Search Results (9)

This prospective, observational, multicenter study assessed the tolerance of Dobenox Forte^®, the first approved over-the-counter product containing calcium dobesilate, in 1795 outpatients with chronic venous disease (CVD) in daily clinical practice. In addition, the effectiveness (decrease in circumferences of a more affected limb at the ankle and middle part of the calf, and changes in the severity of CVD signs) was assessed. No adverse events related to use of the preparation were reported in a period of 64 ± 20 days. Dobenox Forte^® use was associated with a reduction in calf circumference by 13.1 mm (95%CI: 12.2–14.1) and in ankle circumference by 9.7 mm (95%CI: 9.2–11.0) in patients reporting swelling of the lower legs (60.0% of the cohort). A reduction in calf and ankle circumference by at least 1 cm was achieved in 34.9% and 24.9% of patients, respectively. The percentages of patients reporting moderate to very severe lower limb heaviness decreased from 96.6% to 56.0%, calf cramps decreased from 91.0% to 41.0%, calf pain decreased from 89.2% to 43.7%, swelling decreased from 86.1% to 38.8%, and burning sensation that worsens when standing decreased from 79.0% to 33.7%. The medicinal product Dobenox Forte^® is well tolerated by patients and seems to effectively reduce the symptoms of CVD. Full article

The radiolytic degradation of vector molecules is a major factor affecting the shelf life of therapeutic radiopharmaceuticals. The development of time-stable dosage forms of radiopharmaceuticals is the key to their successful implementation in clinical practice. Using [¹⁷⁷Lu]Lu-PSMA-617 molecule as an example, the time dependence of the change in radiochemical purity (RCP, %) under radiolysis conditions was studied. The dependence of [¹⁷⁷Lu]Lu-PSMA-617 radiolysis on parameters such as time, radionuclide activity, buffer agent concentration, precursor amount, and preparation volume was evaluated. It was shown that the absorbed dose was the dominant factor influencing the RCP. The RCP value is inversely proportional to the absorbed dose in the [¹⁷⁷Lu]Lu-PSMA-617 preparation and has an exponential dependence. The lutetium-177 dose factor ψ (Gy·mL·MBq⁻¹) and PSMA-617 concentration-dependent dose constant κ (Gy⁻¹) were evaluated for absorbed dose estimation via computer modeling, chemical dosimetry, and radiochemical purity monitoring under various conditions. The further refinement and application of the dependencies found can be useful for predicting the RCP value at the stage of optimizing the composition of the finished dosage form of therapeutic radiopharmaceuticals. The influence of the buffer agent (sodium acetate) concentration on [¹⁷⁷Lu]Lu-PSMA-617 radiolytic degradation was shown and should be considered both when developing a dosage form, and when comparing the results of independent studies. The effectiveness of the addition of various stabilizing agents, such as DMSA, cysteine, gentisic acid, vanillin, methionine, adenine, dobesilic acid, thymine, uracil, nicotinamide, meglumine, and mannitol, in suppressing the effects of radiolysis was evaluated. Full article

NMR-based approaches play a pivotal role in providing insight into molecular recognition mechanisms, affording the required atomic-level description and enabling the identification of promising inhibitors of protein–protein interactions. The aberrant activation of the fibroblast growth factor 2 (FGF2)/fibroblast growth factor receptor (FGFR) signaling pathway drives several pathologies, including cancer development, metastasis formation, resistance to therapy, angiogenesis-driven pathologies, vascular diseases, and viral infections. Most FGFR inhibitors targeting the intracellular ATP binding pocket of FGFR have adverse effects, such as limited specificity and relevant toxicity. A viable alternative is represented by targeting the FGF/FGFR extracellular interactions. We previously identified a few small-molecule inhibitors acting extracellularly, targeting FGFR or FGF. We have now built a small library of natural and synthetic molecules that potentially act as inhibitors of FGF2/FGFR interactions to improve our understanding of the molecular mechanisms of inhibitory activity. Here, we provide a comparative analysis of the interaction mode of small molecules with the FGF2/FGFR complex and the single protein domains. DOSY and residue-level NMR analysis afforded insights into the capability of the potential inhibitors to destabilize complex formation, highlighting different mechanisms of inhibition of FGF2-induced cell proliferation. Full article

A drug–drug multicomponent crystal consisting of metformin (MET) and dobesilate (DBS) was prospectively connected by solvent cooling and evaporating co-crystallization using the multicomponent crystal strategy, not only to optimize the physicochemical properties of single drugs, but also to play a role in the cooperative effect of DBS with the potential vascular protective effects of MET against diabetic retinopathy (DR). The crystal structure analysis demonstrated that MET and DBS were coupled in a 3D supramolecular structure connected by hydrogen-bonding interactions with a molar ratio of 1:1. Almost all hydrogen bond donors and receptors of MET and DBS participated in the bonding, which hindered the combination of remaining potential hydrogen bond sites and water molecules, resulting in a lower hygroscopicity property than MET alone. Full article

Monocyte-to-macrophage differentiation results in the secretion of various inflammatory mediators and oxidative stress molecules necessary for atherosclerosis pathogenesis. Consequently, this differentiation represents a potential clinical target in atherosclerosis. Calcium dobesilate (CaD), an established vasoactive and angioprotective drug in experimental models of diabetic microvascular complications reduces oxidative stress and inhibits inflammation via diverse molecular targets; however, its effect on monocytes/macrophages is poorly understood. In this study, we investigated the anti-inflammatory mechanism of CaD during phorbol 12-myristate 13-acetate (PMA)-induced monocyte-to-macrophage differentiation in in vitro models of sepsis (LPS) and hyperglycemia, using THP-1 monocytic cell line. CaD significantly suppressed CD14, TLR4, and MMP9 expression and activity, lowering pro-inflammatory mediators, such as IL1β, TNFα, and MCP-1. The effects of CaD translated through to studies on primary human macrophages. CaD inhibited reactive oxygen species (ROS) generation, PKCδ, MAPK (ERK1/2 and p38) phosphorylation, NOX2/p47phox expression, and membrane translocation. We used hydrogen peroxide (H2O2) to mimic oxidative stress, demonstrating that CaD suppressed PKCδ activation via its ROS-scavenging properties. Taken together, we demonstrate for the first time that CaD suppresses CD14, TLR4, MMP9, and signature pro-inflammatory cytokines, in human macrophages, via the downregulation of PKCδ/NADPH oxidase/ROS/MAPK/NF-κB-dependent signaling pathways. Our data present novel mechanisms of how CaD alleviates metabolic and infectious inflammation. Full article

Reactive carbonyl species (RCS) such as methylglyoxal (MGO) or glyoxal (GO) are the main precursors of the formation of advanced glycation end products (AGEs). AGEs are a major factor in the development of vascular complications in diabetes. Vasoprotectives (VPs) exhibit a wide range of activities beneficial to cardiovascular health. The present study aimed to investigate selected VPs and their structural analogs for their ability to trap MGO/GO, inhibit AGE formation, and evaluate their antioxidant potential. Ultra-high-performance liquid chromatography coupled with an electrospray ionization mass spectrometer (UHPLC-ESI-MS) and diode-array detector (UHPLC-DAD) was used to investigate direct trapping capacity and kinetics of quenching MGO/GO, respectively. Fluorimetric and colorimetric measurements were used to evaluate antiglycation and antioxidant action. All tested substances showed antiglycative effects, but hesperetin was the most effective in RCS scavenging. We demonstrated that rutin, diosmetin, hesperidin, and hesperetin could trap both MGO and GO by forming adducts, whose structures we proposed. MGO-derived AGE formation was inhibited the most by hesperetin, and GO-derived AGEs by diosmetin. High reducing and antiradical activity was confirmed for quercetin, rutin, hesperetin, and calcium dobesilate. Therefore, in addition to other therapeutic applications, some VPs could be potential candidates as antiglycative agents to prevent AGE-related complications of diabetes. Full article

The long-term treatment of mice with D-galactose (D-gal) induces the overproduction of reactive oxygen species (ROS) and is a well-accepted experimental model of oxidative stress-linked cognitive disorders in physiological aging. Calcium dobesilate (CaD, Doxium^®) is an established vasoactive and angioprotective drug commonly used for the clinical treatment of diabetic retinopathy and chronic venous insufficiency. It has antioxidant properties and controls vascular permeability. In the current study, we evaluated the protective effects of CaD (50 and 100 mg/kg/day p.o.) in male mice treated with D-gal (500 mg/kg/day p.o.) for six weeks. Results demonstrated that body weight loss, anxiety-like and cognitive impairments of D-gal-treated animals were reversed by CaD administration as evaluated by the measurement of mice performance in elevated plus-maze, Y-maze, and shuttle box tests. CaD treatment also inhibited the oxidative stress in aging mouse brains by decreasing malondialdehyde (MDA) levels and increasing superoxide dismutase (SOD), glutathione peroxidase (GPx), and catalase (CAT) enzyme activities. These results could open new perspectives for the clinical use of CaD in treating and preventing cognitive impairment in older people. Full article

Lyophilization is the process of drying and improving the stability of various pharmaceutical preparations. In this work we evaluated the properties of 11 hydrophilic gels calcium dobesilate with liposomes based on soybean lecithin, subjected to the freeze-drying procedure. Liposomes were produced by using method thin lipid film. Lyophilization was carried out under conditions of temperature equal (−30 °C) and pressure 0.37 mbar. We evaluated the preparations with dynamic light scattering (DLS) method, optical microscopy and Fourier-transform infrared spectroscopy (FTIR). In this work we presented the average results for the particle diameter in the sample and PDI (polydispersity index) value for the samples that produced the results. When testing using the DLS method on a Malvern Zetaseizer, results for 7 samples were not obtained. Two of next four samples were characterized by an increased size of the liposome particle resulting from a lower concentration of ethanol compared to the rest of them. Three samples under the microscope did not show any differences. It was possible only to see single crystals probably of undissolved calcium dobesilate. Some clusters were observed in the 4 samples, and when they appeared they were very small. The aggregates and irregular liposomes present in the rest of the samples may have been formed due to the destabilizing activity of ethanol towards lipid membranes. In the FTIR spectrum for MC, the peak was observed at the wavenumber of ca. 2900 cm⁻¹ and of about 1050 cm⁻¹. In case of pure calcium dobesilate we observed low pick at the wavenumber of about 3400 cm⁻¹. The spectrum has a low peak at the wavenumber of 1450 cm⁻¹ and intense peaks ranging from approx. 1000 cm⁻¹ to approx. 1200 cm⁻¹. Decay of the lecithin peak in formulations with liposomes at 1725 cm⁻¹ wavelength may indicate the occurrence of the hydrolysis reaction in the system. Probably there was a hydrolysis of the ester bond connecting the rest of the phosphoric acid and the choline with the glycerol residue. Full article

Cyclic edema is a clinical condition in women that leads to fluid retention in the orthostatic position. The aim of the present study was to evaluate the prevalence of idiopathic cyclic edema in women with lower limb lymphedema. The prevalence of idiopathic cyclic edema was evaluated in a retrospective study of 100 consecutive female patients submitted to leg lymphedema treatment at the Clínica Godoy. The diagnosis of lymphedema was clinical, based on patient history and a physical examination. Patients with clinical stage II lymphedema were included in the study with those in stages I and III being excluded. The diagnosis of idiopathic cyclic edema was based on the patient’s history and fluid retention of more than one kilogram between 7:00 a.m. and 5:00 p.m. Clinical signs of this disease include difficulty removing rings in the morning that becomes easier during the course of the day, waking up with a swollen face, and abdominal discomfort during the day. After diagnosing cyclic edema, a therapeutic test was performed using aminaphtone or calcium dobesilate with which fluid retention was reduced to less than 300 g during the same period. The patients were instructed to drink liquids only when they were thirsty. Full article