Stability studies of β-Amino- and β-Hydroxy difluoromethyl ketones in rat serum and rat liver microsomes.

Although difluoromethyl ketones are used as tools in chemical biology and leads in drug discovery, the metabolic stability of these compounds is generally uncharacterized and must be inferred from in vivo pharmacological assays. In order to address this gap which impedes their wider use, we have synthesized and performed metabolic stability studies for thirty-nine β-amino and β-hydroxy difluoromethyl ketones. These investigations provide structure-stability relationships of the difluoromethyl ketones following incubation with rodent serum and liver microsomes.

Analyzing Tumor Budding Scores in Invasive Breast Carcinoma: A Tertiary Care Center Study in South India.

Introduction And Aim: Tumor budding is a distinctive phenomenon which involves the presence of small clusters or individual cancer cells at the invasive front of tumors. Tumor budding has garnered attention due to its potential implications for prognosis, treatment strategies, and our understanding of cancer progression. Our aim is to study the distribution of tumor buds and its scoring in patients with infiltrating breast carcinoma and to associate with other histopathological parameters like the size of the tumor, its grade, lymphovascular invasion, and lymph node metastasis.

Synthesis of α,α-Difluoro-β-amino Ketones from -Boc-α-Amidosulfones and Pentafluoro--diols.

To circumvent the synthesis and isolation of imines, a method was devised to construct α,α-difluoro-β-amino ketones from -Boc-α-amidosulfones. The reactive nucleophiles, difluoroenolates, are generated in situ from the pentafluoro--diols using cesium fluoride in pyridine. NMR studies confirm the role of the α-amidosulfones in this process.

Formulation and In Vitro-Ex vivo Evaluation of Cannabidiol and Cannabidiol-Valine-Hemisuccinate Loaded Lipid-Based Nanoformulations for Ocular Applications.

The goal of this investigation is to develop stable ophthalmic nanoformulations containing cannabidiol (CBD) and its analog cannabidiol-valine-hemisuccinate (CBD-VHS) for improved ocular delivery. Two nanoformulations, nanoemulsion (NE) and nanomicelles (NMC), were developed and evaluated for physicochemical characteristics, drug-excipient compatibility, sterilization, thermal analysis, surface morphology, ex-vivo transcorneal permeation, corneal deposition, and stability. The saturation solubility studies revealed that among the surfactants tested, Cremophor EL had the highest solubilizing capacity for CBD (23.

Postpolymerization Modification of Poly(2-vinyl-4,4-dimethyl azlactone) as a Versatile Strategy for Drug Conjugation and Stimuli-Responsive Release.

Postpolymerization modification of highly defined "scaffold" polymers is a promising approach for overcoming the existing limitations of controlled radical polymerization such as batch-to-batch inconsistencies, accessibility to different monomers, and compatibility with harsh synthesis conditions. Using multiple physicochemical characterization techniques, we demonstrate that poly(2-vinyl-4,4-dimethyl azlactone) (PVDMA) scaffolds can be efficiently modified with a coumarin derivative, doxorubicin, and camptothecin small molecule drugs. Subsequently, we show that coumarin-modified PVDMA has a high cellular biocompatibility and that coumarin derivatives are liberated from the polymer in the intracellular environment for cytosolic accumulation.

Interval delivery of 5HT agonists using multilayered polymer films.

There is an urgent unmet medical need to develop therapeutic options for the ~50% of depression patients suffering from treatment-resistant depression, which is difficult to treat with existing psycho- and pharmaco-therapeutic options. Classical psychedelics, such as the 5HT agonists, have re-emerged as a treatment paradigm for depression. Recent clinical trials highlight the potential effectiveness of 5HT agonists to improve mood and psychotherapeutic growth in treatment-resistant depression patients, even in those who have failed a median of four previous medications in their lifetime.

Synthesis and biological evaluation of tert-butyl ester and ethyl ester prodrugs of L-γ-methyleneglutamic acid amides for cancer.

In cancer cells, glutaminolysis is the primary source of biosynthetic precursors. Recent efforts to develop amino acid analogues to inhibit glutamine metabolism in cancer have been extensive. Our lab recently discovered many L-γ-methyleneglutamic acid amides that were shown to be as efficacious as tamoxifen or olaparib in inhibiting the cell growth of MCF-7, SK-BR-3, and MDA-MB-231 breast cancer cells after 24 or 72 h of treatment.

Development of α-Tocopherol Succinate-Based Nanostructured Lipid Carriers for Delivery of Paclitaxel.

The management of retinoblastoma (RB) involves the use of invasive treatment regimens. Paclitaxel (PTX), an effective antineoplastic compound used in the treatment of a wide range of malignant tumors, poses treatment challenges due to systemic toxicity, rapid elimination, and development of resistance. The goal of this work was to develop PTX-loaded, α-tocopherol succinate (αTS)-based, nanostructured lipid carrier (NLCs; αTS-PTX-NLC) and PEGylated αTS-PTX-NLC (αTS-PTX-PEG-NLC) to improve ocular bioavailability.

Identification of an Orally Bioavailable, Brain-Penetrant Compound with Selectivity for the Cannabinoid Type 2 Receptor.

Modulation of the endocannabinoid system (ECS) is of great interest for its therapeutic relevance in several pathophysiological processes. The CB2 subtype is largely localized to immune effectors, including microglia within the central nervous system, where it promotes anti-inflammation. Recently, a rational drug design toward precise modulation of the CB2 active site revealed the novelty of Pyrrolo[2,1-c][1,4]benzodiazepines tricyclic chemotype with a high conformational similarity in comparison to the existing leads.

HIV-1 Tat Protein Promotes Neuroendocrine Dysfunction Concurrent with the Potentiation of Oxycodone's Psychomotor Effects in Female Mice.

Human immunodeficiency virus (HIV) is associated with neuroendocrine dysfunction which may contribute to co-morbid stress-sensitive disorders. The hypothalamic-pituitary-adrenal (HPA) or -gonadal (HPG) axes are perturbed in up to 50% of HIV patients. The mechanisms are not known, but we have found the HIV-1 trans-activator of transcription (Tat) protein to recapitulate the clinical phenotype in male mice.

Targeted Metabolomic and Biochemical Changes During Nitrogen Stress Mediated Lipid Accumulation in CASA CC202.

CASA CC202, a potent freshwater microalga is being used as a biofuel feedstock, which accumulates 2.27 fold lipid during nitrogen stress induction. Upon nitrogen starvation, undergoes biochemical and metabolic changes that perturb the cell to cope up the stress condition.

A concise review of bioanalytical methods of small molecule immuno-oncology drugs in cancer therapy.

Immuno-oncology (IO) is an emerging option to treat cancer malignancies. In the last two years, IO has accounted for more than 90% of the new active drugs in various therapeutic indications of oncology drug development. Bioanalytical methods used for the quantitation of various IO small molecule drugs have been summarized in this review.

Pharmacokinetics of Darolutamide in Mouse - Assessment of the Disposition of the Diastereomers, Key Active Metabolite and Interconversion Phenomenon: Implications to Cancer Patients.

Background: Darolutamide is recently approved for the treatment of non-metastatic castrate resistance prostate cancer. Hitherto, no stereoselective pharmacokinetic data have been published pertaining to darolutamide and its diastereomers in animals or humans. The key aims of the experiment were to examine darolutamide, S,S-darolutamide and S,R-darolutamide with respect to (a) assessment of in vitro metabolic stability and protein binding and (b) characterization of in vivo oral and intravenous pharmacokinetics in mice.

Validated LC-MS/MS Method for Simultaneous Quantitation of SAFit-1 and SAFit-2 in Mice Plasma: Application to a Pharmacokinetic Study.

SAFit-1 and SAFit-2 are selective FKBP51 (FK506-binding protein 51) ligands. In this paper, we present the development and validation data of an LC-MS/MS method for the simultaneous quantitation of SAFit-1 and SAFit-2 in mice plasma as per FDA regulatory guideline. SAFit-1 and SAFit-2 along with internal standard were extracted from mice plasma using liquid-liquid extraction method.

Discovery and optimization of novel phenyldiazepine and pyridodiazepine based Aurora kinase inhibitors.

Aurora B plays critical role in the process of chromosome condensation and chromosome orientation during the regulation of mitosis. The overexpression of Aurora B has been observed in several tumor types. As a part of our ongoing effort to develop Aurora B inhibitors, herein, we described the design, synthesis and evaluation of phenyl/pyridine diazepine analogs.

Validated LC-ESI-MS/MS method for the determination of tunicamycin in rat plasma: Application to a pharmacokinetic study.

A liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) method has been developed and validated for the quantification of tunicamycin in rat plasma as per regulatory guideline. Chromatography of tunicamycin and the IS in the processed plasma samples was achieved on an X-Terra phenyl column using a binary gradient (mobile phase A, acetonitrile and mobile phase B, 5 mm ammonium formate) elution at a flow rate of 0.6 ml/min.

Prediction of Human Pharmacokinetics of Fomepizole from Preclinical Species Pharmacokinetics Based on Normalizing Time Course Profiles.

Fomepizole is used as an antidote to treat methanol poisoning due to its selectivity towards alcohol dehydrogenase. In the present study, the goal is to develop a method to predict the fomepizole human plasma concentration versus time profile based on the preclinical pharmacokinetics using the assumption of superimposability on simulated time course profiles of animals and humans. Standard allometric equations with/without correction factors were also assimilated in the prediction.

Simultaneous determination of bendamustine and γ-hydroxybendamustine in mice dried blood spots and its application in a mice pharmacokinetic study.

A selective, sensitive and rapid mice dried blood spot (DBS) method has been developed and validated for the simultaneous quantification of bendamustine (BM) and γ-hydroxy-bendamustine (HBM) as per regulatory guidelines using an LC-MS/MS. Quality control, calibration curve and study sample DBS cards were sonicated with 5% formic acid in water before extraction with ethyl acetate enriched with internal standard (I.S.

Uptake and pharmacokinetics of cefuroxime in rabbits after intravitreal, intracameral, and topical dosing: relevance to human ocular injection of cefuroxime.

Cefuroxime is one of the widely used antibiotics. The objective of this study was to determine pharmacokinetics and disposition in various ocular tissues following topical (TOP), intracameral (IC) and intravitreal (IVT) administration of cefuroxime to rabbits.Following TOP, IC and IVT dosing plasma and various ocular tissues (aqueous humor (AH), vitreous humor (VH), conjunctiva, trabecular mesh (TM), lens and retina-choroid (RC)) were collected and analyzed to understand the disposition of cefuroxime.

Stereoselective pharmacokinetics and tissue distribution of levodropropizine after administration of pure levodropropizine and the -dropropizine to Sprague-Dawley rats.

Levodropropizine (LDP) is a non-opioid anti-tussive. The stereoselective pharmacokinetics and tissue distribution (TD) of LDP vs. dextrodropropizine (DDP) have been characterized after oral and (IV) administration of LDP and -dropropozine in rats.

RP-HPLC-UV Method for Simultaneous Quantification of Second Generation Non-Steroidal Antiandrogens Along with their Active Metabolites in Mice Plasma: Application to a Pharmacokinetic Study.

A simple, specific and reproducible high-performance liquid chromatography (HPLC) assay method has been developed and validated for the quantitation of second generation antiandrogens and their active metabolites namely apalutamide, enzalutamide, -desmethylenzalutamide (active metabolite of enzalutamide), darolutamide and ORM-15341 (active metabolite of darolutamide) in mice plasma. The method involves extraction of apalutamide, enzalutamide, -desmethylenzalutamide, darolutamide and ORM-15341 along with internal standard (IS) from 100 µL mice plasma through a simple protein precipitation process. The chromatographic analysis was performed on a Waters Alliance HPLC system using a gradient mobile phase (comprising 10 mM ammonium acetate and acetonitrile in a flow-gradient) and X-Terra Phenyl column.

Review of DBS methods as a quantitative tool for anticancer drugs.

An overview of published dried blood spot (DBS) methods for the quantitation of various classes of anticancer drugs from clinical and preclinical studies is presented. The increased reporting of DBS methods in the literature for quantitation of various classes of drugs is a testimony to their utility in bioanalytical applications. While DBS offers several advantages as compared with conventional wet sampling techniques, there remain a number of nuances that may impede the assay adaptability of DBS method in routine quantitative bioanalysis.

Enantioselective LC-ESI-MS/MS determination of dropropizine enantiomers in rat plasma and application to a pharmacokinetic study.

We developed and validated a simple, sensitive, selective and reliable LC-ESI-MS/MS method for direct quantitation of dropropizine enantiomers namely levodropropizine (LDP) and dextrodropropizine (DDP) in rat plasma without the need for derivatization as per regulatory guidelines. Dropropizine enantiomers and carbamazepine (internal standard) were extracted from 50 μL rat plasma using ethyl acetate. LDP and DDP resolved with good baseline separation (R  = 4.

Determination of Tofacitinib in Mice Whole Blood on Dried Blood Spots Using LC-ESI-MS/MS: Application to Pharmacokinetic Study in Mice.

A simple, sensitive and rapid assay method has been developed and validated as per regulatory guideline for the estimation of tofacitinib on mice dried blood spots (DBS) using liquid chromatography coupled to tandem mass spectrometry with electro spray ionization in the positive-ion mode. The method employs liquid extraction of tofacitinib from DBS disk of mice whole blood followed by chromatographic separation using 5 mM ammonium acetate (pH 6.5):acetonitrile (20:80, v/v) at a flow rate of 0.