A significant advancement in contemporary healthcare is the introduction of biosimilars into the pharmaceutical sector. Because they are physiologically identical to reference biological products, biosimilars offer a more affordable option for the treatment of serious chronic illnesses such multiple sclerosis, diabetes, cancer, and autoimmune diseases. Biosimilars must exhibit similar efficacy, safety, and quality to the reference biologics despite differences in production methods. In the United States, regulatory frameworks like the Biologics Price Competition and Innovation Act (BPCIA) of 2009 have streamlined the biosimilar approval process, promoting competition and possibly lowering healthcare costs. Nevertheless, negotiating the patent landscape remains challenging due to the intricate “patent dance” litigation process and exclusivity periods for original biologics. Biosimilars also encounter competition from biobetters, improved biologics versions, and non-original biologics in less regulated markets.Recent technologies such as artificial intelligence (AI) and big data analytics are reshaping biosimilar development by enhancing clinical trial efficiency and product accuracy. Manufacturers are increasingly concentrating on biosimilars, driven by strategic partnerships, regulatory advancements, and the potential for substantial cost savings. Despite challenges like regulatory complexity and market competition, biosimilars are positioned to have a crucial role in widening patient access to essential therapies while fostering innovation in pharmaceutical sector.
This study adopted a preclinical model to develop and evaluate the photoprotective efficacy of nanoemulsions (NEs) containing Robusta green coffee extract (GCE) and linseed oil (LO) against UVB-induced skin damage. The GCE, rich in polyphenols and caffeine, demonstrated antioxidant activity in vitro. The LO met quality standards based on physicochemical analyses (peroxide, acid, and saponification values), confirming its suitability for formulation. Using Chremophor® RH 40 and Span® 80 as surfactants yielded stable and nanometric NEs, since both the control with only LO (NE-C) and the NEs loaded with GCE at concentrations of 0.25% (NE-0.25), 0.5% (NE-0.5), and 1.0% (NE-1.0) showed D50 < 90 nm, PDI ≤ 0.2, and ZP < -26.0 mV. Morphological studies confirmed a spherical shape and uniform droplet distribution, with no aggregation. Moreover, all NEs presented a pH of around 5, compatible with human skin. The NEs were topically applied to the dorsal skin of hairless mice before and after UVB exposure. Besides being well tolerated following an acute irritation test, NE-0.25 markedly reduced neutrophil migration (49%) while recovering the skin antioxidant capacity (catalase activity and reduced glutathione levels) to near-baseline values within 12 h of UVB exposure, thus highlighting its potential as a skin anti-aging strategy.
This study aimed to develop and evaluate a floating oral in situ gel with leflunomide (LEF) as a liquid gastro-retentive drug delivery system to increase the residence time of the drug in the stomach and sustain drug delivery. Floating in situ gel system of leflunomide was prepared using sodium alginate as a gelling polymer, calcium carbonate as floating agent and different polymers to extended release. The physicochemical properties of in situ gels of leflunomide were in the acceptable range. An analysis of the release kinetics showed that the drug release followed a zero order, except for the formula containing hydroxypropylmethylcellulose (HPMC), which followed Higuchi’s model. Formula (F2) (0.4% HPMC K100M) was considered the best formulation as it had a minimum FLT (36 sec), optimum viscosity (230.5 cps), optimum drug release (97.34%) after 24 h, and the highest t90 value (205.17 days). Therefore, formula (F2) was chosen for further ex-vivo and bioavailability studies. The pharmacokinetic parameters were compared to those of commercially tablets (Apetoid®), and F2 exhibited a relative bioavailability of 197.73%. The prepared floating in situ gel system is a novel approach which indicate a remarkable increase in the residence time of LEF in the stomach and sustain its delivery.
This study aims to optimize the process of extrusion spheronization for the development of rifaximin pellets and target them to the colon. Microcrystalline cellulose (MCC) is used to spheronizing aid in formulating pellets. MCC concentration, water content, spheronization speed, and time were optimized against roundness and % usable yield using Box-Behnken design. Coating levels of both the polymers were optimized using central composite design for drug release at 2, 4, 7, and 12 h at pH levels of 1.2, 6.8, 7.4, and 6.8 respectively. A gamma scintigraphy study helps in identifying transit pattern of coated pellets in GIT. Optimal conditions for rifaximin pellets with the desired pellet characteristics were identified as 34.19% MCC, 8.6% water, 1004 rpm, and 5.12 minutes. The observed values for drug release at 2, 4, 7, and 12 h at the aforesaid pH conditions were 0.17±0.00%, 3.08±0.13%, 39.01±1.17%, and 99.37±2.73%, respectively. This shows strong concordance between the observed and predicted values. The average durations for colon arrival, small intestine transit, and stomach emptying were 6.26±0.142 h, 5.72±0.408 h, and 0.70±0.265 h, respectively. This shows that the higher number of pellets reaches the colon in the desired time period. The study concluded with the development of optimized pellets and gamma scintigraphy confirms that the coating improves colonic rifaximin delivery.
Gastrointestinal problems are common and affect quality of life, leading patients to seek treatment. Safe pharmaceutical prescribing and health education are essential to ensure quality healthcare, but require evidence-based training. The aim of this study was to evaluate the development of clinical skills for the management of five gastrointestinal issues by pharmacists and students in a training course. This is a quasi-experimental study carried out with participants in a minor illness scheme training course. The course included classes with specialists, theoretical assessments and initial and final practical simulations. After applying the eligibility criteria, 17 participants were selected for the study. In the knowledge analysis, the topics that progressed the most were diarrhea and nausea and vomiting, in which the participants' confidence level increased significantly in the final evaluations. In addition, in the behavioral analysis there was a 70% progression, with better scores for diarrhea and aphthous stomatitis. The clinical guidelines-based course proved to be a viable strategy for promoting knowledge and confidence in the management of gastrointestinal problems. Researchers can comprehensively explore the domains involved in the formation of competencies and skills necessary for clinical practice.
ABCB1 gene polymorphisms have been associated with drug-resistant epilepsy (DRE). This integrative review evaluates the impact of key ABCB1 single nucleotide polymorphisms (SNPs)- C3435T (rs1045642), G2677T/A (rs2032582), and C1236T (rs1128503)-on the pharmacokinetics and therapeutic response to antiseizure medications (ASMs), including carbamazepine (CBZ), lamotrigine (LTG), and topiramate (TPM). Evidence suggests that these polymorphisms significantly affect CBZ and LTG efficacy by altering drug pharmacokinetics and increasing systemic exposure. In contrast, no consistent association has been observed between these variants and TPM response. These findings support the integration of pharmacogenetic information into clinical decisionmaking to optimize ASM therapy and reduce the risk of drug resistance in epilepsy management.
The leaves of Aegle marmelos (AML) and Bryophyllum pinnatum (BPL), and unripe fruit peels of Carica papaya (CPFP) are traditionally used, either alone or in combination, to treat inflammatory conditions, without substantial scientific evidence. Therefore, this study aimed to investigate their phytochemical constituents and anti-inflammatory activities. Petroleum ether, chloroform, and methanol extracts were prepared by sequential extraction and subjected to qualitative and quantitative phytochemical analyses. The extracts were screened for in vitro free radical scavenging and anti-inflammatory activities. The extracts showing higher activities were tested at 125, 250, and 500 mg/ kg doses for anti-inflammatory activity using carrageenan-, CFA-, and potassium oxonate-induced inflammation models. The three plants’ methanol extracts showed comparatively higher flavonoids, polyphenols, and glycosaponins contents. The same extracts showed higher antioxidant and anti-inflammatory activities (p < 0.05). The anti-inflammatory activity was dose-dependent, along with restoration of morphology and histology of the inflamed tissues. The current study’s findings provide chemical composition and evidence for these folklore medicinal plants in treating inflammatory conditions like arthritis and gout. These studies suggest bioassay-guided isolation of these ingredients.
Prostate cancer changes from an androgen-dependent to an independent type during its progression, and metastasis greatly limits treatment options and survival rates. Matrix metalloproteinases (MMPs) play an essential role in inflammation, malignant cell proliferation, invasion, and metastasis by inducing matrix degradation. Endogenous tissue inhibitors of MMPs (TIMPs) limit the activities of MMPs. The integrin signalling regulates cancer cell adhesion, proliferation, and migration by promoting MMP activation. Clinoptilolite is a micronized type of zeolite, which is a hydrated aluminosilicate. It is used as a chelation and detoxification agent to remove heavy metals from the body. This study investigated the effects of clinoptilolite on the expression and/or activity of gelatinases (MMP-2/MMP-9), MMP-14, TIMP-2, and αvβ1 integrin in PC3 cells. PC3 cells were incubated with/without clinoptilolite (25 mg/ml) for 24 h. The expression and/or activity of MMP-2 and MMP-9 were determined by gelatin zymography. The expression levels of MMP-14, TIMP-2, and αvβ1 were examined by immunostaining. Clinoptilolite inhibited MMP-2 activity and MMP-14 expression while up-regulating TIMP-2 expression, and it decreased MMP-2/TIMP-2 and MMP-14/ TIMP-2 ratios, which are critical for MMP/TIMP balance. Clinoptilolite also down-regulated αvβ1 integrin expression. Clinoptilolite may be useful in prostate cancer treatment due to its αvβ1 integrin-mediated MMP inhibitory effects.
Diltiazem hydrochloride (DH) is a calcium channel blocker used to modify or restore normal heart rhythm in cardiovascular diseases. The aim of this study was to develop and validate a new innovative method using UV molecular absorption spectrophotometry to evaluate the in vitro dissolution of DH using a factorial design of experiments. Physical and physicochemical tests were performed. The dissolution profiles of DH tablets (30 and 60 mg) available as the reference, generic and similar drugs were compared. The dissolution test was used to obtain and compare dissolution profiles and to determine the similarity of pharmaceutical formulations (USP type 2 apparatus at 75 rpm, with 750 mL of water at 37.0 ± 0.5 oC for 120 minutes). Only samples G30 and G60 showed compliance with the parameters established by the Brazilian Pharmacopoeia in all tests. Drug dissolution percentages are in accordance with the Brazilian and American Pharmacopoeias (>75% dissolution in 180 minutes). Using the proposed new method, it was observed that > 80% of DH was released in approximately 60 minutes. The proposed method was found to be sensitive, rapid and efficient for the quality control of DH tablets.
Organ failure remains one of the leading causes of death worldwide, posing a formidable challenge for healthcare systems. Conventional organ transplants are limited by the scarcity of donors and the risks associated with immune rejection. In response, 3D bioprinting has emerged as a revolutionary approach with the potential to fabricate tailor-made, patient-specific organs. Central to this technology is the use of bioinks-smart materials that ensure structural integrity, biocompatibility, and the functional performance of printed organs. This review delves into the latest advancements in 3D bioprinting, specifically targeting the heart and cardiac tissues, such as heart valves and entire hearts. It evaluates the capabilities of various bioprinting techniques in creating intricate tissue structures using patient-specific cells, while also addressing the potential for bioprinting to transform the landscape of organ transplantation. Furthermore, the review explores the essential properties of bioinks, the selection of cell sources, and the current progress in clinical trials and patents, offering insights into the future prospects and challenges of cardiac tissue bioprinting. This comprehensive assessment underscores the promise of bioprinting in overcoming the limitations of traditional transplants and advancing personalized medicine.
Ilhéus virus (ILHV), an arbovirus belonging to the Flaviviridae family, poses a significant health threat with limited knowledge about its protein structures. This study aims to fill this gap by using structural analysis and molecular dynamics-based pharmacophore modeling. These advanced molecular tools enable us to develop a robust virtual screening model for identifying potential antiviral drugs against ILHV. The present study used the Robetta protein molecular modeling tool (https://robetta.bakerlab.org), molecular dynamics simulations using GROMACS, molecular docking using AutoDock Vina, and the nAPOLI server for analysis of protein-ligand interactions. Our molecular docking results reveal the remarkable affinity of caffeic acid to act like an allosteric inhibitor by binding the NS2B- NS3 protease. This finding is important as the NS2B-NS3 protease has highly conserved domains among Flavivirus, suggesting that caffeic acid could be a pan-flavivirus antiviral drug. Although this research is in silico, it provides insights into essential molecular interactions, paving the way for targeted drug discovery in the fight against ILHV and related arboviruses.
The high prevalence of vulvovaginal candidiasis necessitates the development of better treatments. This study aimed to develop a novel nanocomposite vaginal suppository incorporating gelatin and clotrimazole-loaded coconut oil nanocapsules. The nanocapsule suspensions, prepared using Eudragit® RS100, achieved a size of under 190 nm, a polydispersity index of below 0.15, nearly 100% drug content and encapsulation efficiency, a positive zeta potential of +8.5 mV, and an acidic pH. The mucoadhesive properties were confirmed through mucin interaction tests. Suppositories were formulated by integrating gelatin and glycerin into the nanocapsule suspension, maintaining the nanometric size at 135 nm and attaining a high drug content of 97.48%. The nanocomposite suppository demonstrated an enhanced control of drug release, with 40% released in 5 hours, in contrast to 80% from the non-nanotechnological formulation. Additionally, drug retention in cow vaginal mucosa was superior with the nanocomposite suppository (11.95 μg/cm2) compared to the non-nanotechnological formulation (8.18 μg/cm2). The dispersion time did not exceed 60 minutes (24.29 ± 1.91 minutes). The washability test confirmed high mucosal retention, evidenced by drug concentrations in the lavage fluid being lower than 5% for both formulations (nanocomposite and control). These results suggest the feasibility of a nanocomposite suppository with desirable characteristics for vaginal drug delivery, representing a promising alternative for the management of vulvovaginal candidiasis.
This study evaluated the neuroprotective effects of fluoxetine in the retina of 45 Wistar rats exposed to intense light (3000 LUX for 12 hours). The animals were assigned to prevention (CG, PhotoG, and FG) and regeneration (RCG, RPhotoG, FG 7, FG 14, FG 21, and FG 30) groups, receiving daily fluoxetine treatment (10 mg/kg/day, intraperitoneally [i.p.]) either before or after photoexposure. Retinal analysis was performed using histology and histomorphometry (hematoxylin and eosin staining), detection of apoptosis (TUNEL assay), and electroretinography (ERG). Rats in the PhotoG group demonstrated reduced outer nuclear layer (ONL) thickness (~25 µm), an increased apoptotic index, and decreased b-wave amplitudes in the ERG (~60 µV), compared to controls. The FG group maintained ONL thickness (~36 µm), exhibited reduced apoptosis, and demonstrated improved electrophysiological responses. In the FG 30 group, ONL thickness increased to approximately 39 µm, apoptosis decreased, and the b-wave amplitude increased to ~120 µV, accompanied by reduced implicit times. These findings indicate that fluoxetine protects the retina against light-induced damage through antioxidant, anti-inflammatory, and antiapoptotic mechanisms, with enhanced efficacy following prolonged administration, suggesting its potential as a therapeutic agent for retinal degenerative diseases.
The biosafety of cow’s milk-derived extracellular vesicles (mEVs) has not been fully explored, particularly regarding its potential as an in vivo drug carrier. This study systematically evaluated the biosafety of mEVs by assessing their in vitro cytotoxicity as well as in vivo toxicity, immunogenicity, and potential for irritation in mice. The results showed that mEVs exhibited minimal cytotoxicity in vitro, with no significant effect on cell viability. Furthermore, repeated injections of mEVs did not induce aberrant immune responses, irritation or toxicity in mice, indicating that mEVs are a highly biocompatible and safe drug carrier with promising biomedical applications. However, further research is needed to fully understand their long-term effects and optimize their use.
The present study aimed to investigate the chemical composition of essential oils (EOs) and methanol extracts of Orthomnion rostratum and Orthomnion medium species. The EOs were obtained using hydrodistillation (HD) and microwave distillation (MWD) and analyzed by GC-FID-MS. Octanal (24.12%, HD; 20.22%, MWD), pentanal (31.45%, HD), and n-pentanol (25.50%, MWD) were found to be significant compounds, respectively. Analysis of the phenolic constituents of the methanol extracts of O. rostratum and O. medium yielded apigenin glucoside derivatives as the major compounds, with concentrations of 1.355 and 0.382 mg/g, respectively. The antimicrobial activities of the EOs and solvent extracts (n-hexane, chloroform, methanol, and water) of both species were evaluated against nine microorganisms. EOs obtained using MWD from both species exhibited the strongest antimicrobial activity against Staphylococcus aureus (15.9 µg/mL and 15.0 µg/mL), Enterococcus faecalis (31.9 µg/mL and 30.0 µg/mL), Bacillus cereus (15.9 µg/mL and 15.0 µg/mL), respectively.
Senescence or aging is often associated with onset of morbidities, which have been attributed to the harmful phenomenon of glycation. To date, no drug is available to combat this deleterious process. The drug repurposing is a robust and cost-effective approach to identify potential candidate molecules for drug discovery programs. In present study, Meloxicam (MEL) was evaluated for its capacity to be repurposed against glycation. Using the Fructose-BSA model, the anti-glycation effect was evaluated by measuring intrinsic fluorescence of Advanced Glycation End Products (AGEs). The fructoseamine load and free lysine availability was estimated using NBT and TNBSA assays respectively. The BSA secondary structure was assessed by Thioflavin-T, Congo red and Circular Dichroism tests. Finally, lysine blockade and carbonyl entrapment was evaluated as a possible mode of anti-glycation action. Our data showed that MEL (0.5, 1, and 2mM) has significantly reduced the AGEs formation (IC50 = 0.25mM). The load of fructosamine adducts along with free lysine availability was found to be reduced. The secondary structure of BSA was preserved. Regarding mode of action, MEL did not block lysine residues, which was also supported by computational data. However, it was found to entrap carbonyl intermediates. In conclusion, the present study demonstrate that MEL possess anti-glycation potential, which can be attributed to entrapment of carbonyl intermediates. Hence, MEL, a clinically used NSAIDs, present itself as promising candidate to be repurposed against deleterious phenomenon of glycation.
This study aimed to determine the chemical composition and biological activities of extracts from commercial samples of Aspidosperma excelsum stem bark. The extracts underwent preliminary phytochemical screening, chromatographic fractionation, and spectrometric and spectroscopic analyses, including mass spectrometry and nuclear magnetic resonance. Antioxidant and antimicrobial activities were also evaluated. Phytochemical screening revealed the presence of alkaloids, anthrones, triterpenes, and steroids. Fractionation led to the isolation and structural identification of the indole alkaloids carapanaubine and O-acetylyohimbine. APCI-MS/MS analysis of the crude extracts identified three additional indole alkaloids: spruceanumine B, 10-methoxydihydrocorinanteol, and 11-methoxy-yohimbine. In antimicrobial assays, the hexane extract exhibited moderate antifungal activity against Candida parapsilosis (MIC = 400 µg/mL), while the other extracts displayed weak activity (MIC = 1600 µg/mL). Against Candida albicans, all extracts demonstrated weak antifungal activity, and none showed antibacterial activity at the tested concentrations. Total phenolic content was low, ranging from 31.25 to 138.06 ± 0.9 mg GAE/g. The hexane extract lacked antioxidant activity, while the chloroform, ethyl acetate, and methanol extracts exhibited relatively high activity in the ABTS•+ assay (801.88 ± 42.22 to 936.33 ± 61.28 μM TE) compared to Trolox (500–1000 μM TE). However, all extracts displayed low activity in the DPPH• assay. These findings suggest that A. excelsum warrants further investigation to explore the antioxidant and antimicrobial properties of its identified constituents.
A series of fused pyrimido[4,5-d]pyridazin-2(1H)-one, pyrimido[3’,4’:3,2]pyrimido[5,4-d]pyridazin-10-one, pyridazino[4’,5’:5,6]pyrimido[2,1-i]purine and pyridazino[4’,5’:4,5]pyrimido[2,3-b]purin-4(5H)-one were designed and prepared by condensation of hydrazine with pyrimidinone dicarboxylic acid esters in methanol as a solvent. The in vitro antioxidant potential of the target compounds and their precursors was demonstrated by applying free radical scavenging assays using 1,1-diphenyl-1-picrylhydrazyl (DPPH•) and 2,2′-azino-bis-3-ethylbenzothiazoline-6-sulfonic acid (ABTS+•) methods. The synthesized compounds 6b and 7b showed the highest antioxidant activity against DPPH with IC50 of 6.55 and 7.93 μg/mL, respectively, compared to ascorbic acid (IC50 = 5.42 μg/ mL). In addition, compounds 5a and 6b showed a greater ABTS radical scavenging effect than BHT (IC50=75.39 μg/mL). The antibacterial activity of the synthesized compounds was evaluated and compared with Gentamicin. Four bacterial strains were considered: Staphylococcus aureus ATCC-6538, Salmonella typhimurium ATCC-14028 (Gram-positive: G+), Pseudomonas aeruginosa ATCC-9027 and Escherichia coli ATCC-8737 (Gram-negative: G-). Compound 4a showed good activity against Pseudomonas aeruginosa, Staphylococcus aureus and Salmonella typhimurium with inhibition zones of 23, 22 and 21 mm, respectively, compared to gentamicin (23, 25 and 22 mm). These results encourage exploration of new biological evaluations and applications of these compounds.
Increasing numbers of HIV infections have been reported over the last years. Despite the availability of antiretroviral therapy, the emergence of drug-resistant strains and side effects of marketed drugs makes the search for new drugs needed. Herein, we investigated the antiviral potential of 3-acylhydrazone-4-quinolones (compounds 2-4) against HIV-1 replication in MT-2 cells, their mechanism of action, and pharmacokinetic and toxicological (ADMET) properties using in vitro and in silico methods. All compounds showed lower cytotoxicity (CC50 > 700 µM) than the drug zidovudine (CC50 = 128 µM). Compound 2 showed the most potent anti-HIV-1 activity (EC50 = 3.37 µM), followed by compounds 3 (EC50 = 3.79 µM) and 4 (EC50 = 4.03 µM). Mechanistic studies indicated that these compounds act at post-entry steps of virus replication, such as reverse transcription. Enzymatic assays confirmed that compounds 2 and 4 (IC50 = 29.52 µM and 22.77 µM) inhibit HIV-1 reverse transcriptase (RT). Molecular docking with HIV-1 RT showed that compounds 2 and 4, but not 3, share a similar binding mode with the non-nucleoside RT inhibitor delavirdine, explaining their different activity. Further, ADMET studies reinforced their potential as drug candidates which, in turn, support the design of new derivatives as anti-HIV-1 drug candidates.
The World Health Organization has listed Snakebite Envenomation as a significantly ignored tropical disease with a worldwide annual snakebite affecting millions of people, especially in Africa. This study evaluated the in vivo and in vitro neutralising effects of the aqueous extract from the aerial parts of Caralluma dalzielii against snake venom. In the in vivo study, 35 Wistar rats were divided into seven groups, receiving snake venom and treatments with plant extract or standard anti-venom. Mortality rates, haematological, and biochemical parameters were recorded. Whereas, in the in vitro study, different concentrations of plant extract were tested for enzyme inhibition against Naja nigricollis venom. The results showed that the plant extract prevented mortality in all treated groups, comparable to standard anti-venom, and exhibited immunostimulatory effects, increasing WBC levels. It also prevented biochemical disturbances caused by venom, with the highest dose (500 mg/kg) maintaining normal liver enzyme levels. The extract at 100 mg/ml achieved 64.29% enzyme inhibition of PLA2, while the standard anti-venom reached 82.63%, showing concentration-dependent inhibition. In conclusion, the aqueous extract of C. dalzielii exhibits significant anti-venom activity both in vivo and in vitro, demonstrating its potential as a therapeutic option for treating snake bites.
