Search Results (1,904)

Background: There is a paucity of systematic investigations of the acceptability and preference of alternative oral drug formulations in multiple sclerosis (MS) patients. The use of appropriate oral dosage forms has the potential to circumvent challenges associated with the ingestion of tablets. Objective: This randomized, open, cross-over study aimed to investigate acceptability, swallowability, palatability, and preference of four oral placebo drug formulations of similar sizes/given volumes but different modes of ingestion (film-coated tablet, orodispersible tablet, orodispersible film, and gel) in MS patients. Methods: Acceptability was tested in two patient subgroups (32 participants each) of different MS disability levels (expanded disability status scale [EDSS] < 4 and ≥4). The primary endpoint was acceptability derived as a composite of swallowability (rated by investigator) and palatability (rated by participant). Results: The film-coated tablet showed the highest acceptability rates for EDSS < 4 and EDSS ≥ 4 (100.0%, 93.8%), followed by gel (81.3%, 68.8%). Acceptability rates for all formulations were consistently higher for EDSS < 4 compared to EDSS ≥ 4. Concerning the subjective assessment of palatability, the gel received the highest rate of positive ratings, but also was frequently judged as ‘Unpleasant’. Furthermore, the gel was ranked as the first or second choice as the most-preferred formulation, followed by the film-coated tablet. All formulations were considered safe in the study population. Conclusions: Film-coated tablets are well-suited for use in MS patients and gels may represent an interesting alternative for a certain subgroup of MS patients. Full article

Background: Ribociclib, initially approved for HR+/HER2− advanced breast cancer (ABC) at a 600 mg dose, was recently approved for HR+/HER2− early breast cancer (EBC) at a 400 mg dose based on the NATALEE trial. Differences in dose and patient population warrant reassessment of ribociclib drug–drug interactions (DDIs) and the impact of hepatic or renal impairment (HI/RI) in EBC patients to guide co-medication management and subpopulation dose recommendations. Methods: Physiologically-based pharmacokinetic (PBPK) modeling based on a healthy volunteer population was conducted to assess ribociclib DDIs with CYP3A4 substrates/modulators in patients with EBC. Subgroup analysis from NATALEE assessed HI/RI impact on ribociclib PK in EBC patients. Existing data from ABC/advanced cancer patients and non-cancer subjects were also integrated to inform dose recommendations for EBC subpopulations. Results: PBPK modeling predicted that ritonavir or erythromycin (strong and moderate CYP3A4 inhibitors) would increase ribociclib steady-state area under the concentration–time curve (AUC) by 1.84-fold or show no meaningful impact, respectively. Steady-state ribociclib AUC was estimated to decrease by 83% and 74% with rifampicin and efavirenz, strong and moderate CYP3A4 inducers, respectively. Ribociclib was estimated to increase CYP3A4 substrate midazolam exposure by 280%. Mild HI or mild/moderate RI did not show an apparent impact on ribociclib PK. Conclusions: Using relevant data and methodology for EBC patients, this analysis informed the approved ribociclib label of no dose adjustment for EBC patients with concomitant use of a moderate CYP3A inhibitor, any degree of HI, or mild/moderate RI, and a reduced 200 mg dose for patients with concomitant use of a strong CYP3A inhibitor or severe RI. Full article

Gamma-aminobutyric acid (GABA) has been implicated in gut–brain interactions and neuronal activation. We hypothesized that GABA could ameliorate memory decline. We investigated whether oral GABA administration ameliorated age-related cognitive decline in aged mice (C57BL/6J, male) and explored the role of circulating exosomes in mediating these effects. Aged mice that drank water containing 0.5% GABA exhibited significantly improved discrimination index scores compared with that of controls, indicating enhanced memory function. Their plasma-derived exosomes induced neurite outgrowth and mitochondrial activation and restored neuronal activity in SH-SY5Y cells. GABA enhanced the exosomal expression of several miRNAs linked to neuronal activation, longevity, and anti-senescence pathways. Plasma-derived exosomes also restored object recognition memory, reduced hippocampal neuroinflammation, and decreased senescent cell markers (p21 and γH2AX) in aged mice. Additionally, mitochondria- and neurite-related genes were upregulated, and pathways associated with oxidative phosphorylation and Alzheimer’s disease were enriched. Collectively, long-term GABA administration was found to improve cognitive function of aged mice through the secretion of functional exosomes. Full article

Glioblastoma is one of the most aggressive tumours with a poor prognosis and a modest survival rate after diagnosis. Several trials for a more targeted and effective treatment are in progress. Protein kinase CK2 is upregulated in glioblastoma and creates a favourable environment for cell proliferation by supporting several survival pathways. Inhibitors of CK2 kinase activity were shown to restrict growth rate or to induce apoptosis in different cell culture and animal models. Recently, we described the selective CK2 inhibitor 6,7-dichloro-1,4-dihydro-8-hydroxy-4(4 methylphenylamino)methylen]dibenzo [b,d]furan 3(2H)-one (TF). In this study, we found that TF effectively reduces the proliferation of A1207 glioblastoma cells with an EC₅₀ value of 13.7 µM, which is equal to the EC₅₀ value of CX-4945, which was the first CK2 inhibitor in clinical phase II trials (13.9 µM). We investigated the effect of TF and temozolomide (TMZ) as a single or combination treatment in two glioblastoma cell lines, A1207 and U87. The treatment was carried out over 48 or 72 h, and, subsequently, the biological effects were evaluated. The proliferation of both cell lines was significantly impaired by the application of the drugs, and combination treatment with TF and TMZ proved superior to the individual treatments. Not only proliferation, as determined by cell confluence assays and BrdU incorporation, but also viability in terms of metabolic activity and cytotoxicity were affected by the treatment. The decrease in proliferation and viability is partly due to the induction of apoptosis, with both cell lines differing in terms of the pattern of apoptotic caspases. Taken together, TF in combination with TMZ may be a promising candidate for the treatment of glioblastoma in the future. Full article

Objectives: This study aimed to evaluate the effectiveness and safety of paracetamol 1000 mg/ibuprofen 300 mg administered three times daily (TID) in comparison with ibuprofen 600 mg TID in the management of patients with acute moderate/severe non-specific low back pain (LBP). Methods: This was a phase IV, randomized, open-label, parallel-group study conducted in adults with moderate/severe LBP (Visual Analogue Scale [VAS] score ≥ 40 mm). Results: A total of 171 patients were included in the modified intention-to-treat (m-ITT) population (paracetamol 1000 mg/ibuprofen 300 mg: 83 patients; ibuprofen 600 mg: 88 patients). No significant between-group difference on the primary endpoint (SPID 0–3 days) was found. Patients were mainly women (60.2% and 55.7%), with a mean age of 42.8 and 43.3 years, respectively. In the m-ITT population, the effectiveness, safety and tolerability were similar between groups. In the per-protocol population, clinical pain reduction was observed with paracetamol 1000 mg/ibuprofen 300 mg. At visit 1, significant differences in the Clinical Global Impression–Improvement scale (paracetamol 1000 mg/ibuprofen 300 mg: 63.9%; ibuprofen 600 mg: 45.5%; p = 0.0137) and a trend favouring paracetamol 1000 mg/ibuprofen 300 mg in Patients’ Global Impression of Change (63.9% vs 44.4%; p = 0.0539) score were observed. Conclusions: Given the open-label design and the exploratory nature of study’s secondary endpoints, no claims of superiority can be drawn; but our findings confirm that good management of acute moderate/severe LBP can be achieved with multimodal therapy with paracetamol 1000 mg/ibuprofen 300 mg. EudraCT Number: 2020-005278-86 (EudraCT Number 2020-005278-86—Clinical trial results—EU Clinical Trials Register; date of registration: 14 June 2021). Full article

Background/Objectives: During cataract surgery, topical anesthesia is routinely achieved through the instillation of topical anesthetic eye drops, while different agents may be applied to the corneal surface during the procedure to support lubrication and protection. The impact of these intraoperative strategies on corneal integrity and postoperative ocular surface recovery remains an area of clinical interest. This study aimed to compare the intraoperative and postoperative effects of applying a topical anesthetic gel (Ophtesic, Horus Pharma) on the corneal surface versus the use of balanced salt solution (BSS) during cataract surgery. Methods: In this longitudinal, observational prospective study, 24 eyes of 24 patients undergoing phacoemulsification received either topical anesthetic gel (n = 15) or BSS irrigation (n = 9). Central corneal thickness (CCT) and epithelial thickness were measured preoperatively and on postoperative days 1, 5, and 15 using anterior segment optical coherence tomography (AS-OCT). Basal epithelial cell (BEC) density was assessed by in vivo confocal microscopy (IVCM), while OSDI score, non-invasive breakup time (NI-BUT), and Schirmer test I values were evaluated preoperatively and on postoperative days 5 and 15. Patient and surgeon satisfaction were rated using a Likert-like scale. Results: Both groups showed increased CCT and epithelial thickness at day 1. In the gel group, CCT returned to baseline by day 15 (p = 0.361), and epithelial thickness normalized by day 5 (p = 0.066). In the BSS group, CCT remained elevated at day 15 (p < 0.05), and epithelial thickness decreased at day 5 (p < 0.05) before returning to baseline. BEC density normalized at day 15 in the gel group (p = 0.107) but remained altered in the BSS group (p < 0.05). NI-BUT Schirmer I, and OSDI showed a trend toward faster recovery in the gel group than in the BSS group. Conclusions: In this exploratory study, intraoperative application of a topical anesthetic gel appeared to support early normalization of corneal and tear film parameters while providing effective anesthesia. Further studies are warranted to confirm these observations and evaluate potential long-term benefits. Full article

Background/Objectives: Natural polysaccharides have many bio-pharmacological effects, which make them compounds with potential in healthcare. Limnospira platensis (Spirulina), a well-known blue–green cyanobacterium with relevance in the market of nutraceuticals, produces polysaccharides with recognized antioxidant and anti-inflammatory activities. Noteworthy, the growth of the cyanobacterium biomass may be obtained in a more sustainable manner under mixotrophic conditions. In the present study, we compared the antioxidant and anti-inflammatory effects of polysaccharide-enriched extracts from the cyanobacterium cultured under autotrophism (Auto−P extract) or mixotrophism (Mixo−P extract); this latter was realized using medium added with brewery wastewater (BWW). Methods and Results: Non-cellular investigation showed a better antioxidant profile for Mixo−P extract in the OH radical scavenging assay and a similar activity between the extracts in ABTS and ferrous chelation assays. The antioxidant protective activity of L. platensis extracts investigated on HaCat cells in the range of 0.3–10 μg/mL (not cytotoxic concentrations), against hydrogen peroxide (H₂O₂, 600 μM)-induced damage, revealed a similar activity by the two extracts. When tested against the inflammatory stimuli with lipopolysaccharide (LPS, 10 μg/mL) or tumor necrosis factor-α (TNF-α, 10 ng/mL), both Auto−P and Mixo−P showed an ability to prevent the effects of the inflammatory agents on cell viability and on interleukin-1β (IL-1β) and interleukin-6 (IL-6) release, with a slightly greater potency by Mixo−P extract. Conclusions: In conclusion, our data suggest the possible use of L. platensis polysaccharide-enriched extracts in biological-made pharmaceuticals for skin disorders or in cosmeceuticals. In addition, this study demonstrates that mixotrophic cultivation of L. platensis may be an alternative and sustainable way for biotechnological applications of the cyanobacterium biomass. Full article

Background/Objectives: Surfactants are commonly used to protect proteins from denaturation and particle formation, thereby ensuring the long-term stability of biopharmaceuticals. Polysorbates (PS) 20 and 80 are the most widely used surfactants in the pharmaceutical industry. However, alternative excipients such as poloxamers are currently under investigation. In this study, mixed micelles (MMs) composed of phospholipids (PL) and polysorbate 20 (PS20) were explored as a novel stabilisation strategy, aiming to reduce the PS content in protein formulations by partial substitution with PL. Despite their favourable properties, including thermodynamic stability and small particle size, MMs have seen limited application, and no reports exist on their use for stabilising antibody solutions. Results: In a first step, PS20/PL ratios were identified, which are advantageous to form stable MM solutions, followed by an optimization of the formulation process by introducing a second heating step using the direct dispersion method. Successful MM formation was confirmed via transmission and dynamic light scattering analyses at total surfactant concentrations of up to 20 mg·mL⁻¹ and 50 mg·mL⁻¹, with PL contents of 50% and up to 40%, respectively. These surfactant concentrations of up to 20 mg·mL⁻¹ and 50 mg·mL⁻¹ are substantially higher than the surfactant concentrations that are typically used in final biopharmaceutical formulations (0.01–2 mg·mL⁻¹). Consequently, the mixed micellar system enables operation even at concentrations substantially above practical formulation limits. In the ensuing study, the stabilizing potential of the PL/PS20 micellar system was appraised through agitation studies. Methods: In these studies, bovine serum albumin was employed as a model protein, while a monoclonal antibody was used as a candidate therapeutic molecule. Stability was assessed through visual inspection, turbidity measurements, particle analysis, and size-exclusion chromatography. Conclusions: A protective effect comparable to that of PS20 alone was observed for both model proteins, demonstrating for the first time that MMs can effectively stabilise biologics. Full article

The increasing prevalence of antimicrobial resistance, especially in methicillin-resistant Staphylococcus aureus (MRSA), underscores the need for alternative therapies from natural sources. This study investigated the chemical composition, antibacterial activity, and gene expression modulation of Melaleuca cajuputi essential oils. Gas chromatography–mass spectrometry (GC-MS) identified 91 compounds, with naphthalene (23.90%), guaiol (12.92%), caryophyllene oxide (9.69%), D-limonene 98% (8.59%), and gamma terpinene (7.54%) among the most abundant. In Silico molecular docking against MRSA virulence proteins revealed that alloaromadendrene had the strongest binding to toxic shock syndrome toxin-1 (TSST-1) (−7.948 kcal/mol), suggesting high inhibitory potential, while cyclohexane showed weak binding with staphylococcal enterotoxin A (SEA) (−3.532 kcal/mol). Antibacterial assays demonstrated concentration-dependent inhibition, with the zones ranging from 6.33 ± 0.33 mm to 16.67 ± 0.88 mm. MIC and MBC values ranged from 1.56 to 12.5% and 3.13 to 25%, respectively, with most isolates showing bactericidal effects (MBC/MIC ≤ 2). Gene expression analysis of MRSA isolate 4 indicated that sea was moderately upregulated (FC = 1.44), while sec remained unchanged (FC = 1.02). In contrast, fnbA (FC = 0.72), seb (FC = 0.33), and mecA (FC = 0.23) genes were downregulated, and the tsst-1 gene (FC = 0.05) was nearly silent. These findings highlight M. cajuputi essential oils as a promising candidate with both antibacterial efficacy and regulatory effects on MRSA virulence genes. Full article

Culturally adapted cognitive behavioral therapy (CaCBT) is increasingly used to reduce disparities in mental health outcomes among ethnoculturally diverse populations. Although CBT is a well-established evidence-based intervention, little is known about CaCBT’s effectiveness across diagnostic groups and global contexts. This meta-analysis synthesizes CaCBT efficacy for common mental health conditions. Using PRISMA guidelines, five electronic databases were used to search for RCTs reporting mental health variables for CaCBT. Funnel plots, Egger’s test, and the trim-and-fill method were used to evaluate publication bias. Hedges’ g was used to compute effect sizes, and heterogeneity was assessed through DerSimonian and Laird I² statistics. Variations in populations, settings, and adaptation strategies were accounted for through random-effects models. Sixteen articles (n = 4787) met the inclusion criteria. CaCBT was associated with significant reductions in anxiety (g = −0.86, 95% CI [−1.66, −0.07], p = 0.032), somatic symptoms (g = −0.89, 95% CI [−1.61, −0.16], p = 0.016), and improved emotion regulation (g = 1.50, 95% CI [0.72, 2.28], p = 0.0002), though adjusted models reduced effects. For depression, PTSD, stress, and quality of life, pooled estimates favored CaCBT but did not reach statistical significance and were characterized by substantial heterogeneity. Significant heterogeneity was noted across studies, demonstrating diverse cultural contexts and intervention methods. CaCBT demonstrated significant benefits for anxiety, somatic symptoms, and emotional regulation across diverse groups. While depression and PTSD had varying outcomes, overall trends support this culturally responsive intervention’s efficacy. Further research on CaCBT, including understudied populations and standardized adaptation methods, could improve global mental health equity. Full article

Background/Objectives: Hydrogels infused with silver nanoparticles (AgNPs) are widely used for their antibacterial properties, yet their stability, specifically upon contact with solid growth media (agar), remains poorly explored. This study compared two hydrogel matrices, anionic Carbopol 934 and non-ionic Pluronic F127, incorporating AgNPs of three different sizes. The evaluation focused on colloidal stability and antibacterial efficacy against Gram-positive and Gram-negative bacteria. Methods: In this study AgNPs (~20, ~55, and ~65 nm) were synthesised via a wet-chemical method and characterised by UV–visible spectroscopy, dynamic light scattering (DLS), and transmission electron microscopy (TEM). AgNPs were incorporated into Carbopol 934 and Pluronic F127 hydrogel matrices. Colloidal stability was monitored over four months of storage and upon contact with tryptic soy agar (TSA). Antibacterial activity was assessed using agar diffusion assays. Results: Showed that both hydrogel systems maintained AgNP stability during storage, comparable to aqueous suspensions. However, upon contact with TSA, aggregation of Carbopol–AgNP hydrogels occurred, whereas Pluronic–AgNP hydrogels remained stable. In antibacterial assays, both hydrogels produced larger zones of inhibition (ZOI) than AgNP suspensions against Gram-negative bacteria (E. coli, P. aeruginosa), with Carbopol–AgNP hydrogels demonstrating superior efficacy in an inverse size-dependent manner. Against Gram-positive bacteria (S. aureus, S. epidermidis), Pluronic–AgNP hydrogels initially showed larger ZOIs due to the polymer’s intrinsic antibacterial activity. However, after correcting for this baseline, Carbopol–AgNP hydrogels exhibited superior net efficacy, with S. epidermidis showing greater susceptibility than S. aureus. Conclusions: While both Carbopol 934 and Pluronic F127 stabilise AgNPs during storage, the matrix type significantly influences behaviour at the biological interface. Carbopol–AgNP hydrogels aggregate upon contact with solid agar yet deliver superior, size-dependent antibacterial activity compared to the stable but less potent Pluronic systems. Full article

The essential oil or extract of Lemon myrtle (Backhousia citriodora F. Muell.), belonging to the family Myrtaceae and the genus Backhousia, exhibits anti-inflammatory and antioxidant properties. However, limited information exists on the safety of water extracts from its leaves. The present study aimed to assess the safety of lemon myrtle water extract as a functional food by performing genotoxicity studies and repeated-dose oral toxicity. Although the bacterial reverse mutation test (Ames test) yielded positive results, in vivo mammalian erythrocyte micronucleus and alkaline comet assays yielded negative results. In a 28-day oral toxicity study, the extract was orally administered to male and female Crl:CD rats at doses of 0, 250, 500, and 1000 mg/kg bw/day. Notably, the extract induced no adverse effects, and the no-observed-adverse-effect level was 1000 mg/kg bw/day in male and female rats. Despite its genotoxicity in vitro, the extract did not exhibit genotoxicity in vivo. Moreover, no signs of toxicity were observed in the general toxicity study. Overall, these results suggest that lemon myrtle water extract does not pose a substantive genotoxic risk at practical oral exposure levels. Full article

Background/Objectives: Dry eye disease (DED) is a multifactorial condition affecting the ocular surface. It is characterized by tear film instability, hyperosmolarity, inflammation, and oxidative stress. First-line treatment for DED relies on lubricating and hydrating eye drops, usually containing hyaluronic acid (HA), which supports tear film stability and epithelial healing. However, HA alone cannot correct oxidative stress, a key driver of cellular damage and inflammation in DED. Accordingly, this study aimed to evaluate the antioxidant capacity of Malva sylvestris tincture (MalvaT) and its physicochemical properties in experimental eye-drop formulations containing HA. Methods: The antioxidant activity of reconstituted MalvaT lyophilisate (Malva) was assessed in cell-free assays against several oxygen radicals and in cell-based assays using the human HaCat keratinocyte cell line. The refractive index was measured in eye-drop formulations containing 0.15% or 0.3% HA and 0.5% MalvaT. Surface tension was assessed in eye-drop formulations containing 0.15% HA and increasing concentrations (0.25–2.0%) of MalvaT. Results: Malva showed potent oxygen radical scavenging activity in both cell-free and cell-based assays, indicating its antioxidant capacity and the efficient cellular uptake of antioxidant components. The refractive indices of experimental eye-drop solutions containing HA and MalvaT were close to that of tear fluid (1.334). The surface tension of the experimental eye-drop formulations, while not impacted by 0.15% HA, was significantly reduced by increasing concentrations of MalvaT (p < 0.0001). At the concentration of 0.5% MalvaT, the mean surface tension was reduced from 68.17 mN/m (HA control) to 59.80 mN/m (HA + MalvaT), thereby bringing it closer to that of tear fluid. Conclusions: This pre-clinical study suggests that combining the antioxidant properties of Malva tincture with the lubricating and hydrating effects of HA in eye-drop formulations exhibiting optimal rheological characteristics may offer a promising therapeutic approach for managing DED. Full article