (IC50 12.9 ± 0.0573 µM/mL) by compound 2d while compound 2a showed AChE inhibitory potential with maximum %age inhibition of 75.49 (IC50 7.8 ± 0.0218 µM/mL).Communicated by Ramaswamy H. Sarma.

A Comprehensive Physiologically Based Pharmacokinetic Model of Nadolol in Adults with Renal Disease and Pediatrics with Supraventricular Tachycardia.

Nadolol is a long-acting non-selective ß-adrenergic antagonist that helps treat angina and hypertension. The current study aimed to develop and validate the physiologically based pharmacokinetic model (PBPK) of nadolol in healthy adults, renal-compromised, and pediatric populations. A comprehensive PBPK model was established by utilizing a PK-Sim simulator. After establishing and validating the model in healthy adults, pathophysiological changes i.e., blood flow, hematocrit, and GFR that occur in renal failure were incorporated in the developed model, and the drug exposure was assessed through Box plots. The pediatric model was also developed and evaluated by considering the renal maturation process. The validation of the models was carried out by visual predictive checks, calculating predicted to observed (Rpre/obs) and the average fold error (AFE) of PK parameters i.e., the area under the concentration-time curve (AUC0-t), the maximum concentration in plasma (Cmax), and CL (clearance). The presented PBPK model successfully simulates the nadolol PK in healthy adults, renal-impaired, and pediatric populations, as the Rpre/obs values of all PK parameters fall within the acceptable range. The established PBPK model can be useful in nadolol dose optimization in patients with renal failure and children with supraventricular tachycardia.

A Systematic Critical Review of Clinical Pharmacokinetics of Torasemide.

PURPOSE: Torasemide is a potassium-sparing loop diuretic used to treat fluid retention associated with congestive heart failure and kidney and hepatic diseases. This systematic review was conducted to combine all accessible data on the pharmacokinetics (PK) of torasemide in healthy and diseased populations, which may help clinicians avert adverse drug reactions and determine the correct dosage regimen. METHODS: Four databases were systematically searched to screen for studies associated with the PK of torasemide, and 21 studies met the eligibility criteria. The review protocol was registered in the PROSPERO database (CRD42023390178). RESULTS: A decrease in maximum plasma concentration (C max ) was observed for torasemide after administration of the prolonged-release formulation in comparison to that after administration of the immediate-release formulation, that is, 1.12 ± 0.17 versus 1.6 ± 0.2 mcg/mL. After administering an oral dose of torasemide, a 2-fold increase in the area under the concentration-time curve (AUC) was reported in patients with congestive heart failure compared with the healthy population. Moreover, the patients with renal failure (clearance < 30 mL/min) showed an increase in value of AUC 0-∞ that is, 42.9 versus 8.091 mcg.h -1 .mL -1 compared with healthy subjects. In addition, some studies have reported interactions with different drugs, in which irbesartan showed a slight increase in the AUC 0-∞ of torasemide, whereas losartan and empagliflozin did not. CONCLUSIONS: The current review summarizes all available PK parameters of torasemide that may be beneficial for avoiding drug-drug interactions in subjects with renal and hepatic dysfunction and for predicting doses in patients with different diseases.

Antihypertensive Effects of Sacubitril/Valsartan Versus Olmesartan: An Updated Systemic Review and Meta-Analysis of Randomized Controlled Trials.

Sacubitril/valsartan is a drug commonly prescribed for the management of hypertension. However, the complete understanding of its efficacy and safety as an antihypertensive agent remains a subject of ongoing investigation. To address this gap, a meta-analysis was conducted to assess and compare the efficacy and safety of sacubitril/valsartan in relation to olmesartan, an angiotensin receptor blocker (ARB). A thorough search of PubMed, Google Scholar, and Cochrane databases was performed to identify relevant randomized controlled trials (RCTs) and observational studies that could contribute to this meta-analysis. The selected studies were evaluated for their efficacy and safety parameters, including mean sitting and ambulatory blood pressure measurements, common side effects, adverse events, and drug discontinuation rates. A total of eight studies, involving 4488 hypertensive patients, were included in this analysis. Among the participants, 63.5% were administered sacubitril/valsartan, while 36.5% received olmesartan. The analysis revealed significant changes in mean sitting systolic blood pressure (MsSBP), mean sitting diastolic blood pressure (MsDBP), and mean sitting pulse pressure (MsPP) favoring sacubitril/valsartan, with p-values <0.00001, 0.07, and <0.00001, respectively. Additionally, sacubitril/valsartan demonstrated a significant reduction in mean ambulatory systolic blood pressure (MaSBP), mean ambulatory diastolic blood pressure (MaDBP), and mean ambulatory pulse pressure (MaPP) with p-values of 0.001, 0.001, and 0.02, respectively. However, it is important to note that safety outcomes indicated that sacubitril/valsartan was associated with slightly less favorable results compared to olmesartan. This meta-analysis highlights that sacubitril/valsartan exhibits superior efficacy in reducing blood pressure parameters compared to olmesartan in hypertensive patients. Nevertheless, its safety profile appears to be slightly less favorable. To reinforce these findings and provide more robust evidence, further studies with larger sample sizes should be conducted in the future. This comprehensive review serves as a valuable resource for healthcare professionals and researchers seeking to make informed decisions regarding antihypertensive treatment options.

Non-prescription antibiotics dispensing by community pharmacies: implications for antimicrobial resistance.

Introduction: The non-prescription antibiotics dispensing (NPAD) from pharmacies is on the rise in low- and middle-income countries, which contributes to the emergence of antimicrobial resistance (AMR). This study was conducted with the objective to determine the community pharmacy personnel's perspectives on NPAD and its implications for AMR. Methods: A questionnaire-based cross-sectional survey was conducted in Pakistan among 336 pharmacies. The data were analyzed using SPSS v21 and MedCalc for Windows v12.3.0. Modified Bloom's cut-off point was utilized to categorize the participants' overall knowledge, attitude, and practice. For univariable logistic regression analyses, odds ratio (OR) was calculated at 95% confidence interval (CI). For multivariable logistic regression analyses, adjusted OR was calculated at 95% CI. Spearman's rank correlation coefficient test was used to assess the relationships among knowledge, attitude, and/or practice scores. Results: The majority of the respondents were staff pharmacists (45.5%). About four-fifths (78.9%) and half (50.9%) of the participants demonstrated moderate to good knowledge and practice, respectively. However, about only one-third (33.1%) had a moderate to good attitude. Staff pharmacists had higher odds of moderate to good knowledge (OR: 2.4, 95% CI: 1.2-4.7) and practice (OR: 2.3, 95% CI: 1.4-3.8). Total knowledge and practice (Spearman's ρ: 0.280; P <0.001) and total attitude and practice (Spearman's ρ: 0.299; P <0.001) scores were significantly correlated. Conclusion: The qualified pharmacists had satisfactory knowledge, attitude, and practices toward antibiotics. However, non-pharmacist staff lacked knowledge and had probable NPAD practice, which has a negative impact on public health. Regular refresher training, seminars, and strict enforcement of rules and regulations are essential.

Insight to phytochemical investigation and anti-hyperlipidemic effects of Eucalyptus camaldulensis leaf extract using in vitro, in vivo and in silico approach.

Hyperlipidemia is a key risk factor mainly for hypertension and cardiac abnormalities. Previously eucalyptus plant (river red gum) had been used for its medicinal value for the treatment of many ailments. This study focused on phytochemical examination, investigation of an in vitro potential and in vivo effects in mice fed with high cholesterol diet, GC-MS analysis of extracts of Eucalyptus camaldulensis leaves and further confirmation of anti-hyperlipidemic potential of different constituents of plant extracts by using in silico technique. For in vitro study screening of different extracts of Eucalyptus camaldulensis leaves was performed by using pancreatic lipase enzyme inhibition assay. Ethanolic extract presented the highest potential among all the extracts by inhibiting pancreatic lipase having IC50-11.88 µg/mL. For in vivo study mice were fed with high cholesterol diet for induction of Hyperlipidemia. Water extract showed great anti-hyperlipidemic potential by reducing the level of cholesterol, triglycerides, low density lipoproteins and increasing high density lipoproteins level significantly (p < 0.05). Moreover, molecular docking and prime MM-GBSA study were applied for screening of compounds having anti-hyperlipidemic potential which showed that Alpha-cadinol was the lead compound for inhibition of pancreatic lipase enzyme having docking score (-6.604). The ADMET properties and toxicity profile of the top docked compounds were also detailed for ensuring their safety aspects. In this way in silico analysis substantiate the experimental findings by showing anti-hyperlipidemic potential in constituents of eucalyptus plant. Thus, there is a need of advanced research for isolation of active constituents having said anti-hyperlipidemic potential in the Eucalyptus camaldulensis plant.Communicated by Ramaswamy H. Sarma.

Docetaxel-Loaded Methoxy poly(ethylene glycol)-poly (L-lactic Acid) Nanoparticles for Breast Cancer: Synthesis, Characterization, Method Validation, and Cytotoxicity.

This study aimed to synthesize and characterize DTX-mPEG-PLA-NPs along with the development and validation of a simple, accurate, and reproducible method for the determination and quantification of DTX in mPEG-PLA-NPs. The prepared NPs were characterized using AFM, DLS, zetasizer, and drug release kinetic profiling. The RP-HPLC assay was developed for DTX detection. The cytotoxicity and anti-clonogenic effects were estimated using MTT and clonogenic assays, respectively, using both MCF-7 and MDA-MB-231 cell lines in a 2D and 3D culture system. The developed method showed a linear response, high precision, accuracy, RSD values of ≤2%, and a tailing factor ≤2, per ICH guidelines. The DTX-mPEG-PLA-NPs exhibited an average particle size of 264.3 nm with an encapsulation efficiency of 62.22%. The in vitro drug kinetic profile, as per the Krosmeyers-Peppas model, demonstrated Fickian diffusion, with initial biphasic release and a multistep sustained release over 190 h. The MTT assay revealed improved in vitro cytotoxicity against MCF-7 and MDA-MB-231 in the 2D cultures and MCF-7 3D mammosphere cultures. Significant inhibitions of the clonogenic potential of MDA-MB-231 were observed for all concentrations of DTX-mPEG-PLA-NPs. Our results highlight the feasibility of detecting DTX via the robust RP-HPLC method and using DTX-mPEG-PLA-NPs as a perceptible and biocompatible delivery vehicle with greater cytotoxic and anti-clonogenic potential, supporting improved outcomes in BC.

The anticancer potential of chemical constituents of Moringa oleifera targeting CDK-2 inhibition in estrogen receptor positive breast cancer using in-silico and in vitro approches.

Most of the breast cancers are estrogen receptor-positive recurring with a steady rate of up to 20 years dysregulating the normal cell cycle. Dinaciclib is still in clinical trials and considered as a research drug against such cancers targeting CDK2.The major goal of this study was to identify the potential inhibitors of CDK-2 present in Moringa oleifera for treating hormonal receptor positive breast cancers. For this purpose, in silico techniques; molecular docking, MM-GBSA and molecular dynamics simulations were employed to screen Moringa oleifera compounds and their anticancer potential was determined against CDK-2 protein targets. Among 36 compounds of Moringa oleifera reported in literature, chlorogenic acid (1), quercetin (2), ellagic acid (3), niazirin (4), and kaempferol (5) showed good affinity with the target. The interaction of the compounds was visualized using PYMOL software. The profiles of absorption, distribution, metabolism, excretion (ADME) and toxicity were determined using SWISS and ProTox II webservers. The MTT assay was performed in-vitro using MCF-7 cancer cell lines to validate the anticancer potential of Moringa oleifera leaf extract.MTT assay results revealed no significant change in proliferation of Mcf-7 cells following 24 h treatment with fraction A (petroleum ether). However, significant antiproliferative effect was observed at 200 µg/mL dose of fraction B (ethyl acetate) and cell viability was reduced to 40%.In conclusion, the data suggested that all the compounds with highest negative docking score than the reference could be the potential candidates for cyclin dependent kinase-2 (CDK-2) inhibition while ellagic acid, chlorogenic acid and quercetin being the most stable and potent inhibitors to treat estrogen receptor positive breast cancer targeting CDK-2. Moreover, the data suggested that further investigation is required to determine the optimum dose for significant antiproliferative effects using in-vivo models to validate our findings of in-silico analysis.

A systematic review on the clinical pharmacokinetics of vildagliptin in healthy and disease populations.

INTRODUCTION: Vildagliptin, a dipeptidyl peptidase-4 inhibitor, is indicated to cure type 2 diabetes mellitus (T2DM). This systematic literature search aims to assess the current knowledge about the clinical pharmacokinetics (PK) of vildagliptin to provide recommendations for clinical use to prevent the harmful effects of this drug. METHODS: The PubMed, Science Direct, EBSCO, Cochrane Central Register of Controlled Trials, and Google Scholar databases were screened for articles related to the clinical PK of vildagliptin using systematic search strategies. RESULTS: The literature search identified 2118 records, among which 28 were subsumed in this systematic review that fulfilled the inclusion standards. CONCLUSIONS: This systematic review can help dose optimization among critically ill patients (e.g. renal impairment) without exposing them to the drug's toxic effects.

Development and characterization of polyamidoamine based doxorubicin loaded polymeric nanocarriers and in-vitro evaluation on liver cancer cell lines.

In order to achieve the benefits of targeted drug delivery, this study intended to encapsulate doxorubicin in a linear polyamidoamine and its PEGylated co-polymer. The drug was loaded by using the emulsion solvent evaporation method. By adjusting the doxorubicin to polymer ratios to 1:10, 1:20 and 1:30, three formulations of each polymer/copolymer were prepared. The drug release profile was investigated using phosphate buffered saline. In vitro cytotoxicity investigation was executed on liver cancer cell line (Hep G2 cell lines) by 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide assay. The outcome demonstrated that doxorubicin had been successfully loaded on polyamidoamine and its PEGylated co-polymer with a drug loading efficiency of about 90%. Nanocarrier sizes were between 245±1.10 nm -579±1.00 nm and the zeta potential range was +22.4±0.5 mV-+37.9±0.3 mV. In-vitro drug release investigations revealed a characteristic pH-dependent drug release. The cytotoxicity testing of optimal formulation revealed that the doxorubicin was successfully released from the formulations and exerted therapeutic effect. According to our research, doxorubicin could be loaded onto linear polyamidoamines for potent antitumor effects on the target liver cancer cell lines (Hep G2).

Clinical pharmacokinetics of nebivolol: a systematic review.

Nebivolol is a beta-1 receptor blocker used to treat hypertension, heart failure, erectile dysfunction, vascular disease, and diabetes mellitus. This review investigated the data regarding pharmacokinetic (PK) parameters, drug-drug interactions, dextrorotatory (D), and levorotatory (L) stereoisomers of nebivolol. The articles related to the PK of nebivolol were retrieved by searching the five databases; Google Scholar, PubMed, Cochrane Library, ScienceDirect, and EBSCO. A total of 20 studies comprising plasma concentration-time profile data following the nebivolol's oral and intravenous (IV) administration were included. The area under the concentration-time curve from zero to infinity (AUC0-∞) was 15 times greater in poor metabolizers (PMs) than in extensive metabolizers (EMs). In hypertensive patients, L-nebivolol expressed a higher maximum plasma concentration (Cmax) than D-nebivolol, i.e. 2.5 ng/ml vs 1.2 ng/ml. The AUC0-∞ of nebivolol was 3-fold greater in chronic kidney disease (CKD). The clearance (CL) was increased in obese than in controls from 51.6 ± 11.6 L/h to 71.6 ± 17.4 L/h when 0.5 mg/ml IV solution was infused. Nebivolol showed higher Cmax, AUC0-∞ and half-life (t1/2) when co-administered with bupropion, duloxetine, fluvoxamine, paroxetine, lansoprazole, and fluoxetine. This concise review of nebivolol would be advantageous in assessing all PK parameters, which may be crucial for clinicians to avoid drug-drug interactions, prevent adverse drug events and optimize the dosage regimen in diseased patients diagnosed with hypertension and cardiovascular disorders.

Knowledge, beliefs and hesitancy among medical and non-medical university students toward COVID-19 vaccination in Punjab, Pakistan.

This study assessed the knowledge, beliefs, and hesitancy toward COVID-19 vaccination among medical (MS) and nonmedical students (NMS) in Punjab, Pakistan. An online cross-sectional survey was conducted by enrolling 624 MS and 476 NMS in the largest province of Pakistan, i.e., Punjab. Chi-square tests were used to determine significant frequency distributions, and logistic regression to determine associations. The majority of students, males and females, were between 18-25 years of age and had good self-reported health. MS demonstrated adequate knowledge and positive beliefs about COVID-19. Fewer MS were indecisive about the vaccination; nonetheless, overall, 71.5% of MS and 78.2% of NMS were willing to receive the vaccine. A greater number of MS students were concerned about vaccine safety or side effects. A greater number of NMS demonstrated misconceptions about the COVID-19 vaccine - its effect on fertility and alterations in genomic DNA. The binary logistics regression exhibited a significant association between students' knowledge in the medical sciences (OR;1.53,p = 0.002) and area of residence (OR;1.60,p = 0.008). Compared to NMS, MS had a better understanding of the COVID-19 vaccine and were concerned about the acceptability of the vaccine, although NMS had misconceptions about the COVID-19 vaccine. Knowledge was significantly associated with the field of study.

Synthesis of curcuma longa doped cellulose grafted hydrogel for catalysis, bactericidial and insilico molecular docking analysis.

Curcumin (diferuloylmethane), the primary curcuminoid in turmeric rhizome, has been acknowledged as a bioactive compound for numerous pharmacological activities. Nonetheless, the hydrophobic nature, rapid metabolism, and physicochemical and biological instability of this phenolic compound correspond to its poor bioavailability. So, recent scientific advances have found many components and strategies for enhancing the bioavailability of curcumin with the inclusion of biotechnology and nanotechnology to address its existing limitations. Therefore, In this study, copolymerized aqua-gel was synthesized by graft polymerization of poly-acrylic acid (P-AA) on cellulose nanocrystals (CNC), after that Curcuma longa (Cur) was incorporated as dopant (5, 10, 15, and 25 mg) in hydrogel (Cur/C-P) as a stabilizing agent for evaluation of bacterial potential and sewage treatment. The antioxidant tendency of 25 mg Cur/C-P was much higher (72.21 %) than other samples and displayed a catalytic activity of up to 93.89 % in acidic conditions and optimized bactericidal inclinations toward gram-positive bacterial strains. Furthermore, ligand binding was conducted against targeted protein enoyl-[acylcarrier-protein] reductase (FabI) enzyme to comprehend the putative mechanism of microbicidal action of CNC-PAA (CP), Cur/C-P, and curcumin. Our outcomes suggest that 25 mg Cur/C-P hydrogels are plausible sources for hybrid, multifunctional biological activity.

Physiologically Based Pharmacokinetic Model To Predict Metoprolol Disposition in Healthy and Disease Populations.

The evolution in the development of drugs has increased the popularity of physiologically based pharmacokinetic (PBPK) models. This study seeks to assess the PK of metoprolol in populations with healthy, chronic kidney disease (CKD), and acute myocardial infarction (AMI) conditions by developing and evaluating PBPK models. An extensive literature review for identifying and selecting plasma concentration vs time profile data and other drug-related parameters was undergone for their integration into the PK-Sim program followed by the development of intravenous, oral, and diseased models. The developed PBPK model of metoprolol was then evaluated using the visual predictive checks, mean observed/predicted ratios (Robs/pre), and average fold error for all PK parameters, i.e., the area under the curve (AUC), maximal plasma concentration, and clearance. The model evaluation depicted that none of the PK parameters were out of the allowed range (2-fold error) in the case of the mean Robs/pre ratios. The model anticipations were executed to determine the influence of diseases on unbound and total AUC after the application of metoprolol in healthy, moderate, and severe CKD. The dosage reductions were also suggested based on differences in unbound and total AUC in different stages of CKD. The developed PBPK models have successfully elaborated the PK changes of metoprolol occurring in healthy individuals and those with renal and heart diseases (CKD & AMI), which may be fruitful for dose optimization among diseased patients.

Phytochemical, anti-hyperlipidemic and in silico studies of extracts of Ficus carica seeds.

Hyperlipidemia has been considered a disease primarily causing death along with other prevailing diseases such as coronary heart diseases, atherosclerosis and stroke. The present study aims to evaluate the anti-hyperlipidemic potential of Ficus carica. Extracts of seeds of Ficus carica were investigated for bioactive compounds and screened using in-vitro and in-vivo anti-hyperlipidemic activities. Fig seeds showed potential in-vitro by inhibition of pancreatic lipase while in-vivo study revealed that methanol extract of fig seeds exhibited the anti-hyperlipidemic property by beneficially modifying lipid profile of albino mice comparable to standard drug. GC-MS analysis of methanol extract of seeds of Ficus carica exhibited a variety of bioactive compounds. After further evaluation of ligands for their activity by using molecular docking and MM-GBSA study, it is concluded that 1,2,3-benzentriol has the highest binding affinity for pancreatic lipase enzyme. Hence, it is concluded that seeds of Ficus carica are medicinally important and have promising anti-hyperlipidemic potential.

Bioassay-guided isolation and in silico study of antihyperlipidemic compounds from Onosma hispidum Wall.

Isolation of bioactive compounds from plants and their therapeutic evaluation is crucial in the pursuit of novel phytochemicals and contributes an indispensable role in drug discovery and design. The literature has documented the hypolipidemic effect of numerous Onosma species. Taking that into consideration, the current study was designed to isolate, purify and evaluate the antihyperlipidemic potential of leaves of Onosma hispidum Wall. For the first time, the bioassay-guided isolation led to the separation of 3 compounds that were identified by spectroscopic techniques as o-phthalic acid bis-(2-ethyl decyl)-ester (1), bis (2-ethyloctyl) phthalate (2), and 1,2 benzenedicarboxylic acid bis(2-methyl heptyl) ester (3). Lipase inhibition assay was utilized to scrutinize the antihyperlipidemic potential of methanolic extract fractions and subsequently isolated compounds. Further, the isolated compounds were employed for in silico studies via molecular docking, molecular mechanics with generalized born and surface area solvation (MM-GBSA), and MD simulations with Pancreatic Lipase Colipase (PDB ID: 1LPB). Molecular docking and MM-GBSA of isolated compounds were employed to explain the mode of binding between the protein-ligand complex and binding free energy calculation, respectively. Since compound (3) displayed the best docking score of -6.689 kcal/mol as compared to orlistat -5.529 kcal/mol with PDB: 1LPB. So, it was chosen for MD simulations to evaluate ligand stability and flexibility of the complex which was validated by the fluctuation of α-carbon chain, root mean square deviation (RMSD), root mean square fluctuation (RMSF), and type of interactions involved which authenticated the in vitro lipase inhibitory potential. Overall, in silico and in vitro results validated that compound (3) could be exploited as a promising pancreatic lipase inhibitor.Communicated by Ramaswamy H. Sarma.