Pharmaceuticals最新文献

Background/objectives: Cancer remains one of the major challenges of our century. Organometallic ruthenium complexes are gaining recognition as a highly promising group of compounds in the development of cancer treatments.

Methods: Building on the auspicious results obtained for [Ru(η⁵-C₅H₅)(PPh₃)(bipy)][CF₃SO₃] (TM34), our focus has shifted to examining the effects of incorporating bioactive ligands into the TM34 framework, particularly within the cyclopentadienyl ring.

Results: In this study, we report the synthesis and characterization of two new ruthenium(II) complexes with the general formula [Ru(η⁵-C₅H₄CCH₃=R)(PPh₃)(bipy)][CF₃SO₃], where R represents a nicotinic acid derivative (NNHCO(py-3-yl)) (1) or an isoniazid derivative (NNHCO(py-4-yl)) (2). The complexes were fully characterized using a combination of spectroscopic techniques and computational analysis, revealing the presence of E/Z-hydrazone isomerism. Stability studies confirmed the robustness of both complexes in biological media, with compound 1 maintaining good stability in buffer solutions mimicking physiological (pH 7.4) and tumor-like (pH 6.8) environments. The cytotoxicity of the complexes was evaluated in vitro in several human cancer cell lines, namely melanoma (A375), alveolar adenocarcinoma (A549), epidermoid carcinoma (A431), and breast cancer (MDA-MB 231).

Conclusions: Both compounds exhibited moderate to high cytotoxic activity, with complex 1 showing a greater propensity to induce cell death, particularly in the A431 and MDA-MB 231 cell lines.

Background: Recent evidence supports the protective role of metformin on kidney function in patients with type 2 diabetes mellitus. However, its potential to prevent new-onset chronic kidney disease (CKD) in patients with type 2 diabetes mellitus with normal renal function remains unclear. Therefore, this study aimed to investigate whether metformin could prevent the development of new-onset CKD in such patients. Methods: This retrospective, observational, multicenter cohort study included 316,693 patients with type 2 diabetes mellitus. After matching using the inverse probability of treatment weighting, 9109 metformin users and 1221 nonusers were analyzed. The primary outcomes were an estimated glomerular filtration rate (eGFR) of <60 mL/min/1.73 m², urinary albumin-to-creatinine ratio of ≥30 mg/g, and a composite outcome defined as new-onset CKD. Results: The multivariable Cox survival model showed that metformin users had significantly better renal outcomes, with a notably lower risk of sustained eGFR of <60 mL/min/1.73 m² (hazard ratio (HR), 0.71; 95% confidence interval (CI), 0.56-0.90) and new CKD onset (HR, 0.78; 95% CI, 0.65-0.94). Conclusions: Metformin plays a key role in delaying renal events in individuals with type 2 diabetes mellitus and in those with initially normal renal function.

Orodispersible thin film (ODF) is an innovative dosage form that allows for adjustable dosing and improved patient compliance. It is administered by mouth, where it dissolves, making it suitable for children.

Objectives: The aim of the study was to develop and characterize an optimal ODF formulation containing equivalent hydrocortisone at 0.5 mg/cm² using the solvent-casting method. A stability-indicating assay for the simultaneous quantification of hydrocortisone and hydrocortisone 21-hemissucinate (HMS) was developed. ODFs were characterized by organoleptic properties and by testing for uniformity of mass, content, stability, thickness, and dissolution.

Results: When optimized, ODF is thin, flexible, and transparent, making it suitable for production in hospital pharmacies using standard equipment. In contrast to the water-insoluble hydrocortisone, the HMS-loaded cast gel successfully satisfied the tests, including content uniformity. Disintegration appeared acceptable as compared to the commercial grade ondansetron ODF (Setofilm^®). The physicochemical stability of the active ingredients (i.e., HMS, hydrocortisone) contained in the ODF at 0.5 mg/cm² is demonstrated for at least 84 days at 23 °C.

Conclusion: The ODF formulated with the water-soluble hydrocortisone prodrug HMS allows accurate drug level to be achieved, thus opening up new opportunities for use in pediatric patients.

Pseudomonas aeruginosa is one of world's most threatening bacteria. In addition to the emerging prevalence of multi-drug resistant (MDR) strains, the bacterium also possesses a wide variety of virulence traits that worsen the course of the infections. Particularly, its ability to form biofilms that protect colonies from antimicrobial agents is a major cause of chronic and hard-to-treat infections in immune-compromised patients. This protective barrier also ensures cell growth on abiotic surfaces and thus enables bacterial survival on medical devices. Hence, as the WHO alerted to the need to develop new treatments, the use of anti-biofilm agents (ABAs) appeared as a promising approach. Given the selection pressure imposed by conventional antibiotics, a new therapeutic strategy has emerged that aims at reducing bacterial virulence without inhibiting cell growth. So-called anti-virulence agents (AVAs) would then restore the efficacy of conventional antibiotics (ATBs) or potentiate the effectiveness of the immune system. The last decade has seen the development of ABAs as AVAs against P. aeruginosa. This review aims to highlight the design strategy and critical features of these molecules to pave the way for further discoveries of highly potent compounds.

Inherited retinal disorders (IRDs) represent a group of challenging genetic conditions that often lead to severe visual impairment or blindness. The complexity of these disorders, arising from their diverse genetic causes and the unique structural and functional aspects of retinal cells, has made developing effective treatments particularly challenging. Recent advancements in gene therapy, especially non-viral nucleic acid delivery systems like liposomes, solid lipid nanoparticles, dendrimers, and polymersomes, offer promising solutions. These systems provide advantages over viral vectors, including reduced immunogenicity and enhanced targeting capabilities. This review delves into introduction of common IRDs such as Leber congenital amaurosis, retinitis pigmentosa, Usher syndrome, macular dystrophies, and choroideremia and critically assesses current treatments including neuroprotective agents, cellular therapy, and gene therapy along with their limitations. The focus is on the emerging role of non-viral delivery systems, which promise to address the current limitations of specificity, untoward effects, and immunogenicity in existing gene therapies. Additionally, this review covers recent clinical trial developments in gene therapy for retinal disorders.

Background: Lappula patula (L. patula) is a plant with known medicinal properties, and its extracts have shown promise as potential anti-cancer agents. This study aimed to evaluate the nematocidal effects of L. patula extracts and investigate their impact on germline development, DNA damage responses, and apoptosis in Caenorhabditis elegans (C. elegans), a model organism for studying these processes.

Methods: C. elegans was exposed to L. patula extracts to assess survival, development, and incidence of male phenotype. Germline abnormalities were examined using microscopy at different developmental stages. The DNA damage response was evaluated through the expression of the atm-1, atl-1 and pCHK-1. Apoptosis was quantified by monitoring cell death during the pachytene stage. LC-MS was used to identify bioactive compounds within the extracts.

Results: Exposure to L. patula extracts resulted in a dose-dependent reduction in worm survival and larval developmental progress, with no significant impact on the male incidence. Germline defects were observed, including increased nuclear spacing at premeiotic and pachytene stages, altered number of bivalents during diakinesis. These defects correlated with a significant decrease in brood size. Also, L. patula extracts activated the DNA damage response pathway, marked by increased expression of atm-1 and atl-1. Moreover, the extracts induced apoptosis in the germline in a pCHK-1-independent manner. LC-MS analysis revealed 31 potential anti-tumor compounds, supporting the extract's cytotoxic properties.

Conclusions: Lappula patula extracts exhibit potent nematocidal and cytotoxic properties, suggesting their potential for cancer therapy. The observed DNA damage and apoptosis in C. elegans emphasize the extract's promising role in anti-cancer drug development. Further studies are needed to explore the therapeutic potential of these compounds in clinical settings.

Backgroud/Objectives: Silymarin, an extract from milk thistle, is widely recognized for its therapeutic potential in treating liver disorders. However, its clinical utility is limited by the poor solubility and low bioavailability of its key active ingredient, Silybin. In this study, we sought to address this issue through the development of a novel cocrystal of Silyin. Methods: Silybin-L-proline cocrystal was synthesized and the physicochemical properties of the cocrystal were characterized by PXRD, TGA, DSC, and FTIR. Dissolution tests were conducted in various pH solutions, and the impact of precipitation inhibitors was evaluated. Furthermore, pharmacokinetic study in rats were performed to assess the bioavailability. Results: The dissolution studies demonstrated that the cocrystal has a significant improvement in dissolution performance, particularly in acidic environments. Furthermore, the use of precipitation inhibitors, such as PVP, prolonged the supersaturation period for adequate absorption. Pharmacokinetic studies in rats revealed that the cocrystal exhibited a 16-fold increase in bioavailability compared to the raw Silybin extract, outperforming the commercial Silybin-phosphatidylcholine complex. Conclusions: The Silybin-L-proline cocrystal significantly enhances dissolution and bioavailability, indicating its potential to improve the therapeutic efficacy of Silybin in clinical applications.

Background: Gentamicin (GM) administration is associated with decreased metabolism, increased oxidative stress, and induction of nephrotoxicity. Sambucus nigra L., containing flavonoids, anthocyanins, and phytosterols, possesses antioxidant and anti-inflammatory potential. Objectives: The present study aimed to investigate the nephroprotective and anti-inflammatory potential of lyophilized Sambucus nigra fruit extract (S. nigra extract) to reduce acute oxidative stress and residual toxicity of GM in a 7-day experimental model in Balb/c rodents. Methods: The S. nigra extract was lyophilized (300 rpm; 10 min; -45 °C) to improve pharmacological properties. Balb/c mice were divided into four (n = 6) groups: controls; S. nigra extract per os (120 mg kg^-1 day^-1 bw); GM (200 mg kg^-1 day^-1 bw) (4); and GM + S. nigra therapy. The activities of antioxidant and renal enzymes, cytokines, and levels of oxidative stress biomarkers-Hydroxiproline, CysC, GST, KIM-1, PGC-1α, MDA, GSPx-were analyzed by ELISA tests. The ROS and RNS levels, as well as 5-MSL-protein oxidation, were measured by EPR spectroscopy. Results: The antioxidant-protective effect of S. nigra extract (120 mg kg^-1) was demonstrated by reduced MDA, ROS, and RNS and increased activation of endogenous enzymes. Furthermore, S. nigra extract significantly reduced the expression of IL-1β, IL-6, IL-10, TNF-α, IFN-γ, and KIM-1 and regulated collagen/protein (PGC-1α and albumin) deposition in renal tissues. Conclusions: Histological evaluation confirmed that S. nigra (120 mg kg^-1) attenuated renal dysfunction and structural damage by modulating oxidative stress and acute inflammation and could be used as an anti-fibrotic alternative in GM nephrotoxicity.

Background: Methylenebisphosphonic derivatives including hydroxy-methylenebisphosphonic species may be of potential biological activity, and a part of them is used in the treatment of bone diseases. Methods: Methylenebisphosphonates may be obtained by the Michaelis-Arbuzov reaction of suitably α-substituted methylphosphonates and trialkyl phosphites or phosphinous esters, while the hydroxy-methylene variations are prepared by the Pudovik reaction of α-oxophosphonates and different >P(O)H reagents, such as diethyl phosphite and diarylphosphine oxides. Results: After converting α-hydroxy-benzylphosphonates and -phosphine oxides to the α-halogeno- and α-sulfonyloxy derivatives, they were utilized in the Michaelis-Arbuzov reaction with trialkyl phosphites and ethyl diphenylphosphinite to afford the corresponding bisphosphonate, bis(phosphine oxide) and phosphonate-phosphine oxide derivatives. The Pudovik approach led to α-hydroxy-methylenebisphosphonic species and to their rearranged products. A part of the derivatives revealed a significant cytotoxic effect on pancreatic adenocarcinoma or multiple myeloma cells. Conclusions: The new families of compounds synthesized by our novel approaches may be of practical importance due to the significant cytotoxic activity on the cell cultures investigated. Compounds lacking hydroxy groups showed anti-myeloma activity or limited effect on pancreatic cancer (PANC-1) cells unless substituted with para-trifluoromethyl group. Hydroxy-containing bisphosphonates and their rearranged derivatives demonstrated varying effects depending on structural modifications. While myeloma (U266) cells indicated greater sensitivity overall, the most significant reductions in cell viability were observed in PANC-1 cancer cells, raising potential therapeutic applications of bisphosphonates beyond myeloma-associated bone disease, particularly for malignancies like pancreatic ductal adenocarcinoma.

Background: In this study, two chalcone analogs were synthesized through in silico and experimental methods, and their potential to inhibit the lipoxygenase enzyme, which plays a role in the inflammation pathway, was assessed. Specifically, this study is a continuation of previous research in which chalcone derivatives were synthesized and characterized.

Objectives/methods: In the current work, we present the re-synthesis of two chalcones, with a focus on their docking studies, NMR analysis, and dynamic simulations. The structure of each chalcone was elucidated through a combination of Nuclear Magnetic Resonance (NMR) and Density Functional Theory (DFT). The substituent effect on the absorption spectrum of the two chalcone derivatives was studied.

Results: A "LOX-chalcone" complex, predicted by docking studies, was further examined using molecular dynamics (MD) simulations to evaluate the stability of the complex. After fully characterizing the "LOX-chalcone" complexes in silico, the atomic details of each chalcone's interaction with LOX-1 and 5-LOX were revealed through Saturation Transfer Difference (STD) NMR (Nuclear Magnetic Resonance). Finally, their selectivity profile was investigated against human 15-LOX-1 and general Lipoxidase activity.

Conclusions: The in silico methods suggest that chalcones could be promising lead compounds for drug designs targeting the LOX enzyme.