Potential Drug Research Articles

Esterase-Responsive Floxuridine-Tethered Multifunctional Nanoparticles for Targeted Cancer Therapy.

Floxuridine is a potential clinical anticancer drug for the treatment of various cancers. However, floxuridine typically causes unfavorable side effects due to its very poor tumor selectivity, and, hence, there is a high demand for the development of novel approaches that permit the targeted delivery of floxuridine into cancerous cells. Herein, the design and synthesis of an esterase-responsive multifunctional nanoformulation for the targeted delivery of floxuridine in esterase-overexpressed cancer cells is reported. Photopolymerization of floxuridine-tethered lipoic acid results in the formation of amphiphilic floxuridine-tethered poly(disulfide). Self-assembly of the amphiphilic polymer results in the formation of nanoparticles with floxuridine decorated on the surfaces of the particles. Integration of aptamer DNA for nucleolin onto the surface of the nanoparticle is demonstrated by exploring the base-pairing interaction of floxuridine with adenine. Targeted internalization of the aptamer-decorated nanoparticle into nucleolin-expressed cancer cells is demonstrated. Esterase triggered cleavage of the ester bond connecting floxuridine with the polymer backbone, and the subsequent targeted delivery of floxuridine into cancer cells is also shown. Excellent therapeutic efficacy is observed both in vitro and also in the 3D tumor spheroid model. This noncovalent strategy provides a simple yet effective strategy for the targeted delivery of floxuridine into cancer cells in a less laborious fashion.

Proteomic Mendelian randomization to identify protein biomarkers of telomere length

Shortening of telomere length (TL) is correlated with many age-related disorders and is a hallmark of biological aging. This study used proteome-wide Mendelian randomization to identify the protein biomarkers associated with telomere length. Protein quantitative trait loci (pQTL) were derived from two studies, the deCODE Health study (4907 plasma proteins) and the UK Biobank Pharma Proteomics Project (2923 plasma proteins). Summary data from genome-wide association studies (GWAS) for TL were obtained from the UK Biobank (472,174 cases) and GWAS Catalog (418,401 cases). The association between proteins and TL was further assessed using colocalization and summary data-based Mendelian randomization (SMR) analyses. The protein–protein network, druggability assessment, and phenome-wide MR were used to further evaluate the potential biological effects, druggability, and safety of the target proteins. Proteome-wide MR analysis identified 22 plasma proteins that were causally associated with telomere length. Five of these proteins (APOE, SPRED2, MAX, RALY, and PSMB1) had the highest evidence of association with TL and should be prioritized. This study revealed telomere length-related protein biomarkers, providing new insights into the development of new treatment targets for chronic diseases and anti-aging intervention strategies.

A Systematic Review of Barley (Hordeum vulgare Linn.) in Unani Medicine with Recent Advances

Objective: The present review article focuses on exploring the wide dimensions of barley including botanical description, nutritional composition, phytochemistry, experimental pharmacology, and clinical studies along with its traditional uses in Unani medicine. Background: Barley (Hordeum vulgare L.) which is referred to as ‘Jao’ in the Unani system of medicine has a long history of utilization as a food and medicine. It belongs to family Poaceae and is considered as one of the founder crops of old-world agriculture. Methodology: A manual literature survey of classical Unani texts was conducted to collect the information available on ‘Jao’. Besides, a comprehensive search of electronic databases like PubMed, Google Scholar, and Science Direct, was carried out to collect all the available information regarding its phytochemical, pharmacological and clinical studies. Result: In Unani medicine, barley is an important drug commonly used in many disorders of the respiratory system, gastrointestinal system, musculoskeletal system, skin, etc. It is used to treat obesity, diabetes, headache, pain and inflammation of the throat, acute swelling of joints and gout, chronic swellings, diarrhoea, fever, skin eruptions, hyperpigmentation of the skin, etc. Recent studies revealed that barley constitutes beta-glucan and a myriad of bioactive compounds that play numerous biological activities such as hypoglycemic, hypocholesterolemic, anti-inflammatory, antioxidant, anti-obesity, anticancer, and wound healing activities. Conclusion: Barley is a potent drug that exhibits a wide range of health benefits, most of which have been confirmed via preclinical and clinical studies. This review may thus be helpful for the research community as well as common people to avail the benefits of this drug. Keywords: Barley, Beta-glucan, Hordeum vulgare, Jao, Unani medicine

A novel encapsulation approach to enhance the delivery and antitumor activity of docetaxel in breast cancer therapy

Docetaxel (DTX) is one of the most potent anticancer drugs but its extensive side effects necessitate innovative formulations. In this study, we aimed to investigate the expression pattern of apoptotic proteins, cell cycle arrest, and apoptosis induction after treatment with encapsulated DTX in alginate-chitosan nanoparticles in both breast cancer cells (MCF-7) and peripheral blood mononuclear cells (PBMCs). The characterization of the nanoparticles revealed a spherical shape with a size <50 nm, a hydrodynamic diameter of 200 nm, a Polydispersity Index of 0.5, and an encapsulation efficiency of 98.75 %. The free drug was released completely within 11 h while encapsulated DTX was released only 34 % in 96 h. The encapsulated drug indicated higher cytotoxicity on MCF-7 cells and the half inhibitory concentration (IC50) value was 2 µg/ml after 72 h. Quantitative real-time PCR demonstrated a significant increase in cell death as the expression of apoptosis regulatory protein (Bcl-2) was downregulated with no impact on Bax in the MCF-7 cells. A notable decrease in the expression pattern of pro-inflammatory cytokine (IL-1β) in PBMCs indicated less inflammation induction. Flow cytometry analysis revealed that the newly formulated drug induced less opoptosis in PBMCs than the free DTX. Cell cycle arrest in the sub-G1 phase was observed for the free drug while the encapsulated drug exhibited no significant changes. Our results suggest the high toxicity of the formulated drug in contrast to the free DTX on the MCF-7 cell line, minimal blood cell side effects, and no inflammation positioning it as a promising alternative to free docetaxel.

Exploring the role of topological descriptors to predict physicochemical properties of anti-HIV drugs by using supervised machine learning algorithms

In order to explore the role of topological indices for predicting physio-chemical properties of anti-HIV drugs, this research uses python program-based algorithms to compute topological indices as well as machine learning algorithms. Degree-based topological indices are calculated using Python algorithm, providing important information about the structural behavior of drugs that are essential to their anti-HIV effectiveness. Furthermore, machine learning algorithms analyze the physio-chemical properties that correspond to anti-HIV activities, making use of their ability to identify complex trends in large, convoluted datasets. In addition to improving our comprehension of the links between molecular structure and effectiveness, the collaboration between machine learning and QSPR research further highlights the potential of computational approaches in drug discovery. This work reveals the mechanisms underlying anti-HIV effectiveness, which paves the way for the development of more potent anti-HIV drugs. This work reveals the mechanisms underlying anti-HIV efficiency, which paves the way for the development of more potent anti-HIV drugs which demonstrates the invaluable advantages of machine learning in assessing drug properties by clarifying the biological processes underlying anti-HIV behavior, which paves the way for the design and development of more effective anti-HIV drugs.

Protective role of TRPM7 knockdown in ulcerative colitis via blocking NLRP3 inflammasome-mediated pyroptosis

Transient receptor potential melastatin 7 (TRPM7) has been emerged as a potent drug target for immunomodulation with ion conductance and kinase activities. The research is projected to characterize the influences of TRPM7 on the course of ulcerative colitis (UC) and dissect the latent response mechanisms. The in vivo murine model and in vitro cell model of UC were both stimulated by DSS. RT-qPCR and western blotting tested the abundance of TRPM7. Colonic damage was estimated by Hematoxylin-eosin staining, calculation of colon length, measurement of DAI and MPO assay kit. CCK-8 method and TUNEL staining severally ascertained cell activity and apoptosis. ELISA method assayed the inflammatory levels and relevant assay kits determined oxidative stress levels. FITC-dextran flux, immunohistochemistry, TEER as well as western blotting evaluated intestinal barrier function. Immunofluorescence staining and western blotting appraised NLR family pyrin domain containing 3 (NLRP3)-dependent pyroptosis. Depleted TRPM7 retarded inflammation, oxidative damage as well as intestinal barrier damage both in vitro and in vivo. TRPM7 reduction repressed the pyroptosis mediated by NLRP3 inflammasome. NLRP3 agonist nigericin partly abolished the protection elicited by TRPM7 silencing against inflammation, oxidative damage as well as intestinal barrier damage in vitro. Collectively, TRPM7 deletion might possess the therapeutic potential in UC, the working mechanism of which might involve the inactivation of NLRP3-dependent pyroptosis.

Discovery of Fluorescent Naturally-Occurring Inhibitor of SARS-CoV-2 Main Protease by AIE Fluorescent Probe.

Target-based high-throughput screening (HTS) is an efficient way to identify potent drugs. However, the accuracy of HTS could be affected by Pan-Assay Interference Compounds (PAINS). One reason for the generation of PAINS is that the inherent photophysical property of screened compounds could interfere with typically used assay signals including absorption and fluorescence. Our previous studies indicate that the fluorescent probe based on the fluorophore with characteristics of aggregation-induced emission (AIE) could provide high accuracy of HTS, especially for the fluorescent natural products. Herein, we report an AIE-based fluorescent probe for the main protease (Mpro) of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We designed and synthesized an AIE fluorescent probe ZLHG5, which has a site that can be specifically cleaved by Mpro to produce a light-up fluorescence. Thanks to the large Stokes shift of AIE fluorophore (~200 nm), the probe could be effectively used for HTS of Mpro inhibitors. After screening a library of fluorescent natural products with ZLHG5, we obtained two coumarin-originated natural compounds with potent inhibitory activity towards Mpro protease. This study provides both useful fluorescent HTS probe and potent inhibitors for Mpro protease.

Synthesis, spectroscopy and biological investigation via DFT, ADMET and molecular docking of Thiadiazole/Oxadiazole based bis-Schiff bases: A potential towards diabetes and microbes

A novel series of varied substituted thiadiazole/oxadiazole based bis-Schiff base derivatives (1–10) was synthesized and characterized using NMR (13CNMR and 1HNMR) and HREI-mass spectrometry. To determine their anti-diabetic potential, these analogues were examined against α-amylase and α-glucosidase. These compounds demonstrated varied inhibitory range between IC50 = 1.10 ± 0.50 to 21.40 ± 0.20 µM (α-amylase) and 2.50 ± 0.05 to 21.40 ± 0.10 µM (α-glucosidase), when contrasted with Acarbose, a well-known marketed drug (IC50 = 3.16 ± 0.22 &4.8 ± 0.21 µM for α-amylase and α-glucosidase respectively). Analog-9 having tri-fluoromethyl group at para position of benzene ring emerged as lead candidate among these synthesized compounds. The effective activity of compound-9 may be due to involvement of fluoro atoms interacting via hydrogen-bonding with the selected sites of diabetic enzymes, α-amylase and α-glucosidase. Furthermore, for exploration of binding interactions of potent drugs and reactivity of potent analogues, molecular docking as well as DFT was performed. For investigation of drug likeness and toxicity, ADME analysis was also conducted.

Preparation, Characterization and Quantification of Mangiferin in Mangiferin-loaded Microspheres

Introduction: Mangiferin shows great promise as a potent drug for a wide variety of diseases. Its low bioavailability and poor water solubility, however, restrict its therapeutic use. Methods: The aim of the study goal was to systematically design a UV-spectroscopy method for mangiferin quantification in analytical samples that is quick, easy, and very sensitive. In order to validate the method, UV spectroscopy was used to check for specificity, accuracy, precision, and linearity. The models were constructed with Design ExpertⓇ V.10 and optimised using Box- Behnken Design (BBD), a three-factor and three-level procedure. Results: The devised method demonstrated good levels of sensitivity, specificity, accuracy, and precision, according to the results. The absorbance and concentration showed a strong linear relationship in the given 5-25 μg/ml range for several wavelengths, with correlation coefficients of 0.989, 0.982, 0.905, and 0.896 at 364.5, 370, 378, and 265nm, respectively. The intraday precision was 0.788 at 364.5 nm, 0.801 at 370 nm, 0.739 at 378 nm, and 0.721 at 256 nm for the concentration of 20 μg/ml. Particle size and entrapment efficiency, two dependent variables in the microspheres formulation, were best suited by the models derived when the observed responses were fitted to the design. Microspheres had a high entrapment efficiency and were microsized. Interestingly, drug-encapsulated microspheres containing mangiferin maintained the spherical shape. Conclusion: The existence of well-resolved peaks and good recovery of mangiferin in the analytical method for analysis makes it ideal and acceptable for further use.

Insights into the role of potent thiadiazole based Schiff base derivatives in targeting type-II diabetes: A combine in-vitro and in-silico approaches

A novel series of varied substituted thiadiazole based Schiff base analogues (1–21) were designed and characterized using NMR (13C, 1H) and HREI-mass spectrometry, and secerned against the enzymes responsible for hyperglycemia i-e α-amylase and α-glucosidase. Newly designed analogues demonstrated distinct inhibitory activities having IC50= 1.10 ± 0.50 to 21.40 ± 0.20 µM (for alpha-amylase) and 2.50 ± 0.05 to 21.40 ± 0.10 µM (for alpha-glucosidase) in contrast to acarbose a well-known marketed drug (IC50 = 3.16 ± 0.22 & 4.8 ± 0.21 µM for α-amylase and α-glucosidase, respectively). Compound (20) with tri-fluoromethyl at para position of aromatic ring revealed as lead candidate among the members of synthesized series, having effective inhibitory activity against enzymes α-amylase and α-glucosidase. The excellent activity of compound (20) might be due to involvement of fluoro atom interacting via H-bonding with the active sites of enzymes α-amylase and α-glucosidase being targeted. Furthermore, for exploration of binding interactions of potent drugs, molecular docking was performed. For investigation of drug likeness and toxicity, ADME analysis was also conducted.

Curcumin-Dichloroacetate Hybrid Molecule as an Antitumor Oral Drug against Multidrug-Resistant Advanced Bladder Cancers.

Tumor cells produce excessive reactive oxygen species (ROS) but cannot detoxify ROS if they are due to an external agent. An agent that produces toxic levels of ROS, specifically in tumor cells, could be an effective anticancer drug. CMC-2 is a molecular hybrid of the bioactive polyphenol curcumin conjugated to dichloroacetate (DCA) via a glycine bridge. The CMC-2 was tested for its cytotoxic antitumor activities and killed both naïve and multidrug-resistant (MDR) bladder cancer (BCa) cells with equal potency (<1.0 µM); CMC-2 was about 10-15 folds more potent than curcumin or DCA. Growth of human BCa xenograft in mice was reduced by >50% by oral gavage of 50 mg/kg of CMC-2 without recognizable systemic toxicity. Doses that used curcumin or DCA showed minimum antitumor effects. In vitro, the toxicity of CMC-2 in both naïve and MDR cells depended on increased intracellular ROS in tumor cells but not in normal cells at comparable doses. Increased ROS caused the permeabilization of mitochondria and induced apoptosis. Further, adding N-Acetyl cysteine (NAC), a hydroxyl radical scavenger, abolished excessive ROS production and CMC-2's cytotoxicity. The lack of systemic toxicity, equal potency against chemotherapy -naïve and resistant tumors, and oral bioavailability establish the potential of CMC-2 as a potent drug against bladder cancers.

Exploration of 4-tolyl-5-(p-tolyloxymethyl)-4H-1,2,4-triazole thioethers as potent 15-LOX inhibitors supported by in vitro, in silico, MD simulation and DNA binding studies

Inflammation is an intricate process exacerbated by the sequential release of lipid mediators during arachidonic acid metabolism through the LOX and COX pathways. The inhibition of enzymes accountable for the arachidonic acid metabolism is attributed to a synergistic anti-inflammatory impact with a broader spectrum of activity. The present study was concerned with the search for lead 15-LOX inhibitors. A new series of alkyl/aralkyl substituted 4-tolyl-5-(p-tolyloxymethyl)-4H-1,2,4-triazole (6a-h) was designed, synthesized, and characterized to determine their 15-LOX inhibitory potential. The analogue 3-(phenethylthio)-4-tolyl-5-(p-tolyloxymethyl)-4H-1,2,4-triazole (6h) was the most potent with IC50 2.73 ± 0.15 µM while 6g, 6d, 6f, 6c exhibited excellent inhibitory activities with IC50 values between 11.39 ± 0.13 and 14.63 ± 0.17 µM. All analogues maintained > 72 % blood mononuclear cells viability at 0.25 mM concentration during MTT assay. In silico ADME profiles predicted druggability potential. The molecular docking studies disclosed binding free energies of -9.78 to -7.94 kcal/mol and His373 and His378 were majorly involved in π-interactions in all molecules. Van der Waals interactions dominated hydrogen bonding in the stabilization of ligand-receptor complexes. MD simulations and free energy calculations revealed the significance of complexes in stabilizing the biomolecular system and helped in identifying the key active site residues that contributed towards the energetics. Studies against DNA dodecamer displayed minor groove binding and intercalation, suggesting a possible role in modulating DNA-related processes. The results approve the active analogues possessing promising druglike properties and work is in progress on the synthesis of more analogues in search for leads as 15-LOX inhibitors.

PH-sensitive nanoformulation of acetyl-11-keto-beta-boswellic acid (AKBA) as a potential antiproliferative agent in colon adenocarcinoma (in vitro and in vivo)

BackgroundDeveloping a drug delivery system that can transport a higher concentration to the target cells can improve therapeutic efficacy. This study aimed to develop a novel delivery system for acetyl-11-keto-beta-boswellic Acid (AKBA) using chitosan-sodium alginate–calcium chloride (CS-SA-CaCl2) nanoparticles. The objectives were to evaluate the antiproliferative activity of these nanoparticles against colorectal cancer (CRC) cells and to improve the bioavailability and therapeutic efficacy of AKBA.ResultsWith an extraction efficiency of 12.64%, AKBA was successfully extracted from the gum resin of B. serrata. The nanoparticle delivery system exhibited superior cytotoxicity against HT29 cells compared to free AKBA, AKBA extract (BA-Ex), and 5-FU. Furthermore, the nanoformulation (nano-BA-Ex) induced apoptosis in HT29 cells more effectively than the other treatments. In vivo results showed that nanoformulation inhibited chemically induced colon tumorigenesis in mice and significantly reduced the number of aberrant crypt foci (ACFs).ConclusionsThe developed CS-SA-CaCl2 nanoparticles loaded with AKBA extract exhibit potential as a potent drug delivery mechanism for the colorectal cancer model. Nano-BA-Ex is a promising strategy for enhancing the solubility, bioavailability, and therapeutic efficacy of BA derivatives. With its multiple effects on cancer cells and controlled drug release through nanocapsules, nano-BA-Ex stands out as a compelling candidate for further preclinical and clinical evaluation in CRC therapy.

Molecular Insights into the Anticancer Activity of Withaferin-A: The Inhibition of Survivin Signaling.

Survivin, a member of the IAP family, functions as a homodimer and inhibits caspases, the key enzymes involved in apoptosis. Several Survivin inhibitors, including YM-155, Debio1143, EM1421, LQZ-7I, and TL32711, have emerged as potential anticancer drugs awaiting validation in clinical trials. Due to the high cost and adverse side effects of synthetic drugs, natural compounds with similar activity have also been in demand. In this study, we conducted molecular docking assays to evaluate the ability of Wi-A and Wi-N to block Survivin dimerization. We found that Wi-A, but not Wi-N, can bind to and prevent the homodimerization of Survivin, similar to YM-155. Therefore, we prepared a Wi-A-rich extract from Ashwagandha leaves (Wi-AREAL). Experimental analyses of human cervical carcinoma cells (HeLa and ME-180) treated with Wi-AREAL (0.05-0.1%) included assessments of viability, apoptosis, cell cycle, migration, invasion, and the expression levels (mRNA and protein) of molecular markers associated with these phenotypes. We found that Wi-AREAL led to growth arrest mediated by the upregulation of p21WAF1 and the downregulation of several proteins (CDK1, Cyclin B, pRb) involved in cell cycle progression. Furthermore, Wi-AREAL treatment activated apoptosis signaling, as evidenced by reduced PARP-1 and Bcl-2 levels, increased procaspase-3, and elevated Cytochrome C. Additionally, treating cells with a nontoxic low concentration (0.01%) of Wi-AREAL inhibited migration and invasion, as well as EMT (epithelial-mesenchymal transition) signaling. By combining computational and experimental approaches, we demonstrate the potential of Wi-A and Wi-AREAL as natural inhibitors of Survivin, which may be helpful in cancer treatment.

New multifunctional hybrids as modulators of apoptosis markers and topoisomerase II in breast cancer therapy: synthesis, characterization, and in vitro and in silico studies.

Recently, molecular hybrids of two or more active pharmacophores have shown promise for designing and synthesizing anticancer drugs. Herein, a new multifunctional hybrid (PAHMQ), combining azobenzene and quinoline pharmacophores, and its M(ii) complexes (MPAHMQ) have been successfully developed and structurally characterized. The MTT assay revealed CuBHTP as the most efficient and safe breast cancer treatment, with an IC50 of 11.18 ± 0.39 μg mL-1 and a high selectivity index (SI) of 5.63 for cancer MCF-7 cells over healthy MCF10A cells. Moreover, the CuPAHMQ-treated MCF-7 cells experience a dramatic impact with regard to key apoptotic markers, including an increase in P53 and Bax expression, with a decrease in Bcl-2 expression levels compared to the untreated MCF-7 cells. Additionally, CuPAHMQ effectively halted the growth and division of MCF-7 cells by inducing cell cycle arrest in the crucial G1 and S phases, ultimately inhibiting both Topo II activity and cell proliferation. Molecular docking investigations validated the CuPAHMQ complex's groove binding and topoisomerase II binding, establishing it as a potent anticancer drug.

The "Micro"cosm: Magnifying the Nuance of Low Dose Buprenorphine Inductions.

Now that the X-wavier is a thing of the past, patients with Opioid Use Disorder (OUD) who previously lacked access to buprenorphine may have access to lower barrier care and may be looking to make the transition from either methadone or illicit fentanyl to buprenorphine. This can be quite challenging and both fentanyl and methadone are hihghly potent drugs and can result in a difficult transtition to buprenorphine. A transition from high potency opioids to buprenorphine is challenging and can cause discomfort or withdrawal in patients. Procedures/data/observations: Patients tend to have a difficult time when undergoing a transition from significant fentanyl use (> 1 bundle/day) or high dose methadone to buprenorphine. Over the last year, we've supported this transition for our hospitalized patients and have learned some tips and tricks to ease the transitions. Through our work we've come up with a strategy to transition patients that includes utilizing full mu agonists while initiating a low dose buprenorphine induction. We have developed an informal protocol for this transition that takes advantage of the flexibility of low dose buprenorphine induction strategies and includes the use of non-opioid adjuvant medications to control symptoms of discomfort and withdrawal. A transition from the use of significant fentanyl or high dose methadone to buprenorphine is possible and can take place over a matter of a few days. Such a transition requires careful attention to patient symptoms, availability of as needed short acting opioids, and the judicious use of non-opioid adjuvants.

Enhancing Drug Delivery of Glatiramer Acetate Through In Vitro Development of Controlled-Release Nanoliposomes: Investigating Drug Release Kinetics and Cytotoxic Effects

Background: Multiple sclerosis (MS) damages the myelin sheath covering nerve fibers. This condition affects 400,000 individuals in the United States and 2.5 million people globally, with a higher rate of diagnosis in women aged 20 - 40, with a ratio of 2:1. Liposomes facilitate drug dispersion, making them valuable in biomedicine. They enhance the stability of therapeutic medications, improve cellular and tissue absorption, and increase chemical bioactivity at specific locations. This technique delivers encapsulated compounds with high precision while minimizing negative consequences observed in laboratory settings. Objectives: This study aims to develop an optimal nanoliposome formulation using glatiramer acetate (GA) as the active pharmaceutical ingredient by examining drug release and associated adverse effects to achieve the most effective nanoliposomal system. Methods: The thin layer hydration method was used to prepare nanoliposomes. A comprehensive array of analytical techniques, including FE-SEM, FTIR, XRD, HPLC, and DLS, were employed to examine the physicochemical characteristics of the product. Additionally, the biosafety of the nanoliposomes was assessed using the MTT assay on the 1321N1 human astrocytoma cell line. The release profile of GA from the carrier was studied using the dialysis diffusion method, and the stability of the nanoliposomes was also inspected. Results: The size, Polydispersity Index (PDI), and zeta potential of the nanoliposomes were 91.2 ± 1.3 nm, 0.34 ± 0.03, and -27.3 ± 1.2 mV, respectively. The drug entrapment efficiency (DEE%) in nanoliposomes was approximately 70.2 ± 1.7%. The results from XRD and FTIR revealed no chemical interaction between the drug and carrier, and the nanoliposomes were safe for the cultured cell line. The nanoliposomes were stable under storage conditions and exhibited a sustained release profile. Conclusions: Nanoliposomes, as drug carriers, are known to be a potent drug delivery system due to their numerous advantages. Based on the results, GA-nanoliposomes show promise as a strategy for treating MS patients, pending further in vivo experiments and clinical trials.

Identification of 5-aminometonitazene and 5-acetamidometonitazene in a post-mortem case: Are nitro-nitazenes unstable?

In recent years the use of 2-benzylbenzimidazole opioids ('nitazenes') has increased with them becoming one of the most prominent synthetic opioid subclasses of novel psychoactive substances. With the increased prevalence there is also a concern of the dangers to public health with the use of nitazenes due to their high potency especially with polypharmacy. To aid in the detection of such compounds it is important that forensic toxicology laboratories maintain up-to-date compound libraries for drug screening methods and that sensitive analytical instrumentation is available to detect the low blood/plasma concentrations of more potent drugs. This includes not only the compounds themselves but also potential metabolites and/or degradation products. Metonitazene is a 'nitro-nitazene' with a nitro group at position 5 of the benzimidazole ring. As a nitro-nitazene there is a potential for bacterial degradation of metonitazene to 5-aminometonitazene, as occurs with nitro-benzodiazepines. In this study we provide evidence from a post-mortem case of degradation of metonitazene in unpreserved post-mortem blood using LC-QQQ-MS, and putative identification of the degradation/ metabolic products 5-aminometonitazene and 5-acetamidometonitazene by LC-QTOF-MS. The results from LC-QQQ-MS analysis indicated that there did not appear to be such degradation in preserved (fluoride/oxalate) blood. These results suggest that nitro-nitazenes may be subject to similar in vitro stability/degradation issues as nitro-benzodiazepines. These breakdown products should be added to instrument libraries to aid in the detection of the use of nitro-nitazenes, and nitro-nitazenes should be quantified in preserved blood samples where available.

Ocular pharmacokinetics of acetazolamide from intravitreal implants by high-performance liquid chromatography coupled to tandem mass spectrometry

Glaucoma, a leading cause of irreversible blindness, affects about 70 million people globally. Its treatment focuses on reducing intraocular pressure. Acetazolamide, a potent anti-glaucoma drug, is currently used only systemically due to low solubility and permeation, which cause severe side effects. Developing topical medications with acetazolamide requires robust analytical methods for its detection in biological samples. In this context, this study aimed to develop a method to quantify acetazolamide in rabbit vitreous humor samples. The method involved a simple, fast, inexpensive, and environmentally friendly protein precipitation step for sample preparation, needing just 50 μL of sample and 200 μL of organic solvent, with adequate recovery. This was combined with high-performance liquid chromatography coupled to tandem mass spectrometry, enabling highly sensitive (LOQ of 5 ng/mL) quantification within only 5 min. The method proved to be selective, precise, and accurate, with well-fitted analytical curves, with no carryover, and no matrix effect impacting reliability. The method was successfully applied to analyze vitreous humor samples from rabbits in pharmacokinetic studies, monitoring drug release from intravitreal implants. Results showed a controlled release profile, with a maximum drug concentration (Cmax) of 426.01 ± 64.57 ng/mL, time to reach Cmax (Tmax) of 28 days, and area under the curve (AUC0–42 and AUC0-∞) of 7722.66 ± 1125.96 ng days/mL and 8998.11 ± 1311.92 ng days/mL, respectively. The device demonstrated significantly slower elimination, ensuring therapeutic levels for an extended period when compared to intravitreal injection.

Anti-neoplastic Properties of Boswellic Acids and their Novel Semi-synthetic Analogs: In vitro, In vivo and Clinical Evidence

Introduction: Recently, Boswellia gum resin extract has been shown to exhibit therapeutic properties against multiple inflammatory illnesses, comprising arthritis, asthma, diabetes, inflammatory bowel disease, and different malignancies. There are growing shreds of evidence that Boswellia extracts and their phytoconstituents could be used in adjuvant and combinatorial chemotherapeutic approaches for the management and prevention of cancer. Aim: The principal objective of this comprehensive investigation is to offer up-to-date and in-depth insights into the anticancer potential of boswellic acids along with their semisynthetic analog that are novel and preventive/therapeutic substitutes for the management of cancer and inflammatory diseases due to their strong potential. Materials and Methods: In the course of this review, a comprehensive compilation of In-vitro, Invivo, and clinical evidence on the antineoplastic potential of boswellic acids was assembled through systematic computerized searches utilizing platforms such as Google Scholar, PubMed, Sci-Hub, and Research Gate. Result: Boswellic acids, the key compounds found in the resin of nearly all the species of the Boswellia plant, have been reported to exhibit therapeutic effects by modulating various targets in different disease conditions. Moreover, semisynthetic derivatives of boswellic acids show strong cytotoxic effects, particularly those with cyanoenone moieties, endoperoxides, and hybrids, which exhibit enhanced potency. Conclusion: In this review, we have sincerely highlighted the effectiveness of novel boswellic acids as alternative preventive and therapeutic agents for the treatment of cancer and inflammatory conditions. Their strong anticancer potential could provide a basis for promising future direction to develop potent anticancer drugs for human malignancies.