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Ziziphus mauritana Lam leaves were used to treat asthma, diabetes, pain, and inflammation in the Indian traditional system of medicine. The leaves of the Ziziphus mauritiana Lam were consumed as a vegetable in Indonesia and India. The present study aims to predict the pharmacokinetic properties of flavonoids identified & quantified through U(H)PLC and to evaluate the safety of methanol extract of Ziziphus mauritana Lam leaves (MEZ) in rats. A U(H)PLC-ESI-QTOF-MS/MS was performed to identify flavonoids present in MEZ and quantified using U(H)PLC method. The in-silico ADME properties of the flavonoids were analyzed using Schrodinger Maestro software. The acute oral toxicity study was performed by administering a single dose of MEZ (5000 mg/kg) in female rats and observed for 14 days. The sub-chronic studies were carried out by oral administration of MEZ at 500, 750, and 1000 mg/kg daily for 90 days. The changes in hematological parameters, clinical biochemistry, and histopathology were observed after the treatment period. Eight flavonoids rutin, kaempferol, luteolin, myricetin, catechin, and apigenin were identified from were identified in UPLC-QTOF-MS/MS analysis. These results showed the highest amount of luteolin (5.41 µg/ml) and kaempferol (4.02 µg/ml) present in MEZ. No signs of toxicity or mortality were observed in acute toxicity studies. In the sub-chronic studies, data showed that MEZ does not produce any changes in hematological and clinical biochemical parameters compared to control rats. MEZ (1000 mg/kg) significantly (p < 0.05) reduced total cholesterol, triglycerides, in male rats, which was more prominent on day 90. The histopathological analysis also revealed no changes in the vital organs. These results conclude that MEZ was considered safe and well-tolerated in rats.
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Ziziphus , Animales , Femenino , Flavonoides/toxicidad , Quempferoles/análisis , Luteolina/análisis , Masculino , Metanol , Extractos Vegetales/química , Extractos Vegetales/toxicidad , Hojas de la Planta/química , Ratas , Estándares de Referencia , Espectrometría de Masas en Tándem , Ziziphus/químicaRESUMEN
Novel chemotherapeutic agents against multidrug resistant-tuberculosis (MDR-TB) are urgently needed at this juncture to save the life of TB-infected patients. In this work, we have synthesized and characterized novel isatin hydrazones 4(a-o) and their thiomorpholine tethered analogues 5(a-o). All the synthesized compounds were initially screened for their anti-mycobacterial activity against the H37Rv strain of Mycobacterium tuberculosis (MTB) under level-I testing. Remarkably, five compounds 4f, 4h, 4n, 5f and 5m (IC50 = 1.9 µM to 9.8 µM) were found to be most active, with 4f (IC50 = 1.9 µM) indicating highest inhibition of H37Rv. These compounds were further evaluated at level-II testing against the five drug-resistant strains such as isoniazid-resistant strains (INH-R1 and INH-R2), rifampicin-resistant strains (RIF-R1 and RIF-R2) and fluoroquinolone-resistant strain (FQ-R1) of MTB. Interestingly, 4f and 5f emerged as the most potent compounds with IC50 of 3.6 µM and 1.9 µM against RIF-R1 MTB strain, followed by INH-R1 MTB strain with IC50 of 3.5 µM and 3.4 µM, respectively. Against FQ-R1 MTB strain, the lead compounds 4f and 5f displayed excellent inhibition at IC50 5.9 µM and 4.9 µM, respectively indicating broad-spectrum of activity. Further, molecular docking, ADME pharmacokinetic and molecular dynamics simulations of the compounds were performed against the DNA gyrase B and obtained encouraging results.
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Antituberculosos/farmacología , Farmacorresistencia Bacteriana Múltiple/efectos de los fármacos , Hidrazonas/química , Isatina/química , Morfolinas/química , Mycobacterium tuberculosis/efectos de los fármacos , Antituberculosos/química , Antituberculosos/metabolismo , Sitios de Unión , Supervivencia Celular/efectos de los fármacos , Girasa de ADN/química , Girasa de ADN/metabolismo , Diseño de Fármacos , Semivida , Humanos , Hidrazonas/metabolismo , Hidrazonas/farmacología , Pruebas de Sensibilidad Microbiana , Simulación del Acoplamiento Molecular , Rifampin/farmacología , Relación Estructura-ActividadRESUMEN
Two series of carbazole analogs of 8-methoxy-N-substituted-9H-carbazole-3-carboxamides (series 1) and carbazolyl substituted rhodanines (series 2) were synthesized through facile synthetic routes. All the final compounds from these two series were evaluated for their preliminary inâ vitro antifungal and antibacterial activity against four fungal (Candida albicans, Cryptococcus neoformans, Cryptococcus tropicalis and Aspergillus niger) and four bacterial (Staphylococcus aureus, Bacillus subtilis, Escherichia coli and Pseudomonas aeruginosa) strains, respectively. Among the tested compounds, three compounds of series 1 displayed promising antifungal and antibacterial activity, especially against C. neoformans and S. aureus. In addition, one compound of series 1 displayed notable antimicrobial activity (MIC: 6.25â µg/mL) against clinical isolates of C. albicans and C. neoformans (MIC: 12.5â µg/mL). From the second series, four compounds exhibited significant antifungal and antibacterial activity, especially against C. neoformans and S. aureus. The most active compound of series 2 displayed a prominent antimicrobial activity against C. neoformans (MIC: 3.125â µg/mL) and S. aureus (MIC: 1.56â µg/mL), respectively.
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Antibacterianos/farmacología , Antifúngicos/farmacología , Carbazoles/farmacología , Antibacterianos/síntesis química , Antibacterianos/química , Antifúngicos/síntesis química , Antifúngicos/química , Aspergillus niger/efectos de los fármacos , Bacillus subtilis/efectos de los fármacos , Candida albicans/efectos de los fármacos , Carbazoles/síntesis química , Carbazoles/química , Cryptococcus/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Escherichia coli/efectos de los fármacos , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Pseudomonas aeruginosa/efectos de los fármacos , Staphylococcus aureus/efectos de los fármacos , Relación Estructura-ActividadRESUMEN
InhA (Enoyl-ACP reductase) plays a crucial role in the biosynthetic pathway of cell wall synthesis in Mycobacterium tuberculosis (Mtb). Isoniazid (INH) is an important first-line drug, which inhibits InhA. The rapid increase in resistance to INH and currently marketed drugs as well as emergence of MDR-TB and XDR-TB has complicated the diagnosis and treatment of Mtb with ever increasing threat to human kind. Herein, we report novel N-methyl carbazole derivatives as potential anti-TB compounds acting directly via InhA inhibition. All the synthesized final compounds were screened against Mtb virulent cell line H37Rv and investigated the InhA enzyme inhibition. Interestingly, compound 9e displayed promising inhibition (91%) at 50⯵M concentration and IC50 of 2.82⯵M against InhA. To understand the ligand receptor interaction between compound 9e and InhA, molecular docking and molecular dynamics experiments were performed. The computational results were in agreement with the observed experimental data. Further, the cytotoxicity studies on mammalian cells revealed that all the compounds were safe.
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Antituberculosos/farmacología , Carbazoles/farmacología , Descubrimiento de Drogas , Mycobacterium tuberculosis/efectos de los fármacos , Rodanina/farmacología , Antituberculosos/síntesis química , Antituberculosos/química , Carbazoles/química , Relación Dosis-Respuesta a Droga , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Mycobacterium tuberculosis/enzimología , Rodanina/química , Relación Estructura-ActividadRESUMEN
A novel series of 1,3,4-thiadiazole-thiazolone hybrids 5a-v were designed, synthesized, characterized, and evaluated against the basal and the microtubule (MT)-stimulated ATPase activity of Eg5. From the evaluated derivatives, 5h displayed the highest inhibition with an IC50 value of 13.2⯵M against the MT-stimulated Eg5 ATPase activity. Similarly, compounds 5f and 5i also presented encouraging inhibition with IC50 of 17.2⯵M and 20.2⯵M, respectively. A brief structure-activity relationship (SAR) analysis indicated that 2-chloro and 4-nitro substituents on the phenyl ring of the thiazolone motif contributed significantly to enzyme inhibition. An in silico molecular docking study using the crystal structure of Eg5 further supported the SAR and reasoned the importance of crucial molecular protein-ligand interactions in influencing the inhibition of the ATPase activity of Eg5. The magnitude of the electron-withdrawing functionalities over the hybrids and the critical molecular interactions contributed towards higher in vitro potency of the compounds. The drug-like properties of the synthesized compounds 5a-v were also calculated based on the Lipinski's rule of five and in silico computation of key pharmacokinetic parameters (ADME). Thus, the present work unveils these hybrid molecules as novel Eg5 inhibitors with promising drug-like properties for future development.
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Diseño de Fármacos , Cinesinas/antagonistas & inhibidores , Tiadiazoles/farmacología , Tiazoles/farmacología , Adenosina Trifosfatasas/metabolismo , Relación Dosis-Respuesta a Droga , Humanos , Cinesinas/metabolismo , Microtúbulos/metabolismo , Estructura Molecular , Relación Estructura-Actividad , Tiadiazoles/química , Tiazoles/químicaRESUMEN
Pyrazolo[4,3-d]pyrimidine, a fused heterocycle bearing pyrazole and pyrimidine portions has gained a significant attention in the field of bioorganic and medicinal chemistry. Pyrazolo[4,3-d]pyrimidine derivatives have demonstrated numerous pharmacological activities particularly, anti-cancer, anti-infectious, phosphodiesterase inhibitors, adenosine antagonists and cytokinin antagonists etc. This review extensively unveils the synthetic and pharmacological diversity with special emphasis on structural variations around pyrazolo[4,3-d]pyrimidine scaffold. This endeavour has thus uncovered the medicinal worthiness of pyrazolo[4,3-d]pyrimidine framework. To the best of our knowledge this review is the first compilation on synthetic, medicinal and structure activity relationship (SAR) aspects of pyrazolo[4,3-d]pyrimidines since 1956.
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Antiinfecciosos/farmacología , Antineoplásicos/farmacología , Inhibidores Enzimáticos/farmacología , Neoplasias/tratamiento farmacológico , Pirazoles/farmacología , Pirimidinas/farmacología , Adenosina/antagonistas & inhibidores , Adenosina/metabolismo , Antiinfecciosos/síntesis química , Antiinfecciosos/química , Antineoplásicos/síntesis química , Antineoplásicos/química , Citocininas/antagonistas & inhibidores , Citocininas/metabolismo , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Humanos , Estructura Molecular , Hidrolasas Diéster Fosfóricas/metabolismo , Pirazoles/síntesis química , Pirazoles/química , Pirimidinas/síntesis química , Pirimidinas/químicaRESUMEN
A novel series of 4,6-disubstituted pyrazolo[3,4-d]pyrimidines (7-43) bearing various anilines at C-4 position and thiophenethyl or thiopentane moieties at C-6 position have been designed and synthesized by molecular hybridization approach. All the synthesized compounds were evaluated for in vitro CDK2/cyclin E and Abl kinase inhibitory activity as well as anti-proliferative activity against K-562 (chronic myelogeneous leukemia), and MCF-7 (breast adenocarcinoma) cell lines. The structure-activity relationship (SAR) studies revealed that compounds with thiophenethyl group at C-6 with mono-substituted anilines at C-4 exhibited better CDK2 inhibitory activity compared to alkyl group (thiopentane) at C-6 and di-substituted anilines at C-4 of the scaffold. In particular, compounds having 2-chloro, 3-nitro and 4-methylthio aniline groups at C-4 displayed significant enzymatic inhibitory activity against CDK2 with single digit micromolar IC50 values. The in silico molecular docking studies suggested possible binding orientation and the binding energies were in agreement with the observed SAR as well as experimental results. In addition, some of the synthesized compounds showed anti-proliferative effects against K-562 and MCF-7 cancer cell lines with IC50 values in a micromolar range. Thus, the synthesized compounds could be considered as new anticancer hits for further lead optimization.
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Antineoplásicos/farmacología , Quinasa 2 Dependiente de la Ciclina/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/farmacología , Pirazoles/farmacología , Pirimidinas/farmacología , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Dominio Catalítico , Línea Celular Tumoral , Quinasa 2 Dependiente de la Ciclina/química , Diseño de Fármacos , Humanos , Simulación del Acoplamiento Molecular , Estructura Molecular , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Pirazoles/síntesis química , Pirazoles/química , Pirimidinas/síntesis química , Pirimidinas/química , Spodoptera , Relación Estructura-ActividadRESUMEN
Pesticides are chemical substances of natural or synthetic origin that are used to eradicate pests and insects. These are indispensable in the agricultural processes for better crop production. Pesticide use aims to promote crop yield and protect the crops from diseases and damage. Pesticides must be handled carefully and disposed of appropriately because they are dangerous to people and other species by default. Environmental pollution occurs when pesticide contamination spreads away from the intended plants. Older pesticides such as lindane and dichlorodiphenyltrichloroethane (DDT) may remain in water and soil for a longer time. These accumulate in various parts of the food chain and cause damage to the ecosystem. Biological techniques in the management of pest control such as importation, augmentation, and conservation, and the accompanying procedures are more efficient, less expensive, and ecologically sound than other ways. This review mainly focuses on the consequences on the targeted and non-targeted organisms including the health and well-being of humans by the use of pesticides and their toxicity. The side effects that occur when a pesticide's LD50 exceeds the accepted limit through oral or skin penetration due to their binding to various receptors such as estrogen receptors, GABA, EGFR, and others. These pesticide classes include carbamates, pyrethroids, organochlorides, organophosphorus, and others. The current study seeks to highlight the urgent requirement for a novel agricultural concept that includes a major reduction in the use of chemical pesticides.
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Plaguicidas , Piretrinas , Humanos , Plaguicidas/análisis , Ecosistema , Contaminación Ambiental , Productos AgrícolasRESUMEN
Exosomes are a subgroup of extracellular vesicles that function as transmitters, allowing cells to communicate more effectively with each other. However, exosomes may have both beneficial and harmful impacts on central nervous system disorders. Hence, the fundamental molecular mechanisms of the origin of illness and its progression are currently being investigated. The involvement of exosomes in the origin and propagation of neurodegenerative illness has been demonstrated recently. Exosomes provide a representation of the intracellular environment since they include various essential bioactive chemicals. The latest studies have demonstrated that exosomes transport several proteins. Additionally, these physiological vesicles are important in the regeneration of nervous tissue and the healing of neuronal lesions. They also offer a microenvironment to stimulate the conformational variation of concerning proteins for aggregation, resulting in neurodegenerative diseases. The biosynthesis, composition, and significance of exosomes as extracellular biomarkers in neurodegenerative disorders are discussed in this article, with a particular emphasis on their neuroprotective effects.
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Exosomas , Enfermedades Neurodegenerativas , Exosomas/metabolismo , Humanos , Enfermedades Neurodegenerativas/metabolismo , Enfermedades Neurodegenerativas/patología , Animales , Biomarcadores/metabolismo , Comunicación Celular/fisiologíaRESUMEN
The arrival of comprehensive genome sequencing has accelerated the understanding of genetically aberrant advanced cancers and target identification for possible cancer treatment. Fibroblast growth factor receptor (FGFR) gene alterations are frequent findings in various rare and advanced cancers refractive to mainstay chemo-therapy or surgical interventions. Several FGFR inhibitors have been developed for addressing these genetically altered FGFR-harboring malignancies, and some have performed well in clinical trials. In contrast, others are still being investigated in different phases of clinical trials. FDA has approved four anticancer agents such as erdafitinib, pemigatinib, infigratinib, and futibatinib, for clinical use in oncogenic FGFR-driven malignancies. These include cholangiocarcinoma, urothelial carcinoma, and myeloid/lymphoid malignancies. Pemigatinib is the only FGFR inhibitor globally approved (USA, EU, and Japan) and available as a targeted therapy for two types of cancer, including FGFR2 fusion or other rearrangements harboring cholangiocarcinoma and relapsed/refractory myeloid/lymphoid neoplasms with FGFR1 rearrangements. Myeloid/lymphoid neoplasm is the latest area of application added to the therapeutic armamentarium of FGFR inhibitors. Furthermore, futibatinib is the first-in-class covalent or irreversible pan-FGFR inhibitor that has received FDA approval for locally advanced or metastatic intrahepatic cholangiocarcinoma harboring FGFR2 gene aberrations. This review highlights the current clinical progress concerning the safety and efficacy of all the approved FGFR-TKIs (tyrosine kinase inhibitors) and their ongoing investigations in clinical trials for other oncogenic FGFR-driven malignancies.
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Neoplasias de los Conductos Biliares , Carcinoma de Células Transicionales , Colangiocarcinoma , Neoplasias de la Vejiga Urinaria , Humanos , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Colangiocarcinoma/tratamiento farmacológico , Colangiocarcinoma/genética , Conductos Biliares Intrahepáticos/patologíaRESUMEN
Background: Alchornea laxiflora (Benth.) Pax & K. Hoffm. (A. laxiflora) has been indicated in traditional medicine to treat depression. However, scientific rationalization is still lacking. Hence, this study aimed to investigate the antidepressant potential of A. laxiflora using network pharmacology and molecular docking analysis. Materials and methods: The active compounds and potential targets of A. laxiflora and depression-related targets were retrieved from public databases, such as PubMed, PubChem, DisGeNET, GeneCards, OMIM, SwissTargetprediction, BindingDB, STRING, and DAVID. Essential bioactive compounds, potential targets, and signaling pathways were predicted using in silico analysis, including BA-TAR, PPI, BA-TAR-PATH network construction, and GO and KEGG pathway enrichment analysis. Later on, with molecular docking analysis, the interaction of essential bioactive compounds of A. laxiflora and predicted core targets of depression were verified. Results: The network pharmacology approach identified 15 active compounds, a total of 219 compound-related targets, and 14,574 depression-related targets with 200 intersecting targets between them. SRC, EGFR, PIK3R1, AKT1, and MAPK1 were the core targets, whereas 3-acetyloleanolic acid and 3-acetylursolic acid were the most active compounds of A. laxiflora with anti-depressant potential. GO functional enrichment analysis revealed 129 GO terms, including 82 biological processes, 14 cellular components, and 34 molecular function terms. KEGG pathway enrichment analysis yielded significantly enriched 108 signaling pathways. Out of them, PI3K-Akt and MAPK signaling pathways might have a key role in treating depression. Molecular docking analysis results exhibited that core targets of depression, such as SRC, EGFR, PIK3R1, AKT1, and MAPK1, bind stably with the analyzed bioactive compounds of A. laxiflora. Conclusion: The present study elucidates the bioactive compounds, potential targets, and pertinent mechanism of action of A. laxiflora in treating depression. A. laxiflora might exert an antidepressant effect by regulating PI3K-Akt and MAPK signaling pathways. However, further investigations are required to validate.
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A series of novel pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidine derivatives 5 was prepared from 2-amino-3-cyano-4-trifluoromethyl-6-phenylpyridine 1 in two steps via formation of iminoether 3 followed by reaction with different aroylhydrazides 4. Representative products 5 were evaluated for their affinity towards all four subtypes of human adenosine receptors. Compounds 2-(3-fluorophenyl)-8-phenyl-10-(trifluoromethyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidine (5b), 2-(furan-2-yl)-8-phenyl-10-(trifluoromethyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidine (5d), and 2-(furan-2-yl)-5-methyl-8-phenyl-10-(trifluoromethyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidine (5j) showed high affinity for the A3 receptors, with Ki values of 8.1, 10.4, and 12.1 nM, respectively, and were >1000-fold selective versus all other adenosine receptor subtypes.
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Antagonistas del Receptor de Adenosina A3/farmacología , Pirimidinas/farmacología , Receptor de Adenosina A3/efectos de los fármacos , Antagonistas del Receptor de Adenosina A3/síntesis química , Antagonistas del Receptor de Adenosina A3/química , Animales , Humanos , Pirimidinas/síntesis química , Pirimidinas/química , Ratas , Receptor de Adenosina A3/metabolismo , Receptores Purinérgicos P1/efectos de los fármacos , Receptores Purinérgicos P1/metabolismoRESUMEN
The purpose of this work was to develop a novel topical formulation of econazole nitrate based on gel that can be easily scaled up in one pot for the potential treatment of fungal and yeast infections. Econazole nitrate, a topical antifungal, is used to treat tinea versicolor, tinea pedis, and tinea cruris. Compared to applying cream or ointment, topical gels offer numerous advantages, one of which is that the drug is released more quickly to the intended site of action. A viscous mixture of propylene glycol, Capmul® MCM C8, methyl and propyl paraben, and econazole nitrate were mixed together before being formulated into the optimized Carbopol® gel bases. The gel's color, appearance, and homogeneity were assessed visually. For every formulation, the drug content, pH, viscosity, spreadability, and gel strength were characterized. The cup plate diffusion method was used to evaluate the anti-fungal activity of the prepared formulations. To assess the behavior of the developed system, studies on in vitro release and mechanism were conducted. The manufactured formulations were transparent, pale yellow, and exhibited excellent homogeneity. The pH of each formulation was roughly 6.0, making them suitable for topical use. The concentration of Carbopol® 940 resulted in a significant increase in viscosity and gel strength but a significant decrease in spreadability. It was demonstrated that the prepared formulations inhibited the growth of Candida albicans and Aspergillus fumigatus. In contrast, the standard blank gel showed no signs of antifungal action. By increasing the concentration of Carbopol® 940, the in vitro release profile of econazole nitrate significantly decreased. Following the Korsmeyer-Peppas model fitting, all formulations exhibited n values greater than 0.5 and less than 1, indicating that diffusion and gel swelling control econazole nitrate release.
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The present work aimed to formulate and evaluate a polyherbal gel using Aloe barbadensis and extract of Vigna radiata for the treatment of acne, a disorder of the skin in which hair follicles and sebaceous glands are blocked, causing inflammation and redness of the skin. Aloe barbadensis pulp was collected and mixed with the extract of Vigna radiata and formulated into a gel using Carbopol 940, triethanolamine, and propylene glycol as the gelling agent, viscosity modifier, and pH modifier, respectively. The gel was evaluated for its antimicrobial properties against Staphylococcus aureus, Escherichia coli, and Candida albicans. Antimicrobial agents, such as gentamycin and fluconazole, were used as the standards. The developed formulation showed promising zone of inhibition. The gel was further evaluated for its physicochemical properties. The formulation showed a promising effect on acne together with the additive effect of Aloe barbadensis on skin.
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A promising controlled drug delivery system has been developed based on polymeric buccoadhesive bilayered formulation that uses a drug-free backing layer and a polymeric hydrophilic gel buccoadhesive core layer containing nifedipine. The DSC thermogravimetric analysis confirms the drug's entrapment in the gel layer and reveals no evidence of a potential interaction. Various ratios of bioadhesive polymers, including HPMC K100, PVP K30, SCMC, and CP 934, were combined with EC as an impermeable backing layer to ensure unidirectional drug release towards the buccal mucosa. The polymeric compositions of hydrophilic gel-natured HPMC, SCMC, and CP formed a matrix layer by surrounding the core nifedipine during compression. Preformulation studies were performed for all of the ingredients in order to evaluate their physical and flow characteristics. Ex vivo buccoadhesive strength, surface pH, swelling index, in vitro and in vivo drug release, and ex vivo permeation investigations were performed to evaluate the produced gel-based system. Rapid temperature variations had no appreciable impact on the substance's physical properties, pharmacological content, or buccoadhesive strength during stability testing using actual human saliva. It was clear from a histological examination of the ex vivo mucosa that the developed system did not cause any irritation or inflammation at the site of administration. The formulation NT5 was the best one, with a correlation coefficient of 0.9966. The in vitro and in vivo drug release profiles were well correlated, and they mimic the in vitro drug release pattern via the biological membrane. Thus, the developed gel-based formulation was found to be novel, stable, and useful for the targeted delivery of nifedipine.
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Cancer is one of the most common causes of death. So, its lethal effect increases with time. Near about hundreds of cancers are known in humans. Cancer treatment is done to cure or prolonged remission, and shrinkage of the tumor. Cytotoxic agents, biological agents/targeted drugs, hormonal drugs, surgery, radiotherapy/proton therapy, chemotherapy, immunotherapy, and gene therapy are currently used in the treatment of cancer but their cost is high and cause various side effects. Seeing this, some new targeted strategies such as PROTACs are the need of the time. Proteolysis targeting chimera (PROTAC) has become one of the most discussed topics regarding cancer treatment. Few of the PROTAC molecules are in the trial phases. PROTACs have many advantages over other strategies such as modularity, compatibility, sub-stoichiometric activity, acting on undruggable targets, molecular design, and acts on intracellular targets, selectivity and specificity can be recruited for any cancer, versatility, and others. PROTACs are having some unclear questions on their pharmacokinetics, heavy-molecular weight, etc. PROTACs are anticipated to bring about a conversion in current healthcare and will emerge as booming treatments. In this review article we summarize PROTACs, their mechanism of action, uses, advantages, disadvantages, challenges, and future aspects for the successful development of potent PROTACs as a drug strategy.
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Neoplasias , Ubiquitina-Proteína Ligasas , Humanos , Proteolisis , Ubiquitina-Proteína Ligasas/metabolismo , Quimera Dirigida a la Proteólisis , Ubiquitinación , Neoplasias/tratamiento farmacológicoRESUMEN
The nature of microorganisms and the efficiency of antimicrobials have witnessed a huge co-dependent change in their dynamics over the last few decades. On the other side, metals and metallic compounds have gained popularity owing to their effectiveness against various microbial strains. A structured search of both research and review papers was conducted via different electronic databases, such as PubMed, Bentham, Springer, and Science Direct, among others, for the present review. Along with these, marketed products, patents, and Clinicaltrials.gov were also referred to for our review. Different microbes such as bacteria, fungi, etc., and their diverse species and strains have been reviewed and found to be sensitive to metal-carrying formulations. The products are observed to restrict growth, multiplication, and biofilm formation effectively and adequately. Silver has an apt use in this area of treatment and recovery, and other metals like copper, gold, iron, and gallium have also been observed to generate antimicrobial activity. The present review identified membrane disruption, oxidative stress, and interaction with proteins and enzymes to be the primary microbicidal processes. Elaborating the action, nanoparticles and nanosystems are shown to work in our favor in well excelled and rational ways.
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Severe cases of COVID-19 are characterized by hyperinflammation induced by cytokine storm, ARDS leading to multiorgan failure and death. JAK-STAT signaling has been implicated in immunopathogenesis of COVID-19 infection under different stages such as viral entry, escaping innate immunity, replication, and subsequent inflammatory processes. Prompted by this fact and prior utilization as an immunomodulatory agent for several autoimmune, allergic, and inflammatory conditions, Jakinibs have been recognized as validated small molecules targeting the rapid release of proinflammatory cytokines, primarily IL-6, and GM-CSF. Various clinical trials are under investigation to evaluate Jakinibs as potential candidates for treating COVID-19. Till date, there is only one small molecule Jakinib known as baricitinib has received FDA-approval as a standalone immunomodulatory agent in treating critical COVID-19 patients. Though various meta-analyses have confirmed and validated the safety and efficacy of Jakinibs, further studies are required to understand the elaborated pathogenesis of COVID-19, duration of Jakinib treatment, and assess the combination therapeutic strategies. In this review, we highlighted JAK-STAT signalling in the pathogenesis of COVID-19 and clinically approved Jakinibs. Moreover, this review described substantially the promising use of Jakinibs and discussed their limitations in the context of COVID-19 therapy. Hence, this review article provides a concise, yet significant insight into the therapeutic implications of Jakinibs as potential anti-COVID agents which opens up a new horizon in the treatment of COVID-19, effectively.
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Conventional oral formulations are mainly absorbed in the small intestine. This limits their use in the treatment of some diseases associated with the colon, where the drug has to act topically at the inflammation site. This paved the way for the development of a smart colonic drug delivery system, thereby improving the therapeutic efficacy, reducing the dosing frequency and potential side effects, as well as improving patient acceptance, especially in cases where enemas or other topical preparations may not be effective alone in treating the inflammation. In healthy individuals, it takes an oral medication delivery system about 5 to 6 h to reach the colon. A colonic drug delivery system should delay or prohibit the medication release during these five to six hours while permitting its release afterward. The main aim of this study was to develop a smart drug delivery system based on pH-sensitive polymeric formulations, synthesized by a free-radical bulk polymerization method, using different monomer and crosslinker concentrations. The formulations were loaded with 5-amino salicylic acid as a model drug and Capmul MCM C8 as a bioavailability enhancer. The glass transition temperature (Tg), tensile strength, Young's modulus, and tensile elongation at break were all measured as a part of the dried films' characterization. In vitro swelling and release studies were performed to assess the behavior of the produced formulations. The in vitro swelling and release evaluation demonstrated the potential ability of the developed system to retard the drug release at conditions mimicking the stomach and small intestine while triggering its release at conditions mimicking the colon, which indicates its promising applicability as a potential smart colonic drug delivery system.