Pharmaceuticals最新文献

Background/Objectives: The present experiment aimed to formulate four ointments that included mixtures of plant extracts (Hippophae rhamnoides, Calendula officinalis, Arctium lappa, and Achillea millefolium), apitherapy products (honey, propolis, and apilarnil) and natural polymers (collagen, chitosan, and the lyophilisate of egg white) in an ointment base. Methods: In order to investigate the therapeutic properties of the ointments, experimental in vivo injury models (linear incision, circular excision, and thermal burns) were performed on laboratory animals, namely Wistar rats. The treatment was applied topically, once a day, for 21 days. Clinical and macroscopic evaluation, determination of lesion shrinkage rate, re-epithelialization period, and histopathological examination were performed. Results: The results demonstrate that the tested ointments have a significant effect in healing skin lesions. On the ninth day of treatment, the wound contraction rate was 98.17 ± 0.15% for the mixed ointment group, compared to the negative control group's rate of 14.85 ± 2.95%. At day 21, dermal collagenization and restoration of histological structure occurred for all treated groups. Conclusions: The tested ointments exerted in vivo wound healing and re-epithelialization effects on incision, excision, and thermal burn injuries.

Background: Tumors, as intricate ecosystems, comprise oncocytes and the highly dynamic tumor stroma. Tumor stroma, representing the non-cancerous and non-cellular composition of the tumor microenvironment (TME), plays a crucial role in oncogenesis and progression, through its interactions with biological, chemical, and mechanical signals. This review aims to analyze the challenges of stroma mimicry models, and highlight advanced personalized co-culture approaches for recapitulating tumor stroma using patient-derived tumor organoids (PDTOs). Methods: This review synthesizes findings from recent studies on tumor stroma composition, stromal remodeling, and the spatiotemporal heterogeneities of the TME. It explores popular stroma-related models, co-culture systems integrating PDTOs with stromal elements, and advanced techniques to improve stroma mimicry. Results: Stroma remodeling, driven by stromal cells, highlights the dynamism and heterogeneity of the TME. PDTOs, derived from tumor tissues or cancer-specific stem cells, accurately mimic the tissue-specific and genetic features of primary tumors, making them valuable for drug screening. Co-culture models combining PDTOs with stromal elements effectively recreate the dynamic TME, showing promise in personalized anti-cancer therapy. Advanced co-culture techniques and flexible combinations enhance the precision of tumor-stroma recapitulation. Conclusions: PDTO-based co-culture systems offer a promising platform for stroma mimicry and personalized anti-cancer therapy development. This review underscores the importance of refining these models to advance precision medicine and improve therapeutic outcomes.

Background: Melanoma is the most aggressive and lethal skin cancer that affects thousands of people worldwide. Ruthenium complexes have shown promising results as cancer chemotherapeutics, offering several advantages over platinum drugs, such as potent efficacy, low toxicity, and less drug resistance. Additionally, anthraquinone derivatives have broad therapeutic applications, including melanoma.

Objectives: Thus, two new ruthenium complexes with 1-hydroxy-9,10-anthraquinone were obtained: trans-[Ru(HQ)(PPh₃)₂(bipy)]PF₆ (1) and cis-[RuCl₂(HQ)(dppb)] (2), where HQ = 1-hydroxy-9,10-anthraquinone, PPh₃ = triphenylphospine, bipy = 2,2'-bipyridine, PF₆ = hexafluorophosphate, and dppb = 1,4-bis(diphenylphosphine)butane.

Methods: The complexes were characterized by infrared (IR), UV-vis, ¹H, ¹³C{¹H}, and ³¹P{¹H} NMR spectroscopies, molar conductivity, cyclic voltammetry, and elemental analysis. Furthermore, density functional theory (DFT) calculations were performed.

Results: Compound (2) was determined by single-crystal X-ray diffraction, which confirms the bidentate coordination mode of HQ through the carbonyl and phenolate oxygens. Additionally, DNA-binding experiments yielded constants of 10⁵ M^-1 (Kb = 6.93 × 10⁵ for (1) and 1.60 × 10⁵ for (2)) and demonstrate that both complexes can interact with DNA through intercalation, electrostatic attraction, or hydrogen bonding.

Conclusions: The cytotoxicity profiles of the compounds were evaluated in human melanoma cell lines (SK-MEL-147, CHL-1, and WM1366), revealing greater cytotoxic activity for (1) on the CHL-1 cell line with an IC₅₀ of 14.50 ± 1.09 µM. Subsequent studies showed that (1) inhibits the proliferation of CHL-1 cells and induces apoptosis, associated at least in part with the pro-oxidant effect and cell cycle arrest at the G1/S transition.

Background/objectives: This study aims to assess the effects of combined hormonal contraceptives (CHCs) on bone metabolism markers. It primarily measures osteocalcin and additionally examines other bone health markers, seeking to determine their responses to estrogen-progestogen treatments.

Methods: This study involved a comprehensive evaluation of the pertinent literature and a meta-analysis explicitly conducted on data describing women of reproductive age. The analysis encompassed accessible papers ranging to December 2024 (i.e., those listed in PubMed/Medline, Embase, Scopus, the Cochrane Database, International Clinical Trials Registry, and ClinicalTrials.gov). We examined published randomized controlled trials (RCTs) and prospective studies. The quality of the studies was assessed using the Cochrane tool for RCTs and the Newcastle-Ottawa Scale for prospective studies. The selected indicators for primary and secondary outcomes were ascertained by standardized mean change (SMC), displaying the difference between conditions before and after treatment. Trends were evaluated using meta-regressions.

Results: Ultimately, 34 articles out of 1924 identified items met the inclusion criteria, covering 33 unique studies. In EE/E4 combinations, osteocalcin dropped significantly (SMC -0.54 (CI.95 -0.64/-0.43) and -0.43 (CI.95 -0.76/-0.10)). Similar effects were observed for other bone-formation and reabsorption markers, with less significant reductions observed in E2-containing CHC (e.g., alkaline phosphatase (bone) EE combinations, SMC -0.39 (CI.95 -0.67/-0.11); P1NP E2 combination, 0.12 (CI.95 -0.10/0.33); and EE combinations, -0.55 (CI.95 -0.83/-0.26)). The reduction patterns also exhibited differences according to the women's age (e.g., osteocalcin in EE combinations ≤21, SMC -0.63 (CI.95 -0.77/-0.49) and >21, SMC -0.42 (CI.95 -0.61/-0.24); alkaline phosphatase (bone) EE combinations ≤21, SMC -0.55 (CI.95 -0.86/-0.24) and >21, SMC -0.06 (CI.95 -0.47/0.35)). This analysis found that CHC maintains or reduces bone turnover in childbearing women, with effects varying by age and hormone combination. Moreover, bone-formation and reabsorption markers correlated positively to pro-androgenic progestins (p < 0.05). Thus, estrogen-progestogen combinations reduce bone turnover less when weak estrogens and a pro-androgenic or neutral progestin are present.

Conclusions: This study found that CHCs reduce bone turnover, with natural estrogens and androgenic progestins appearing to be more beneficial than EE and anti-androgenic types. These findings would potentially influence decisions relevant to CHC prescriptions during a woman's reproductive phases, emphasizing the need for additional research to tailor CHC usage to bone health.

Background/objectives: The rise of antibiotic-resistant pathogens has become a global health crisis, necessitating the development of alternative antimicrobial strategies. This study aimed to optimize the antibacterial effects of essential oils (EOs) from Thymus satureioides, Lavandula angustifolia, and Origanum majorana, enhancing their efficacy through optimized mixtures.

Methods: This study utilized a simplex-centroid design to optimize the mixture ratios of EOs for maximal antibacterial and antioxidant effectiveness. The chemical profiles of the EOs were analyzed using gas chromatography-mass spectrometry (GC-MS). The antibacterial activity was assessed against Escherichia coli, Staphylococcus aureus, and Pseudomonas aeruginosa using minimum inhibitory concentration (MIC) tests, while antioxidant activity was evaluated through DPPH (2,2-diphenyl-1-picrylhydrazyl), and ABTS (2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid)) assays.

Results: The optimized essential oil mixtures demonstrated potent antibacterial activity, with MIC values of 0.097% (v/v) for E. coli, 0.058% (v/v) for S. aureus, and 0.250% (v/v) for P. aeruginosa. The mixture ratios achieving these results included 76% T. satureioides, and 24% O. majorana for E. coli, and varying proportions for other strains. Additionally, L. angustifolia essential oil exhibited the strongest antioxidant activity, with IC₅₀ values of 84.36 µg/mL (DPPH), and 139.61 µg/mL (ABTS), surpassing both the other EOs and standard antioxidants like BHT and ascorbic acid in the ABTS assay.

Conclusions: The study successfully demonstrates that optimized mixtures of EOs can serve as effective natural antibacterial agents. The findings highlight a novel approach to enhance the applications of essential oils, suggesting their potential use in food preservation and biopharmaceutical formulations. This optimization strategy offers a promising avenue to combat antibiotic resistance and enhance food safety using natural products.

Chronic wounds present a substantial healthcare obstacle, marked by an extended healing period that can persist for weeks, months, or even years. Typically, they do not progress through the usual phases of healing, which include hemostasis, inflammation, proliferation, and remodeling, within the expected timeframe. Therefore, to address the socioeconomic burden in taking care of chronic wounds, hydrogel-based therapeutic materials have been proposed. Hydrogels are hydrophilic polymer networks with a 3D structure which allows them to become skin substitutes for chronic wounds. Knowing that peptides are abundant in the human body and possess distinct biological functionality, activity, and selectivity, their adaptability as peptide-based hydrogels to individual therapeutic requirements has made them a significant potential biomaterial for the treatment of chronic wounds. Peptide-based hydrogels possess excellent physicochemical and mechanical characteristics such as biodegradability and swelling, and suitable rheological properties as well great biocompatibility. Moreover, they interact with cells, promoting adhesion, migration, and proliferation. These characteristics and cellular interactions have driven peptide-based hydrogels to be applied in chronic wound healing.

Background/Objectives: Reference materials are essential for ensuring the accuracy and traceability of measurements in the quality control of medicinal products. This study explores new principles for the preparation of impure materials of active pharmaceutical substances, focusing on 1-(3-benzoylphenyl)ethanone ketoprofen impurity A (European Pharmacopoeia) as the reference material. Methods: The reference material was synthesised from commercially available acetanilide and benzoyl chloride. The obtained product was purified using preparative chromatography and characterised by infrared spectroscopy (IR), 1H and 13C nuclear magnetic resonance (NMR), and mass spectrometry. The structure was verified using primary research methods to confirm its identity as the target product. Results: The characterisation confirmed the structure and purity of 1-(3-benzoylphenyl)ethanone, achieving a purity of 99.86%, meeting regulatory documentation requirements. The synthesised product was demonstrated to be identical to the target compound and suitable for use as a reference material. Conclusions: The developed method provides a robust approach for the preparation and characterisation of 1-(3-benzoylphenyl)ethanone, enabling its use as a certified reference material in the quality control of medicinal products. This approach ensures compliance with regulatory standards and enhances the reliability of pharmaceutical quality assurance practices.

Objective: Peripheral artery disease (PAD) is a prevalent vascular condition characterized by arterial narrowing, which impairs blood flow and manifests as intermittent claudication, a pain or cramping sensation induced by physical activity or ambulation. Walking distance is a crucial clinical indicator of peripheral artery disease, and it correlates with the disease severity and risk of mortality. It reflects the severity of the disease, with reduced mobility indicating an increased risk of morbidity. It can also inform on the efficacy of the treatment. Cilostazol, a phosphodiesterase III inhibitor, has been demonstrated to enhance walking distance in patients with peripheral artery disease through the dilation of blood vessels and the inhibition of platelet aggregation. With this preliminary study, we aimed to elucidate other possible effects of cilostazol, specifically its influence on the structural properties of red blood cells. Methods: 10 patients (5 men, 5 women) with PAD were treated with cilostazol over a three-month period. Its biochemical effects on RBCs were determined using differential scanning calorimetry (DSC). Patient's blood samples were collected at the start of treatment, then after two weeks, one month, two months, and three months of therapy. Results: The DSC analysis revealed shifts in thermal properties, including change in peak (melting or denaturation) temperature (T_p) and calorimetric enthalpy (ΔH_cal), which indicate significant structural changes in red blood cells. These thermal property changes correlated with clinical improvements in walking distance reported by patients. Conclusions: Our findings suggest that cilostazol induces substantial biochemical modifications in red blood cells, enhancing their functional properties and contributing to improved clinical outcomes. This study highlights the potential of differential scanning calorimetry as an adjunctive method for assessing the effectiveness of treatments for peripheral artery disease at the cellular level. However, further investigation with larger patient cohorts is required to confirm these initial results.

It is critical to sustain the diversity of the microbiota to maintain host homeostasis and health. Growing evidence indicates that changes in gut microbial biodiversity may be associated with the development of several pathologies, including type 2 diabetes mellitus (T2DM). Metformin is still the first-line drug for treatment of T2DM unless there are contra-indications. The drug primarily inhibits hepatic gluconeogenesis and increases the sensitivity of target cells (hepatocytes, adipocytes and myocytes) to insulin; however, increasing evidence suggests that it may also influence the gut. As T2DM patients exhibit gut dysbiosis, the intestinal microbiome has gained interest as a key target for metabolic diseases. Interestingly, changes in the gut microbiome were also observed in T2DM patients treated with metformin compared to those who were not. Therefore, the aim of this review is to present the current state of knowledge regarding the association of the gut microbiome with the antihyperglycemic effect of metformin. Numerous studies indicate that the reduction in glucose concentration observed in T2DM patients treated with metformin is due in part to changes in the biodiversity of the gut microbiota. These changes contribute to improved intestinal barrier integrity, increased production of short-chain fatty acids (SCFAs), regulation of bile acid metabolism, and enhanced glucose absorption. Therefore, in addition to the well-recognized reduction of gluconeogenesis, metformin also appears to exert its glucose-lowering effect by influencing gut microbiome biodiversity. However, we are only beginning to understand how metformin acts on specific microorganisms in the intestine, and further research is needed to understand its role in regulating glucose metabolism, including the impact of this remarkable drug on specific microorganisms in the gut.

Background: We compared the enzymatic, coagulant, and neuromuscular activities of two variants (yellow-CDRy and white-CDRw) of Crotalus durissus ruruima venom with a sample of C. d. terrificus (CDT) venom and examined their neutralization by antivenom against CDT venom. Methods: The venoms were screened for enzymatic and coagulant activities using standard assays, and electrophoretic profiles were compared by SDS-PAGE. Neutralization was assessed by preincubating venoms with crotalic antivenom and assaying the residual activity. Results: SDS-PAGE showed that the venoms had similar electrophoretic profiles, with the main bands being phospholipase A₂ (PLA₂), serine proteinases, L-amino acid oxidase (LAAO), and phosphodiesterase. CDRy venom had the highest proteolytic and LAAO activities, CDRw venom had greater PLA₂ and esterolytic activities at the highest quantity tested, and CDT had greater PLA₂ activity than CDRy. CDRw and CDT venoms had similar proteolytic and LAAO activities, and CDRy and CDT venoms had comparable esterolytic activity. None of the venoms altered the prothrombin time (PT), but all of them decreased the activated partial thromboplastin time (aPPT); this activity was neutralized by antivenom. The minimum coagulant dose potency was CDRw >> CDRy > CDT. All venoms had thrombin-like activity that was attenuated by antivenom. CDRy and CDRw venoms showed α-fibrinogenolytic activity. All venoms partially cleaved the β-chain. CDRy and CDT venoms caused neuromuscular facilitation (enhanced muscle contractions) followed by complete blockade, whereas CDRw venom caused only blockade. Antivenom neutralized the neuromuscular activity to varying degrees. Conclusions: These findings indicate that while CDR and CDT venoms share similarities, they also differ in some enzymatic and biological activities and in neutralization by antivenom. Some of these differences could influence the clinical manifestations of envenomation by C. d. ruruima and their neutralization by the currently used therapeutic antivenom.