A systematic review on understanding the mechanistic pathways and clinical aspects of natural CDK inhibitors on cancer progression.: Unlocking cellular and biochemical mechanisms.

Cell division, differentiation, and controlled cell death are all regulated by phosphorylation, a key biological function. This mechanism is controlled by a variety of enzymes, with cyclin-dependent kinases (CDKs) being particularly important in phosphorylating proteins at serine and threonine sites. CDKs, which contain 20 unique components, serve an important role in regulating vital physiological functions such as cell cycle progression and gene transcription. Methodologically, an extensive literature search was performed using reputable databases such as PubMed, Google Scholar, Scopus, and Web of Science. Keywords encompassed "cyclin kinase," "cyclin dependent kinase inhibitors," "CDK inhibitors," "natural products," and "cancer therapy." The inclusion criteria, focused on relevance, publication date, and language, ensured a thorough representation of the most recent research in the field, encompassing articles published from January 2015 to September 2023. Categorization of CDKs into those regulating transcription and those orchestrating cell cycle phases provides a comprehensive understanding of their diverse functions. Ongoing clinical trials featuring CDK inhibitors, notably CDK7 and CDK4/6 inhibitors, illuminate their promising potential in various cancer treatments. This review undertakes a thorough investigation of CDK inhibitors derived from natural (marine, terrestrial, and peptide) sources. The aim of this study is to provide a comprehensive comprehension of the chemical classifications, origins, target CDKs, associated cancer types, and therapeutic applications.

Therapeutic drug monitoring of vancomycin in surgical patients using a validated HPLC method.

BACKGROUND: Vancomycin is being used for the treatment of a variety of infections caused by methicillin resistant Staphylococcus aureus and methicillin susceptible Staphylococcus aureus. Therapeutic drug monitoring (TDM) is highly recommended for ensuring the safe and effective therapy with vancomycin. A reliable and cost-effective bioanalytical method is required for TDM as well as pharmacokinetic studies of vancomycin. MATERIALS AND METHODS: A selective, sensitive, and cost effective HPLC method was developed and validated for quantification of vancomycin concentrations in human plasma. The mobile phase was a mixture of buffer (50 mM ammonium dihydrogen phosphate, pH 2.4) and acetonitrile 88 : 12 v/v. The separation was carried on C18 column (125 × 4.6 mm, particle size 5 µm) with isocratic flow rate of 0.370 mL/min at room temperature with UV detection at 215 nm. The method was validated for sensitivity, accuracy, and precision as well as stability of vancomycin in human plasma by following European Medicine Agency (EMA) guideline. Therapeutic drug monitoring of vancomycin was performed by quantifying the trough concentrations of vancomycin in 65 human plasma samples after administration of therapeutically relevant dose. RESULTS: The developed method was sensitive enough to quantify vancomycin concentrations as low as 0.25 mg/L in human plasma. Moreover, the method was proved accurate and precise in terms of quantifying the unknown concentration of vancomycin. The evaluation of short-term, long-term, and freeze-thaw stability proved the stability of vancomycin in human plasma. The TDM of vancomycin by using this method showed that 39 (60%) samples were within the target trough concentration range (TTCR), i.e. 10 - 20 mg/L, while 23 samples (35.4%) were below the TTCR, and 3 samples (4.6%) were above this range. CONCLUSION: The developed method is sensitive and cost effective for quantification of vancomycin in human plasma. The results of sample analysis shows that the developed method can be used reliably for TDM of vancomycin.

Molecular modeling of novel 2-aminopyridine derivatives as potential JAK2 inhibitors: a rational strategy for promising anticancer agents.

Janus kinase 2(JAK2) is a potential target for anticancer drugs in the treatment of numerous myeloproliferative diseases due to its central role in the JAK/STAT signaling cascade. In this study, the binding behavior of 2 amino-pyridine derivatives as JAK2 inhibitors was investigated by using multifaceted strategies including 3D-QSAR, molecular docking, Fingerprint analysis, MD simulations, and MM-PBSA calculations. A credible COMFA (q2 = 0.606 and r2 = 0.919) and COMSIA (q2 = 0.641 and r2 = 0.992) model was developed, where the internal and external validation revealed that the obtained 3D-QSAR models could be capable of predicting bioactivities of JAK2 inhibitors. The structural criteria provided by the contour maps of model were used to computationally develop more potent 100 new JAK2 inhibitors. Docking studies were conducted on the model data set and newly developed compounds (in-house library) to demonstrate their binding mechanism and highlight the key interacting residues within JAK2 active site. The selected docked complexes underwent MD simulation (100 ns), which contributed in the further study of the binding interactions. Binding free energy analyses (MMGB/PBSA) revealed that key residues such as Glu930, Leu932 (hinge region), Asp939 (solvent accessible region), Arg980, Asn981and Asp994 (catalytic site) have a significantly facilitate ligand-protein interactions through H-bonding and van der Waals interactions. The preliminary in-silico ADMET evaluation revealed encouraging results for all the modeled and in-house library compounds. The findings of this research have the potential to offer valuable recommendations for the advancement of novel, potent, and efficacious JAK2 inhibitors. Overall, this work has successfully employed a wide range of computer-based methodologies to understand the interaction dynamics between 2-amino-pyridine derivatives and the JAK2 enzyme, which is a crucial target in myeloproliferative disorders.Communicated by Ramaswamy H. Sarma.

Development and characterization of niosomal gel of fusidic acid: in-vitro and ex-vivo approaches.

Niosomes are multilamellar vesicles that efficiently deliver active substance into skin systemic circulation or skin layers. They are used in topical drug delivery system to enhance the skin permeation of active substance. So, the prime objective of this study was to develop a niosomal gel of fusidic acid to increase its skin permeation. Different formulations of niosomes of fusidic acid were designed by varying the cholesterol to surfactant ratio. Formulations containing fusidic acid, cholesterol, dihexadecyl pyridinium chloride, Span 60, or Tween 60 were prepared by thin film hydration method in rotary evaporator. The thin film formed in rotary flask was hydrated by phosphate buffer saline of pH 7.2. The niosomes formed were characterized through entrapment efficiency, size, polydispersity index (PDI), and zeta potential. The S3 formulation containing span 60 showed the highest entrapment efficiency (EE) of niosomes, so it was incorporated into Carbopol gel. Determination of pH, spreadability, rheological, and ex vivo permeation studies was conducted of niosomal gel. The results of ex vivo permeation studies showed high permeation of fusidic acid when gel was applied to an albino rat skin. According to the results and previous studies of niosomes, it can be concluded that niosomes enhanced the permeation of fusidic acid through the skin.

Solid Lipid Nanoparticles of Mycophenolate Mofetil: An Attempt to Control the Release of an Immunosuppressant.

INTRODUCTION: Organ transplantation is a critically important procedure, which requires immune modulation by using immunosuppressants. Development of nanoparticles is an emerging and beneficial engineering process to increase the dissolution rate of poorly soluble immunosuppressants as well as to provide controlled release for better therapeutic outcomes. METHOD: Currently, the nanoprecipitation method was employed to fabricate ß-cyclodextrin (ßCD) facilitated mycophenolate mofetil (MMF)-loaded solid lipid nanoparticles (SLNPs). The prime objectives of the study included, improvement of the dissolution profile of poorly aqueous soluble drug and controlled release from the SLNs to provide steady state drug concentration. Drug release from the prepared SLNs was assessed in two different media, ie, acidic buffer at pH 1.2 and phosphate buffer at pH 7.2 using USP dissolution apparatus for 12 h, followed by the evaluation of drug release mechanism and pattern by applying kinetic models. RESULTS: Justifiably, in acidic medium, the release was found to be 12% more (68%) in comparison to that in basic medium (56%). However, in both dissolution media, drug release was independent of initial concentration (R2>0.95) with non-Fickian type of diffusion mechanism. The outcomes of the study have exhibited that prepared formulations were in nanosized range (80-170 nm) with a net charge of ±23 charge on their surface. They possessed fairly uniform surface with acceptable polydispersity index (0.23±0.09). Scanning electron microscopy (SEM) analysis illustrated that the nanoparticles had uniform particle size and shape. DISCUSSION: The findings show potential applications of the nanoparticles and the method for the development of SLNPs in controlled release of MMF for better therapeutic outcomes. Conclusively, the prepared SLNPs were well designed in nanosized ranges and justifying the once daily controlled release formulation dose of MMF to enhance patient compliance.

Effectiveness of an Alcohol-Free Chitosan-Curcuminoid Mouthwash Compared with Chlorhexidine Mouthwash in Denture Stomatitis Treatment: A Randomized Trial.

Objective: An alcohol-free mouthwash of curcuminoids purified from the turmeric (Curcuma longa Linn.) rhizome was formulated using a cosolvent system, comprising chitosan and polyethylene glycol (PEG) 400, and determined for its efficacy and safety in management of denture stomatitis (DS) in comparison with a chlorhexidine (CHX) mouthwash. Design: A single-center, randomized, controlled parallel-arm trial was conducted. Setting: The study took place at the Faculty of Dentistry, Prince of Songkla University, Hat-Yai, Thailand, between June 2016 and June 2017. Subjects: Participants were 20 years old or older adults of both genders, using removable dentures, and with a confirmed diagnosis of DS from an oral medicine specialist. Interventions: A total of 30 patients were randomly assigned to 3 different interventions, including the chitosan-curcuminoid (CHI-CUR) mouthwash, CHX mouthwash, and a vehicle formulation comprising chitosan and PEG 400. Ten milliliters of each intervention was given to the patient to be used for 30 sec, three times a day at 8 am, 12 pm, and 4 pm, for 2 weeks. Outcome measures: Outcome measures included complete relief of erythematous lesions under the denture and reduction in the number of candida colonies present in the denture-fitting surface. Results: Eight of 10 patients (80%) using the CHI-CUR mouthwash had a complete response after the 2-week treatment course compared with 30% of patients using the CHX mouthwash (p < 0.05). Both interventions exerted comparable anticandida efficacy. No oral or systemic adverse events that could possibly be related to the use of mouthwash were documented. Conclusions: The finding indicated that an alcohol-free CHI-CUR mouthwash may serve as a safe and potential topical therapeutic alternative in treating generalized or candida-associated DS.