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Giant cell tumor affecting distal radius has been considered more aggressive, as compared to its counterparts in other locations. While resection has been advocated as the treatment of choice with lower rates of recurrence, curettage has reportedly led to superior functional outcomes. This retrospective study aimed to evaluate the functional and oncological outcomes of patients managed for GCT distal radius by either extended intralesional curettage (EIC) or resection and arthrodesis with radialisation of ulna (RRU), with respect to rates of local recurrence and function. Twenty-four patients operated for giant cell tumor of distal radius by a single surgeon from 2011 to 2021, were included in the study. The demographic, clinico-radiological, and surgical details were recorded and analyzed, as were the functional and oncological outcomes. At a median (IQR) follow-up of 6.3 years (range 2 years to 15.9 years), the rate of recurrence in curettage was found to be higher than that in resection but was not statistically significant (35.7% vs 20%, p > 0.05). Patients managed elsewhere and then presented to us for recurrence had a higher rate of local recurrence (66.6%, p = 0.01). Average time to recurrence was 14 months (range 2-24 months). On final follow-up, patients in curettage group had better functional outcomes in terms of grip strength and range of motion. Mean Modified Mayo Wrist score and MSTS score were 78.2 and 25.63, respectively, for EIC group and 69.6 and 25.75, respectively, for RRU group. Extended intralesional curettage resulted in an earlier rehabilitation with a mobile wrist and acceptable disease control when compared with resection and arthrodesis with radialisation of ulna.

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BACKGROUND: Evaluation of glenoid bone loss following recurrent anterior shoulder dislocations is normally performed using cross sectional imaging. OBJECTIVES: To assess how anteroposterior (AP) and Bernageau view radiographs compare to computed tomography (CT), magnetic resonance imaging (MRI) and arthroscopy for evaluating glenoid bone loss in patients with recurrent anterior shoulder dislocation. MATERIALS AND METHODS: A prospective observational study was performed on 32 patients over two years at a tertiary orthopedic center. The loss of sclerotic glenoid rim (LSGL) on AP radiograph and the percentage relative glenoid bone loss on the Bernageau radiograph were assessed. The percentage glenoid bone loss and anterior straight line (ASL) were calculated using a best fit en face circle method using CT and MRI. Percentage glenoid bone loss was also calculated during arthroscopy in multiples of 5%. RESULTS: In our study, 90.6% (29) patients were males, while only 9.4% (3) were females. This can be attributed to the involvement of the males in outdoor activities and sports. Also, the maximum number of patients were found to belong to 21-30 years of age, with the mean age being 28.66 years. Of the 32 patients, loss of sclerotic glenoid line (LSGL) on AP radiographs correlated with glenoid bone loss on cross-sectional imaging in 27 patients. Three patients had equivocal LSGL and 2 patients with glenoid bone loss on CT did not demonstrate LSGL. The difference between the two modalities was not statistically significant (p value = 0.002). The glenoid bone loss on Bernageau view correlated with glenoid bone loss on cross sectional imaging in all but one patient. The bone loss as evaluated by radiograph Bernageau view was found to have strong correlation (correlation coefficient r = 0.948, p value < 0.0001). CONCLUSION: AP and Bernageau radiographic views for anterior shoulder dislocations demonstrate good correlation with glenoid bone loss on cross-sectional imaging. They may also be used as an adjunct to predict overall bone loss on CT and at arthroscopy.

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Escherichia coli possesses four initiator tRNA (i-tRNA) genes, three of which are present together as metZWV and the fourth one as metY. In E. coli B, all four genes (metZWV and metY) encode i-tRNAfMet1, in which the G at position 46 is modified to m7G46 by TrmB (m7G methyltransferase). However, in E. coli K, because of a single-nucleotide polymorphism, metY encodes a variant, i-tRNAfMet2, having an A in place of m7G46. We generated E. coli strains to explore the importance of this polymorphism in i-tRNAs. The strains were sustained either on metYA46 (metY of E. coli K origin encoding i-tRNAfMet2) or its derivative metYG46 (encoding i-tRNAfMet1) in single (chromosomal) or plasmid-borne copies. We show that the strains sustained on i-tRNAfMet1 have a growth fitness advantage over those sustained on i-tRNAfMet2. The growth fitness advantages are more pronounced for the strains sustained on i-tRNAfMet1 in nutrient-rich media than in nutrient-poor media. The growth fitness of the strains correlates well with the relative stabilities of the i-tRNAs in vivo. Furthermore, the atomistic molecular dynamics simulations support the higher stability of i-tRNAfMet1 than that of i-tRNAfMet2. The stability of i-tRNAfMet1 remains unaffected upon the deletion of TrmB. These studies highlight how metYG46 and metYA46 alleles might influence the growth fitness of E. coli under certain nutrient-limiting conditions. IMPORTANCE: Escherichia coli harbors four initiator tRNA (i-tRNA) genes: three of these at metZWV and the fourth one at metY loci. In E. coli B, all four genes encode i-tRNAfMet1. In E. coli K, because of a single-nucleotide polymorphism, metY encodes a variant, i-tRNAfMet2, having an A in place of G at position 46 of i-tRNA sequence in metY. We show that G46 confers stability to i-tRNAfMet1. The strains sustained on i-tRNAfMet1 have a growth fitness advantage over those sustained on i-tRNAfMet2. Strains harboring metYG46 (B mimic) or metYA46 (K mimic) show that while in the nutrient-rich media, the K mimic is outcompeted rapidly; in the nutrient-poor medium, the K mimic is outcompeted less rapidly.

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Rubber band constriction syndrome has been described in the literature, although there are very few case reports. Non-healing recurrent tenosynovitis and synovitis of the wrist joint demonstrating a circular rubber band on imaging has not been described before. Imaging studies showed retained circular band deep to the extensor tendons, embedded within the joint capsule. Surgical removal of the band by open incision led to a dramatic improvement in the outcome of the patient. Level of evidence V.

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Cone beam computed tomography (CBCT) and magnetic resonance imaging (MRI) are diagnostic tools frequently employed to evaluate temporomandibular joint (TMJ) disorders, yet their comparative efficacy remains a subject of interest. In this study, we conducted a comparative evaluation of CBCT and MRI in diagnosing TMJ disorders and assessing their association with periodontal health. We recruited a sample of 100 patients presenting with TMJ symptoms and divided them into two groups. Group A underwent CBCT imaging, while Group B received MRI scans. Clinical assessments of periodontal health were performed using established periodontal indices. Diagnostic accuracy, sensitivity, specificity, and interobserver agreement were calculated for each imaging modality. In the current study, CBCT demonstrated superior diagnostic accuracy (85%) compared to MRI (72%) in identifying TMJ disorders. Sensitivity and specificity for CBCT were 87% and 83%, respectively, while for MRI, sensitivity was 68%, and specificity was 76%. Interobserver agreement was substantial for CBCT (κ = 0.75) and moderate for MRI (κ = 0.56). In addition, CBCT revealed a significant correlation between TMJ disorders and periodontal health (P < 0.05), while MRI showed a weaker association (P < 0.1). We concluded from this study and suggest that CBCT is a more accurate imaging modality for diagnosing TMJ disorders compared to MRI. Moreover, CBCT provides valuable insights into the relationship between TMJ disorders and periodontal health, highlighting the importance of comprehensive dental assessments.

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This case report describes a rare occurrence of talar osteochondroma extending into syndesmosis, causing disruption of the interosseous membrane and the posterior inferior tibiofibular ligament (PITFL). This type of presentation for a talar osteochondroma is the first of its kind reported in the literature based on current knowledge. A detailed preoperative radiological assessment was crucial in planning the surgical approach and preparing for syndesmotic stabilization during the excision. The patient underwent successful and complete excision of the osteochondroma, and the syndesmosis was stabilized using a cortical screw along with anatomical repair of the PITFL. Apart from delayed wound healing, the patient exhibited good functional outcomes in terms of gait and ankle range of motion at the six-month follow-up. This case serves as a valuable reference for similar presentations in the future, emphasizing the importance of thorough preoperative assessment and appropriate treatment planning.

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Aging and neurodegeneration entail diverse cellular and molecular hallmarks. Here, we studied the effects of aging on the transcriptome, translatome, and multiple layers of the proteome in the brain of a short-lived killifish. We reveal that aging causes widespread reduction of proteins enriched in basic amino acids that is independent of mRNA regulation, and it is not due to impaired proteasome activity. Instead, we identify a cascade of events where aberrant translation pausing leads to reduced ribosome availability resulting in proteome remodeling independently of transcriptional regulation. Our research uncovers a vulnerable point in the aging brain's biology - the biogenesis of basic DNA/RNA binding proteins. This vulnerability may represent a unifying principle that connects various aging hallmarks, encompassing genome integrity and the biosynthesis of macromolecules.

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BACKGROUND: Tablet formulation could be revolutionized by the integration of modern technology and established pharmaceutical sciences. The pharmaceutical sector can develop tablet formulations that are not only more efficient and stable but also patient-friendly by utilizing artificial intelligence (AI), machine learning (ML), and materials science. OBJECTIVES: The primary objective of this review is to explore the advancements in tablet technology, focusing on the integration of modern technologies like artificial intelligence (AI), machine learning (ML), and materials science to enhance the efficiency, cost-effectiveness, and quality of tablet formulation processes. METHODS: This review delves into the utilization of AI and ML techniques within pharmaceutical research and development. The review also discusses various ML methodologies employed, including artificial neural networks, an ensemble of regression trees, support vector machines, and multivariate data analysis techniques. RESULTS: Recent studies showcased in this review demonstrate the feasibility and effectiveness of ML approaches in pharmaceutical research. The application of AI and ML in pharmaceutical research has shown promising results, offering a potential avenue for significant improvements in the product development process. CONCLUSION: The integration of nanotechnology, AI, ML, and materials science with traditional pharmaceutical sciences presents a remarkable opportunity for enhancing tablet formulation processes. This review collectively underscores the transformative role that AI and ML can play in advancing pharmaceutical research and development, ultimately leading to more efficient, reliable and patient-centric tablet formulations.

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BACKGROUND: Guggulipid, an oleo-gum resin extracted from the bark of Commiphora wightii of the Burseraceae family, holds a significant place in Ayurvedic medicine due to its historical use in treating various disorders, including inflammation, gout, rheumatism, obesity, and lipid metabolism imbalances. OBJECTIVE: This comprehensive review aims to elucidate the molecular targets of guggulipids and explore their cellular responses. Furthermore, it summarizes the findings from in-vitro, in-vivo, and clinical investigations related to arthritis and various inflammatory conditions. METHODS: A comprehensive survey encompassing in-vitro, in-vivo, and clinical studies has been conducted to explore the therapeutic capacity of guggulipid in the management of rheumatoid arthritis. Various molecular pathways, such as cyclooxygenase-2 (COX-2), vascular endothelial growth factor (VEGF), PI3-kinase/AKT, JAK/STAT, nitric oxide synthase (iNOS), and NFκB signaling pathways, have been targeted to assess the antiarthritic and anti-inflammatory effects of this compound. RESULTS: The research findings reveal that guggulipid demonstrates notable antiarthritic and anti-inflammatory effects by targeting key molecular pathways involved in inflammatory responses. These pathways include COX-2, VEGF, PI3-kinase/AKT, JAK/STAT, iNOS, and NFκB signaling pathways. in-vitro, in-vivo, and clinical studies collectively support the therapeutic potential of guggulipid in managing rheumatoid arthritis and related inflammatory conditions. CONCLUSION: This review provides a deeper understanding of the therapeutic mechanisms and potential of guggulipid in the management of rheumatoid arthritis. The collective evidence strongly supports the promising role of guggulipid as a therapeutic agent, encouraging further research and development in guggulipid-based treatments for these conditions.

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Selumetinib (SELU) was recently approved by the US Food and Drug Administration (US FDA) in 2020. However, the degradation impurities of SELU have not been characterized or identified to date. The mechanism for impurity formation and the degradation behavior have not been previously studied. This study aims to elucidate the prototypical degradation mechanism of SELU. Furthermore, the degradation impurities have been identified using LC-quadrupole-time-of-flight tandem mass spectrometry and are reported in this article for the first time. In addition, a stability-indicating analytical method (SIAM) has been developed for this drug. Forced degradation studies revealed the degradation of SELU under various stress conditions, including hydrolytic stress (acid and base), oxidative stress, and photolytic stress (ultraviolet and visible). Three degradation impurities were identified. This article presents the first validated SIAM, capable of accurately quantifying SELU in the presence of its degradation impurities. Furthermore, we have proposed the degradation pathway for SELU and its degradation impurities, a first in the field. The developed SIAM can find applications in process development and quality assurance of SELU in both research laboratories and pharmaceutical industries. Moreover, the identified degradation impurities may serve as impurity standards for quality control testing in pharmaceutical industries.

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Duvelisib (DUV) was first approved globally in 2018. An extensive literature search revealed that the differential role of a potential degradation medium in altering the shelf-life of DUV due to its exposure during storage has not been identified till date. Moreover, its degradation impurities and degradation mechanism are not known. In addition, no analytical method has been reported for the quantification of DUV in the presence of its degradation impurities. Therefore, the aim of this study was to identify the impact of different potential degradation media on the stability of DUV, establish the degradation mechanism, and identify its major degradation impurities. The aim was also to establish a stability-indicating analytical method for the quantification of DUV in the presence of its degradation impurities. This study is the first to report the structure of degradation impurities and the step-by-step degradation mechanism of DUV. This information will be useful for the scientific community and manufacturers in optimizing the formulation parameters and/or storage conditions. The validated method can be employed for analysis of stability study and routine quality control samples of newer DUV formulations in pharmaceutical industries. The identified impurities may serve as impurity standards for specifying their limits in the drug after required qualification studies.

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DK-GV-04P, chemically identified as 3-cinnamyl-2-(4-methoxyphenyl) quinazolin-4(3H)-one, is an investigational molecule synthesized at the Chemical Biology Laboratory of the National Institute of Pharmaceutical Education and Research-Ahmedabad. The compound has shown potential anticancer activity against squamous CAL27 cell lines. Metabolite identification and characterization are critical in drug discovery, providing key insights into a compound's pharmacokinetics, pharmacodynamics safety, and metabolic fate. The primary aim of the study was to identify and characterize the in vitro metabolites of DK-GV-04P. In silico identification of the site of metabolism was also carried out using xenosite online software. The molecule was incubated with human liver microsomes and human S9 liver fraction to generate in vitro metabolites, which were further identified and characterized using ultra-high-performance liquid chromatography-quadrupole time of flight tandem mass spectrometry. A total of nine metabolites (four phase I and five phase II) were identified and characterized through tandem mass spectrometry. The major biotransformation pathways involved in metabolism of DK-GV-04P were hydroxylation, O-demethylation and glucuronidation. In addition to this, a detailed biotransformation pathway of DK-GV-04P has been established in this study.

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Rheumatologic diseases are a widespread group of disorders affecting the joints, bones, and connective tissue, and leading to significant disability. Imaging is an indispensable component in diagnosing, assessing, monitoring, and managing these disorders, providing information about the structural and functional alterations occurring within the affected joints and tissues. This review article aims to compare the utility, specific clinical applications, advantages, and limitations of high-resolution ultrasound and magnetic resonance imaging in the context of rheumatologic diseases. It also provides insights into the imaging features of various types of inflammatory arthritis with clinical relevance and a focus on high-resolution ultrasound and magnetic resonance imaging. By understanding the comparative aspects of high-resolution ultrasound and magnetic resonance imaging, it is easier for the treating physicians to make informed decisions when selecting the optimal imaging modality for specific diagnostic purposes, effective treatment planning, and improve patient outcomes. The patterns of soft tissue and joint involvement; bony erosion and synovitis help in differentiating between various type of arthritis. Involvement of various small joints of the hands also gives an insight into the type of arthritis. We also briefly discuss the potential applications of emerging techniques, such as ultrasound elastography, contrast-enhanced ultrasound, and dual-energy CT, in the field of rheumatology.

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Rotator cuff tears are common shoulder injuries in patients above 40 years of age, causing pain, disability, and reduced quality of life. Most recurrent rotator cuff tears happen within three months. Surgical repair is often necessary in patients with large or symptomatic tears to restore shoulder function and relieve symptoms. However, 25% of patients experience pain and dysfunction even after successful surgery. Imaging plays an essential role in evaluating patients with postoperative rotator cuff pain. The ultrasound and magnetic resonance imaging are the most commonly used imaging modalities for evaluating rotator cuff. The ultrasound is sometimes the preferred first-line imaging modality, given its easy availability, lower cost, ability to perform dynamic tendon evaluation, and reduced post-surgical artifacts compared to magnetic resonance imaging. It may also be superior in terms of earlier diagnosis of smaller re-tears. Magnetic resonance imaging is better for assessing the extent of larger tears and for detecting other complications of rotator cuff surgery, such as hardware failure and infection. However, postoperative imaging of the rotator cuff can be challenging due to the presence of hardware and variable appearance of the repaired tendon, which can be confused with a re-tear. This review aims to provide an overview of the current practice and findings of postoperative imaging of the rotator cuff using magnetic resonance imaging and ultrasound. We discuss the advantages and limitations of each modality and the normal and abnormal imaging appearance of repaired rotator cuff tendon.

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The Maillard reaction, a chemical reaction between amino acids and sugars, is exploited to produce flavorful food ubiquitously, from the baking industry to our everyday lives. However, the Maillard reaction also occurs in all cells, from prokaryotes to eukaryotes, forming advanced glycation end-products (AGEs). AGEs are a heterogeneous group of compounds resulting from the irreversible reaction between biomolecules and α-dicarbonyls (α-DCs), including methylglyoxal (MGO), an unavoidable byproduct of anaerobic glycolysis and lipid peroxidation. We previously demonstrated that Caenorhabditis elegans mutants lacking the glod-4 glyoxalase enzyme displayed enhanced accumulation of α-DCs, reduced lifespan, increased neuronal damage, and touch hypersensitivity. Here, we demonstrate that glod-4 mutation increased food intake and identify that MGO-derived hydroimidazolone, MG-H1, is a mediator of the observed increase in food intake. RNAseq analysis in glod-4 knockdown worms identified upregulation of several neurotransmitters and feeding genes. Suppressor screening of the overfeeding phenotype identified the tdc-1-tyramine-tyra-2/ser-2 signaling as an essential pathway mediating AGE (MG-H1)-induced feeding in glod-4 mutants. We also identified the elt-3 GATA transcription factor as an essential upstream regulator for increased feeding upon accumulation of AGEs by partially controlling the expression of tdc-1 gene. Furthermore, the lack of either tdc-1 or tyra-2/ser-2 receptors suppresses the reduced lifespan and rescues neuronal damage observed in glod-4 mutants. Thus, in C. elegans, we identified an elt-3 regulated tyramine-dependent pathway mediating the toxic effects of MG-H1 AGE. Understanding this signaling pathway may help understand hedonistic overfeeding behavior observed due to modern AGE-rich diets.

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The clivus is a midline anatomical structure in the central skull base. It is affected by a wide range of non-neoplastic, benign and malignant pathologies, some of which typically affect the clivus because of its strategic location and embryological origins. Clival lesions may often be asymptomatic with occasional complaints like headache or cranial neuropathy in few. Cross-sectional imaging techniques, namely, computed tomographic scan and magnetic resonance imaging, thus, play a key role in approximating to the final diagnosis and estimating the disease extent. In this article, we highlight the important imaging features of various clival and paraclival pathologies to facilitate effective diagnosis, therapeutic planning, and management.

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Marine-derived actinobacteria have tremendous potential to produce novel metabolites with diverse biological activities. The Andaman coast of India has a lot of microbial diversity, but it is still a relatively unknown ecology for isolating novel actinobacteria with beneficial bioactive compounds. We have isolated 568 actinobacterial strains from mangrove rhizosphere sediments and sponge samples. Crude extracts from 75 distinct strains were produced by agar surface fermentation and extracted using ethyl acetate. In the disc diffusion method, 25 actinobacterial strains showed antimicrobial activity; notably, the strain MAB56 demonstrated promising broad-spectrum activity. Strain MAB56 was identified as Streptomyces albus by cultural, microscopic, and molecular methods. Conditions for bioactive metabolites from MAB56 were optimized and produced in a lab-scale fermenter. Three active metabolites (C1, C2, and C3) that showed promising broad-spectrum antimicrobial activity were isolated through HPLC-based purification. Based on the UV, FT-IR, NMR, and LC-MS analysis, the chemical nature of the active compounds was confirmed as 12-methyltetradecanoic acid (C1), palmitic acid (C2), and tridecanoic acid (C3) with molecular formulae C14H28O2, C16H32O2, and C13H26O2, respectively. Interestingly, palmitic acid (C2) also exhibited anti-HIV activity with an IC50 value of < 1 µg/ml. Our findings reveal that the actinobacteria from the Andaman marine ecosystems are promising for isolating anti-infective metabolites.

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The aim of the present study is to identify actinobacteria Streptomyces bacillaris ANS2 as the source of the potentially beneficial compound 2,4-di-tert-butylphenol, describe its chemical components, and assess its anti-tubercular (TB) and anti-cancer properties. Ethyl acetate was used in the agar surface fermentation of S. bacillaris ANS2 to produce the bioactive metabolites. Using various chromatographic and spectroscopy analyses, the potential bioactive metabolite separated and identified as 2,4-di-tert-butylphenol (2,4-DTBP). The lead compound 2,4-DTBP inhibited 78% and 74% of relative light unit (RLU) decrease against MDR Mycobacterium tuberculosis at 100ug/ml and 50ug/ml concentrations, respectively. The Wayne model was used to assess the latent/dormant potential in M. tuberculosis H37RV at various doses, and the MIC for the isolated molecule was found to be 100ug/ml. Furthermore, the molecular docking of 2,4-DTBP was docked using Autodock Vinasuite onto the substrate binding site of the target Mycobacterium lysine aminotransferase (LAT) and the grid box was configured for the docking run to cover the whole LAT dimer interface. At a dosage of 1 mg/ml, the anti-cancer activity of the compound 2,4-DTBP was 88% and 89% inhibited against the HT 29 (colon cancer) and HeLa (cervical cancer) cell lines. According to our literature survey, this present finding may be the first report on anti-TB activity of 2,4-DTBP and has the potential to become an effective natural source and the promising pharmaceutical drug in the future.

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Pyruvate kinase (PK) M2 activators ramp up glycolysis in cancer cells, leading to a reversal of the Warburg effect in cancer cells. A promising PKM2 activator molecule, IMID-2, developed by the National Institute of Pharmaceutical Education and Research-Ahmedabad showed promising anticancer activity against MCF-7 and COLO-205 cell lines, which represent breast and colon cancer. Its physicochemical properties, like solubility, ionization constant, partition coefficient and distribution constant, have already been established. Its metabolic pathway is also well established through in vitro and in vivo metabolite profiling and reported previously. In this study, we have evaluated the metabolic stability of IMID-2 using LC-MS/MS and investigated the safety aspect of the molecule through an acute oral toxicity study. In vivo studies in rats confirmed that the molecule is safe even at a dose level of 175 mg/kg. Furthermore, a pharmacokinetic study of IMID-2 was also carried out using LC-MS/MS to understand its absorption, distribution, metabolism, and excretion profile. The molecule was found to have promising bioavailability through the oral route. This research work is thus another step in the drug testing of this promising anticancer molecule. The molecule can be considered to be a potential anticancer lead based on the earlier report substantiated by current findings.

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Most antiretrovirals (ARVs) have intracellular therapeutic target sites and therefore, their plasma concentration may be misleading when relating to their efficacy or toxicity. A bioanalytical method for quantification of the ARV drug bictegravir (BTG) in its target site peripheral blood mononuclear cells (PBMCs) is not available till date. This is the first time to establish a sufficiently sensitive mass spectrometry-based bioanalytical method to quantify BTG in both rat PBMCs and plasma. The developed method was validated over the range of 1 ng/ml to 100 ng/ml and 0.005 ng-10ng/sample for plasma and PBMCs, respectively. For PBMCs, average accuracy and precision at four quality control levels were found to be 93.30%-110.00% and 6.52%-8.25%, respectively. Plasma and intracellular pharmacokinetics of BTG was evaluated by the developed method in rats and a lack of accumulation of BTG in the PBMCs was observed. Pearson correlation coefficient data analysis indicated a moderated correlation between plasma and PBMC concentration of BTG. Therefore, it will be beneficial to include a quantification plan for BTG in its actual therapeutic target site during all its future research and development work. This reported method can be useful for site-specific monitoring of BTG in research laboratories and pharmaceutical industries.

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