Addressing stability issues of vildagliptin: Method optimization and validation for accurate analysis in human plasma.

This research paper introduces novel strategies to address the stability issues arising with vildagliptin, marking the first attempt to tackle this challenge comprehensively. The study incorporates malic acid into the human plasma, a crucial step in stabilizing vildagliptin and preventing its degradation. Additionally, optimization of the elution process on a C18 Asentis Express column, fine-tuned with a combination of acetonitrile and ammonium trifluoroacetate 5mM, ensures optimal chromatographic conditions. For detection and quantification, electrospray ionization (ESI) is employed, monitoring multiple reactions for vildagliptin (304.2 → 154.2) and vildagliptin D7 (311.1 → 161.2). Meticulous validation of the method demonstrates high accuracy (97.30%-104.15%) and precision [(0.32%-3.09% coefficient of variance (CV)] for vildagliptin calibration curve standards (CC STD), establishing its sensitivity and reliability in measuring vildagliptin levels. This refined methodology offers numerous advantages, including the elimination of stability concerns, reduced human plasma sample volume (100 µL), exceptional reproducibility, shortened run time (~2.2 min), and a wide concentration range (1.00 to 851.81 ng/mL). These attributes make it exceptionally well-suited for diverse research applications, spanning from extensive sampling in therapeutic drug monitoring units to bioequivalence and bioavailability studies, as well as pharmacokinetic investigations of vildagliptin.

Barbaloin's Chemical Intervention in Aluminum Chloride Induced Cognitive Deficits and Changes in Rats through Modulation of Oxidative Stress, Cytokines, and BDNF Expression.

Alzheimer's disease (AD) is a long-term neurodegenerative condition characterized by impaired cognitive functions, particularly in the domains of learning and memory. Finding promising options for AD can be successful with a medication repurposing strategy. The goal of the research was to examine the neuroprotective characteristics of barbaloin in aluminum chloride (AlCl3)-induced cognitive deficits and changes in rats through modulation of oxidative stress, cytokines, and brain-derived neurotrophic factor (BDNF) expression. Thirty male Wistar rats were subjected to AlCl3 at a dosage of 100 mg/kg via the per oral route (p.o.), which induced cognitive decline. Morris water maze (MWM) is used to assess behavioral metrics. Assays for catalase (CAT), malondialdehyde (MDA), reduced glutathione (GSH), acetylcholinesterase (AChE), choline-acetyltransferase (ChAT), interleukins-1ß (IL-1ß), superoxide dismutase (SOD), tumor necrosis factor-α (TNF-α), nuclear factor kappa-B (NF-κB), interleukins-6 (IL-6), BDNF, and neurotransmitter levels [dopamine (DA), acetylcholine (Ach), and γ-aminobutyric acid (GABA)] were performed. Results: The transfer latency time was notably decreased, and substantial modifications in the concentrations of GSH, MDA, CAT, SOD, AChE, ChAT and observed modulations in the formation of interleukins-6 (IL-6), TNF-α, IL-1ß, BDNF, and NF-κB were also evidenced after the treatment of rats with barbaloin in comparison to AlCl3-induced control groups. Significant alterations in neurotransmitter levels (DA, Ach, and GABA) were also seen in barbaloin-treated groups in comparison to AlCl3-induced groups. The current investigation has provided evidence that the administration of barbaloin yielded notable enhancements in cognitive function in rats through the inhibition of MDA, enhancing endogenous antioxidant enzymes, reduction of cytokine levels, and enhancement of neurotransmitter contents in the brain. These effects were observed in comparison to a control group treated with AlCl3 and can be attributable to barbaloin's strong anti-inflammatory and antioxidant properties, and metal chelating properties may contribute to its neuroprotective effects. Barbaloin may also promote neuronal survival and enhance learning and memory by upregulating the expression of BDNF.

Pharmacophore generation and atom-based 3D-QSAR of novel 2-(4-methylsulfonylphenyl)pyrimidines as COX-2 inhibitors.

Cyclooxygenase-2 (COX-2) inhibitors are widely used for the treatment of pain and inflammatory disorders such as rheumatoid arthritis and osteoarthritis. A series of novel 2-(4-methylsulfonylphenyl)pyrimidine derivatives has been reported as COX-2 inhibitors. In order to understand the structural requirement of these COX-2 inhibitors, a ligand-based pharmacophore and atom-based 3D-QSAR model have been developed. A five-point pharmacophore with four hydrogen bond acceptors (A) and one hydrogen bond donor (D) was obtained. The pharmacophore hypothesis yielded a 3D-QSAR model with good partial least-square (PLS) statistics results. The training set correlation is characterized by PLS factors (r (2) = 0.642, SD = 0.65, F = 82.7, P = 7.617 e - 12). The test set correlation is characterized by PLS factors (Q (2) (ext) = 0.841, RMSE = 0.24,Pearson-R = 0.91). A docking study revealed the binding orientations of these inhibitors at active site amino acid residues (Arg513, Val523, Phe518, Ser530, Tyr355, His90) of COX-2 enzyme. The results of ligand-based pharmacophore hypothesis and atom-based 3D-QSAR give detailed structural insights as well as highlights important binding features of novel 2-(4-methylsulfonylphenyl)pyrimidine derivatives as COX-2 inhibitors which can provide guidance for the rational design of novel potent COX-2 inhibitors.

3D-QSAR of novel phosphodiesterase-4 inhibitors by genetic function approximation.

Phosphodiesterase-4 (PDE 4) enzyme has emerged as an invaluable target for the treatment of asthma, chronic obstructive pulmonary disease and rheumatoid arthritis. These findings have generated widespread interest in PDE-4 inhibitors as a potential molecular target for the development of new anti-inflammatory drugs. A series of N-substituted cis-tetra- and cis-hexahydrophthalazinone derivatives have been reported as novel, selective PDE-4 inhibitors with potent anti-inflammatory activity. In order to gain further insights into the structural requirements of novel series of N-substituted cis-tetra and cis-hexahydrophthalazinone derivatives as PDE-4 inhibitors, a three-dimensional quantitative structure activity relationship (3D-QSAR) was performed using Genetic Function Approximation (GFA). The QSAR model was generated using a training set of 45 molecules and the predictive ability of the resulting each model was assessed using a test set of 9 molecules. The internal and external consistency of final QSAR model was 0.675 and 0.750 respectively. Analysis of results from the present QSAR study indicates that shape and structural descriptors strongly govern the PDE-4 enzyme inhibitory activity. This QSAR study highlights the structural features required for PDE-4 enzyme inhibition and may be useful for design of potent PDE-4 inhibitors.