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Karolina Dorobisz,1 Tadeusz Dorobisz,2 Katarzyna Pazdro-Zastawny,1 Marzena Kubacka,1 Sara Janczak,2 Dariusz Janczak2 1Department of Otolaryngology, Head and Neck Surgery, Wroclaw Medical University, Wroclaw, Poland; 2Department of Vascular, General and Transplant Surgery, Wroclaw Medical University, Wroclaw, PolandCorrespondence: Karolina Dorobisz, Department of Otolaryngology, Head and Neck Surgery, Wrocław Medical University, Borowska 213, Wrocław, 50-556, Poland, Tel +48 501207964, Email dorobiszkarolina@gmail.comIntroduction: Recurrent laryngeal nerve palsy is a rare but important complication after endarterectomy (CEA). The impact on voice quality after this procedure is also important. The aim of the study was to assess voice quality and vocal cord function after CEA.Material and Methods: 200 patients were enrolled in the study. Inclusion criteria were indications for CEA and patient consent to the procedure. Endoscopic examination of the larynx was performed before the procedure, immediately after the procedure, on the 2nd day after the procedure, then 3 month and 6 months after the procedure. Voice was assessed by maximum phonation time (MPT), GRBAS scale, Voice Handicap Index (VHI) and the Voice-Related Quality of Life (V-RQOL) questionnaire.Results: In the study group, the results on the GRBAS scale were significantly worse and the average MPT was shorter compared to the control group. In the V-RQOL assessment, patients rated their voice as fair or good, significantly more often noticed that they had difficulty speaking loudly and being heard, and that they felt short of air when speaking. In VHI-30, the total score was significantly higher in the study group compared to the control group. Voice disorders after the procedure were reported by 68 patients, while a disorder of the recurrent laryngeal nerve was observed immediately after the procedure in 32 patients. Most vocal cord disorders were transient. Ultimately, 3% of patients were diagnosed with vocal cord paralysis.Conclusion: Cranial nerves paralysis, including the recurrent laryngeal nerve, are a common complication after CEA. Majority the paralysis is transient, but requires appropriate diagnostic and therapeutic procedures. Vocal cord evaluation is a non-invasive and widely available examination and should be performed pre- and postoperatively after all neck surgeries. The incidence of voice disorders after CEA significantly affects the quality of life of patients and requires voice rehabilitation and patient care with psychological support.Keywords: carotid stenosis, endarterectomy, vocal cord paralysis, hoarseness, voice quality

Bogusz Jan Aksak-W&aogon;s,1 Daniel Chober,1 Karol Serwin,1 Kaja Scheibe,1 Jolanta Ni&sacute;cigorska-Olsen,2 Anna Nied&zacute;wied&zacute;,3 Monika Dobrowolska,3 Katarzyna &Zdot;ybul,4 Marta Kubacka,4 Agnieszka Zimo&nacute;,5 Ewa Ho&lstrok;da,4 Joanna Mie&zdot;y&nacute;ska-Kurtycz,4 Marta Gryczman,6 Grzegorz Jamro,7 Pawe&lstrok; Szako&lstrok;a,8 Mi&lstrok;osz Parczewski1 1Department of Infectious, Tropical Diseases and Immune Deficiency, Pomeranian Medical University in Szczecin, Szczecin, Poland; 2Department of Infectious, Tropical Diseases and Immune Deficiency, Provincial Hospital, Szczecin, Poland; 3Department of Diabetology and Internal Diseases, Provincial Hospital, Szczecin, Poland; 4Department of Internal Medicine and Oncology, Provincial Hospital, Szczecin, Poland; 5Department of Rheumatology, Department of Rehabilitation, Provincial Hospital, Szczecin, Poland; 6Department of Nephrology and Kidney Transplantation, Dialysis Station, Provincial Hospital, Szczecin, Poland; 7Department of Otolaryngology with the Sub-Department of Otolaryngology for Children, Provincial Hospital, Szczecin, Poland; 8Department of General and Transplant Surgery, Department of Vascular Surgery, Provincial Hospital, Szczecin, PolandCorrespondence: Bogusz Jan Aksak-W&aogon;s, Pomeranian Medical University, Department of Infectious, Tropical Diseases and Immune Deficiency, Arko&nacute;ska 4, Szczecin, 71-455, Poland, Tel +48918139455, Fax +49918139449, Email bogusz.aw@gmail.comIntroduction: Remdesivir is the first agent with proven clinical efficacy against coronavirus disease 2019 (COVID-19); however, its benefit is associated with early use, and its efficacy has been poorly studied in patients with hemato-oncological diseases, who have an increased risk of a severe course of infection. This study aimed to assess the effects of remdesivir on mortality, mechanical ventilation, and the duration of hospitalization in both the general population and in patients with hemato-oncological diseases.Materials and Methods: Longitudinal data for 4287 patients with confirmed COVID-19 were analyzed, including a subset of 200 individuals with hemato-oncological diseases. In total, 1285 (30.0%) patients received remdesivir, while the remaining patients were treated with other methods. Survival statistics for the 14- and 30-day observation time points were calculated using non-parametric and multivariate Cox models.Results: Mortality for the 14- and 30-day observation time points was notably lower among patients receiving remdesivir (7.2% vs 11.6%, p < 0.001 and 12.7% vs 16.0, p = 0.005, respectively); however, in multivariate models adjusted for age, sex, lung involvement, and lactate dehydrogenase and interleukin-6 levels, the administration of remdesivir did not reduce patient mortality at either the 14-day or 30-day time points. Among patients with haemato-oncological disease, significant survival benefit was observed at 14 and 30 days for patients treated with remdesivir (11.3% vs.16.7% and 24.2% vs 26.1%, respectively; p < 0.001). A favorable effect of remdesivir was also noted for the 14-day time point in multivariate survival analysis (HR:4.03 [95% confidence interval:1.37– 11.88]; p = 0.01).Conclusion: Remdesivir significantly reduced the early mortality rate in COVID-19 patients with comorbid hemato-oncological disease, which emphasizes the need to administer this agent to immunosuppressed patients.Keywords: COVID-19, SARS-COV-2, remdesivir, mortality, hemato-oncology

The article presents the accessibility conditions for carrying out research work for an exemplary site in the southern Baltic Sea region. The basic parameter of the state of the marine environment was the significant wave height determined at a frequency of one hour based on the ERA 5 model data covering the period between 1940 and 2022. A statistical analysis of the variability of this height on a monthly basis, taking into account its conversion into the time of potential availability in conditions enabling research, showed its strong seasonal variability in the form of differences in the number of hours that can be used for operating purposes. This number, depending on the research vessel capabilities, may even be an order of magnitude higher in the summer months than in winter. Additionally, it was found that the variability of the significant wave height has not changed substantially over the last 82 years., (© 2024. The Author(s).)

Motorship wrecks on the seabed pose a serious threat to the marine environment due to oil leaking from their fuel tanks. Such substances can penetrate the sediments and enter the water. There is a need to analyse bottom water and seabed sediment samples for the content of toxic petroleum substances. Tests were undertaken on samples collected near ​​the site of the World War II shipwreck of the s/s "Stuttgart". The wreck is located in the Baltic Sea, in the Gulf of Gdańsk. To answer whether toxic hydrocarbons from wrecks enter the sea environment, a fluorometric analysis was carried out based on measurements of excitation-emission ultraviolet spectra for sediments and near-seabed water. The results of these analyses indicate the presence of oil substances in the sediments and the bottom water at some sampling points close to the wreck site. Studies have shown that the applied method of the so-called fluorometric indicator allows for determining the sites of water pollution with oil substances hidden in sediments., (© 2024. The Author(s).)

Background: Numerous studies highlight the critical role that neural histamine plays in feeding behavior, which is controlled by central histamine H 3 and H 1 receptors. This is the fundamental motivation for the increased interest in creating histamine H 3 receptor antagonists as anti-obesity medications. On the other hand, multiple other neurotransmitter systems have been identified as pharmacotherapeutic targets for obesity, including sigma-2 receptor systems. Interestingly, in our previous studies in the rat excessive eating model, we demonstrated a significant reduction in the development of obesity using dual histamine H 3 /sigma-2 receptor ligands. Moreover, we showed that compound KSK-94 (structural analog of Abbott's A-331440) reduced the number of calories consumed, and thus acted as an anorectic compound. Therefore, in this study, we extended the previous research and studied the influence of KSK-94 on adipose tissue collected from animals from our previous experiment., Methods: Visceral adipose tissue was collected from four groups of rats (standard diet + vehicle, palatable diet + vehicle, palatable diet + KSK-94, and palatable diet + bupropion/naltrexone) and subjected to biochemical, histopathological, and immunohistochemical studies., Results: The obtained results clearly indicate that compound KSK-94 prevented the hypertrophy and inflammation of visceral adipose tissue, normalized the levels of leptin, resistin and saved the total reduction capacity of adipose tissue, being more effective than bupropion/naltrexon in these aspects. Moreover, KSK-94 may induce browning of visceral white adipose tissue., Conclusion: Our study suggests that dual compounds with a receptor profile like KSK-94, i.e., targeting histamine H 3 receptor and, to a lesser extent, sigma-2 receptor, could be attractive therapeutic options for patients at risk of developing obesity or with obesity and some metabolic disorders. However, more studies are required to determine its safety profile and the exact mechanism of action of KSK-94.

In the present study, a series of original alaninamide derivatives have been designed applying a combinatorial chemistry approach, synthesized, and characterized in the in vivo and in vitro assays. The obtained molecules showed potent and broad-spectrum activity in basic seizure models, namely, the maximal electroshock (MES) test, the 6 Hz (32 mA) seizure model, and notably, the 6 Hz (44 mA) model of pharmacoresistant seizures. Most potent compounds 26 and 28 displayed the following pharmacological values: ED 50 = 64.3 mg/kg (MES), ED 50 = 15.6 mg/kg (6 Hz, 32 mA), ED 50 = 29.9 mg/kg (6 Hz, 44 mA), and ED 50 = 34.9 mg/kg (MES), ED 50 = 12.1 mg/kg (6 Hz, 32 mA), ED 50 = 29.5 mg/kg (6 Hz, 44 mA), respectively. Additionally, 26 and 28 were effective in the iv PTZ seizure threshold test and had no influence on the grip strength. Moreover, lead compound 28 was tested in the PTZ-induced kindling model, and then, its influence on glutamate and GABA levels in the hippocampus and cortex was evaluated by the high-performance liquid chromatography (HPLC) method. In addition, 28 revealed potent efficacy in formalin-induced tonic pain, capsaicin-induced pain, and oxaliplatin- and streptozotocin-induced peripheral neuropathy. Pharmacokinetic studies and in vitro ADME-Tox data proved favorable drug-like properties of 28 . The patch-clamp recordings in rat cortical neurons showed that 28 at a concentration of 10 μM significantly inhibited fast sodium currents. Therefore, 28 seems to be an interesting candidate for future preclinical development in epilepsy and pain indications.

In the text, the synthesis and characteristics of the novel ONS-type vanadium (V) complexes with thioanilide derivatives of amino acids are described. They showed the inhibition of human protein tyrosine phosphatases (PTP1B, LAR, SHP1, and SHP2) in the submicromolar range, as well as the inhibition of non-tyrosine phosphatases (CDC25A and PPA2) similar to bis(maltolato)oxidovanadium(IV) (BMOV). The ONS complexes increased [14C]-deoxy-D-glucose transport into C2C12 myocytes, and one of them, VC070, also enhanced this transport in 3T3-L1 adipocytes. These complexes inhibited gluconeogenesis in hepatocytes HepG2, but none of them decreased lipid accumulation in the non-alcoholic fatty liver disease model using the same cells. Compared to the tested ONO-type vanadium complexes with 5-bromosalicylaldehyde and substituted benzhydrazides as Schiff base ligand components, the ONS complexes revealed stronger inhibition of protein tyrosine phosphatases, but the ONO complexes showed greater activity in the cell models in general. Moreover, the majority of the active complexes from both groups showed better effects than VOSO 4 and BMOV. Complexes from both groups activated AKT and ERK signaling pathways in hepatocytes to a comparable extent. One of the ONO complexes, VC068, showed activity in all of the above models, including also glucose utilizatiand ONO Complexes are Inhibitors ofon in the myocytes and glucose transport in insulin-resistant hepatocytes. The discussion section explicates the results within the wider scope of the knowledge about vanadium complexes.

Background and Objectives: Visible perivascular spaces are an MRI marker of cerebral small vessel disease and might predict future stroke. However, results from existing studies vary. We aimed to clarify this through a large collaborative multicenter analysis., Methods: We pooled individual patient data from a consortium of prospective cohort studies. Participants had recent ischemic stroke or transient ischemic attack (TIA), underwent baseline MRI, and were followed up for ischemic stroke and symptomatic intracranial hemorrhage (ICH). Perivascular spaces in the basal ganglia (BGPVS) and perivascular spaces in the centrum semiovale (CSOPVS) were rated locally using a validated visual scale. We investigated clinical and radiologic associations cross-sectionally using multinomial logistic regression and prospective associations with ischemic stroke and ICH using Cox regression., Results: We included 7,778 participants (mean age 70.6 years; 42.7% female) from 16 studies, followed up for a median of 1.44 years. Eighty ICH and 424 ischemic strokes occurred. BGPVS were associated with increasing age, hypertension, previous ischemic stroke, previous ICH, lacunes, cerebral microbleeds, and white matter hyperintensities. CSOPVS showed consistently weaker associations. Prospectively, after adjusting for potential confounders including cerebral microbleeds, increasing BGPVS burden was independently associated with future ischemic stroke (versus 0-10 BGPVS, 11-20 BGPVS: HR 1.19, 95% CI 0.93-1.53; 21+ BGPVS: HR 1.50, 95% CI 1.10-2.06; p = 0.040). Higher BGPVS burden was associated with increased ICH risk in univariable analysis, but not in adjusted analyses. CSOPVS were not significantly associated with either outcome., Discussion: In patients with ischemic stroke or TIA, increasing BGPVS burden is associated with more severe cerebral small vessel disease and higher ischemic stroke risk. Neither BGPVS nor CSOPVS were independently associated with future ICH.

Caramel, defined as a coloring agent and as an antioxidant, is used in several kinds of food products and is consumed by many people in different amounts. In our research we showed that the caramelization of sucrose under special conditions leads to the formation of carbon quantum dots (CQDs). So, it makes sense that humans also consume this type of CQDs, and it is theoretically possible for these particles to affect the body. Despite an increasing number of studies describing different types of CQDs, their biosafety is still not clearly understood. In our in vitro research, we examined the effects on platelet aggregation, protein glycation and lipid peroxidation of CQDs and caramel formed from a 20% sucrose solution. In vitro aggregation tests were conducted using freshly collected whole rat blood in a multiplate platelet function analyzer and measurer of electric impedance. The cytotoxic effect of the tested solutions on blood platelets was evaluated based on the release of lactate dehydrogenase. The formation of glycated bovine serum albumin was measured as fluorescence intensity and fructosamine level. The reducing power of the solutions was determined in adipose tissue, and their effect on lipid peroxidation in adipose tissue in vitro was also assessed. By measuring the intensity of hemolysis after incubation in solutions with red blood cell, we assessed their influence on the integration of the red blood cell membrane. All tests were performed in comparison with glucose and fructose and other frequently used sweeteners, such as erythritol and xylitol. Our study showed that caramel and CQDs formed from caramel may influence the glycation process and integrity of the red blood cell membrane, but unlike glucose and fructose, they decrease lipid peroxidation and may reduce Fe (III). Additionally, it is unlikely that they affect platelet aggregation. Compared to glucose and fructose, they may be safer for patients with metabolic disorders; however, further research is needed on the safety and biological activity of caramel and CQD.

Alzheimer's disease (AD), a neurodegenerative disorder with a complex aetiology, is the most common memory dysfunction particularly affecting the elderly. Various protein targets have been classified to be involved in the AD treatment, including 5-HT 6 receptor (5-HT 6 R). So far, the 5-HT 6 R ligands obtained by our research group have become a good basis for hydrophobicity modulation to give a chance for more effective action toward AD by additional influence on target enzymes, e.g. cyclin-dependent kinase 5 (CDK5). In the search for 5-HT 6 R agents with additional inhibitory action on the enzyme, a series of 25 new 1,3,5-triazines (7-31) as modifications of lead, 4-[1-(2,5-dichlorophenoxy)propyl]-6-(4-methylpiperazin-1-yl)-1,3,5-triazine-2-amine (6), was rationally designed. Molecular modelling, synthesis, crystallographic studies, in vitro biological assays and behavioral studies in vivo were performed. The new triazines showed high affinity (K i  < 100 nM) and selectivity for 5-HT 6 R. The most effective one, 4-[1-(2,5-difluorophenoxy)propyl]-6-(4-methylpiperazin-1-yl)-1,3,5-triazine-2-amine (8), exhibited the strong antagonistic action towards 5-HT 6 R (K i  = 5 nM, pK b  = 8.16), had an impact on the memory processes in the Novel Object Recognition test and displayed anxiolytic-like activity in the Elevated Plus Maze test in rats. Moreover, it had the antiplatelet effect as well as very good permeability (PAMPA model), high metabolic stability (RLMs) and satisfactory safety in vitro. Although the CDK5 inhibitory effects in vitro for the tested compounds (8, 10, 14, 18, 26-31) missed the potency expected from in silico simulations, the novel antagonist (8) with a very satisfying pharmacological and ADMET profile can serve as a new lead structure in further searches for innovative therapy against AD with accompanying symptoms., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

The multifactorial origin and neurochemistry of Alzheimer's disease (AD) call for the development of multitarget treatment strategies. We report a first-in-class triple acting compound that targets serotonin type 6 and 3 receptors (5-HT-Rs) and monoamine oxidase type B (MAO-B) as an approach for treating AD. The key structural features required for MAO-B inhibition and 5-HT 6 R antagonism and interaction with 5-HT 3 R were determined using molecular dynamic simulations and cryo-electron microscopy, respectively. Bioavailable PZ-1922 reversed scopolamine-induced cognitive deficits in the novel object recognition test. Furthermore, it displayed superior pro-cognitive properties compared to intepirdine (a 5-HT 6 R antagonist) in the AD model, which involved intracerebroventricular injection of an oligomeric solution of amyloid-β peptide (oAβ) in the T-maze test in rats. PZ-1922 , but not intepirdine, restored levels of biomarkers characteristic of the debilitating effects of oAβ. These data support the potential of a multitarget approach involving the joint modulation of 5-HT 6 R/5-HT 3 R/MAO-B in AD.

Alzheimer's disease is becoming a growing problem increasing at a tremendous rate. Serotonin 5-HT 6 receptors appear to be a particularly attractive target from a therapeutic perspective, due to their involvement not only in cognitive processes, but also in depression and psychosis. In this work, we present the synthesis and broad biological characterization of a new series of 18 compounds with a unique 1,3,5-triazine backbone, as potent 5-HT 6 receptor ligands. The main aim of this research is to compare the biological activity of the newly synthesized sulfur derivatives with their oxygen analogues and their N-demethylated O- and S-metabolites obtained for the first time. Most of the new triazines displayed high affinity (K i  < 200 nM) and selectivity towards 5-HT 6 R, with respect to 5-HT 2A R, 5-HT 7 R, and D 2 R, in the radioligand binding assays. For selected, active compounds crystallographic studies, functional bioassays, and ADME-Tox profile in vitro were performed. The exciting novelty is that the sulfur derivatives exhibit an agonistic mode of action contrary to all other compounds obtained to date in this chemical class herein and previously reported. Advanced computational studies indicated that this intriguing functional shift might be caused by presence of chalcogen bonds formed only by the sulfur atom. In addition, the N-demethylated derivatives have emerged highly potent antioxidants and, moreover, show a significant improvement in metabolic stability compared to the parent structures. The cholinesterase study present micromolar inhibitory AChE and BChE activity for both 5-HT 6 agonist 19 and potent antagonist 5. Finally, the behavioral experiments of compound 19 demonstrated its antidepressant-like properties and slight ability to improve cognitive deficits, without inducing memory impairments by itself. Described pharmacological properties of both compounds (5 and 19) allow to give a design clue for the development of multitarget compounds with 5-HT 6 (both agonist and antagonist)/AChE and/or BChE mechanism in the group of 1,3,5-triazine derivatives., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Excessive fructose consumption may lead to metabolic syndrome, metabolic dysfunction-associated fatty liver disease (MAFLD) and hypertension. α1-adrenoceptors antagonists are antihypertensive agents that exert mild beneficial effects on the metabolic profile in hypertensive patients. However, they are no longer used as a first-line therapy for hypertension based on Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) outcomes. Later studies have shown that quinazoline-based α1-adrenolytics (prazosin, doxazosin) induce apoptosis; however, this effect was independent of α1-adrenoceptor blockade and was associated with the presence of quinazoline moiety. Recent studies showed that α1-adrenoceptors antagonists may reduce mortality in COVID-19 patients due to anti-inflammatory properties. MH-76 (1-[3-(2,6-dimethylphenoxy)propyl]-4-(2-methoxyphenyl)piperazine hydrochloride)) is a non-quinazoline α1-adrenoceptor antagonist which, in fructose-fed rats, exerted anti-inflammatory, antihypertensive properties and reduced insulin resistance and visceral adiposity. In this study, we aimed to evaluate the effect of fructose consumption and treatment with α1-adrenoceptor antagonists of different classes (MH-76 and prazosin) on liver tissue of fructose-fed rats. Livers were collected from four groups (Control, Fructose, Fructose + MH-76 and Fructose + Prazosin) and subjected to biochemical and histopathological studies. Both α1-adrenolytics reduced macrovesicular steatosis and triglycerides content of liver tissue and improved its antioxidant capacity. Treatment with MH-76, contrary to prazosin, reduced leucocytes infiltration as well as decreased elevated IL-6 and leptin concentrations. Moreover, the MH-76 hepatotoxicity in hepatoma HepG2 cells was less than that of prazosin. The use of α1-adrenolytics with anti-inflammatory properties may be an interesting option for treatment of hypertension with metabolic complications.

Itch and pain are closely related but distinct sensations that share largely overlapping mediators and receptors. We hypothesized that the novel, multi-target compound E153 has the potential to attenuate pain and pruritus of different origins. After the evaluation of sigma receptor affinity and pharmacokinetic studies, we tested the compound using different procedures and models of pain and pruritus. Additionally, we used pharmacological tools, such as PRE-084, RAMH, JNJ 5207852, and S1RA, to precisely determine the role of histamine H 3 and sigma 1 receptors in the analgesic and antipruritic effects of the compound. In vitro studies revealed that the test compound had potent affinity for sigma 1 and sigma 2 receptors, moderate affinity for opioid kappa receptors, and no affinity for delta or μ receptors. Pharmacokinetic studies showed that after intraperitoneal administration, the compound was present at high concentrations in both the peripheral tissues and the central nervous system. The blood-brain barrier-penetrating properties indicate its ability to act centrally at the levels of the brain and spinal cord. Furthermore, the test compound attenuated different types of pain, including acute, inflammatory, and neuropathic. It also showed a broad spectrum of antipruritic activity, attenuating histamine-dependent and histamine-independent itching. Finally, we proved that antagonism of both sigma 1 and histamine H 3 receptors is involved in the analgesic activity of the compound, while the antipruritic effect to a greater extent depends on sigma 1 antagonism.

The platelet aggregation inhibitory activity of selected xanthine-based adenosine A 2A and A 2B receptor antagonists was investigated, and attempts were made to explain the observed effects. The selective A 2B receptor antagonist PSB-603 and the A 2A receptor antagonist TB-42 inhibited platelet aggregation induced by collagen or ADP. In addition to adenosine receptor blockade, the compounds were found to act as moderately potent non-selective inhibitors of phosphodiesterases (PDEs). TB-42 showed the highest inhibitory activity against PDE3A along with moderate activity against PDE2A and PDE5A. The antiplatelet activity of PSB-603 and TB-42 may be due to inhibition of PDEs, which induces an increase in cAMP and/or cGMP concentrations in platelets. The xanthine-based adenosine receptor antagonists were found to be non-cytotoxic for platelets. Some of the compounds showed anti-oxidative properties reducing lipid peroxidation. These results may provide a basis for the future development of multi-target xanthine derivatives for the treatment of inflammation and atherosclerosis and the prevention of heart infarction and stroke.

Poisoning and overdose are very important aspects in medicine and toxicology. Chemical weapons pose a threat to civilians, and emergency medicine principles must be followed when dealing with patients who have been poisoned or overdosed. Antidotes have been used for centuries and modern research has led to the development of new antidotes that can accelerate the elimination of toxins from the body. Although some antidotes have become less relevant due to modern intensive care techniques, they can still save lives or reduce the severity of toxicity. The availability of antidotes is crucial, especially in developing countries where intensive care facilities may be limited. This article aims to provide information on specific antidotes, their recommended uses, and potential risks and new uses. In the case of poisoning, supportive therapies are most often used; however, in many cases, the administration of an appropriate antidote saves the patient's life. In this review, we reviewed the literature on selected antidotes used in the treatment of poisonings. We also characterised the antidotes (bio)chemically. We described the cases in which they are used together with the dosage recommendations. We also analysed the mechanisms of action. In addition, we described alternative methods of using a given substance as a drug, an example of which is N -acetylcysteine, which can be used in the treatment of COVID-19. This article was written as part of the implementation of the project of the Polish Ministry of Education and Science, "Toxicovigilance, poisoning prevention, and first aid in poisoning with xenobiotics of current clinical importance in Poland", grant number SKN/SP/570184/2023.

This study concerns the analysis of navigational risk indicators as a function of the ship's domain width estimated for nine selected representative ships sailing under various hydrometeorological conditions (average and deteriorated ones) observed within the Offshore Wind Farm to be constructed within the Polish offshore zone on the Baltic Sea. For this purpose, the authors compare three types of domain parameters according to the guidelines by the PIANC, Coldwell and Rutkowski (3D). The study enabled selection of a group of ships which can be considered safe and can optionally be allowed to navigate and/or fish in the immediate vicinity and within the offshore wind farm. The analyses required the use of hydrometeorological data, mathematical models and operating data obtained with the use of maritime navigation and manoeuvring simulators., (© 2023. The Author(s).)

Background: Epilepsy frequently coexists with neuropathic pain. Our approach is based on the search for active compounds with multitarget profiles beneficial in terms of potential side effects and on the implementation of screening for potential multidirectional central activity., Methods: Compounds were synthesized by means of chemical synthesis. After antiseizure and neurotoxicity screening in vivo, KM-408 and its enantiomers were chosen for analgesic activity evaluations. Further safety studies included acute toxicity in mice, the effect on normal electrocardiogram and on blood pressure in rats, whole body plethysmography in rats, and in vitro and biochemical assays. Pharmacokinetics has been studied in rats after iv and po administration. Metabolism has been studied in vivo in rat serum and urine. Radioligand binding studies were performed as part of the mechanism of action investigation., Results: Selected results for KM-408: K i sigma = 7.2*10 -8 ; K i 5-HT 1A  = 8.0*10 -7 ; ED 50 MES (mice, ip) = 13.3 mg/kg; formalin test (I phase, mice, ip)-active at 30 mg/kg; SNL (rats, ip)-active at 6 mg/kg; STZ-induced pain (mice, ip)-active at 1 mg/kg (von Frey) and 10 mg/kg (hot plate); hot plate test (mice, ip)-active at 30 mg/kg; ED 50 capsaicin test (mice, ip) = 18.99 mg/kg; tail immersion test (mice)-active at 0.5%; corneal anesthesia (guinea pigs)-active at 0.125%; infiltration anesthesia (guinea pigs)-active at 0.125%., Conclusions: Within the presented study a novel compound, R,S-2-((2-(2-chloro-6-methylphenoxy)ethyl)amino)butan-1-ol hydrochloride (KM-408) with dual antiseizure and analgesic activity has been developed for potential use in neuropathic pain treatment., (© 2022. The Author(s).)

Introduction: Measures of cerebral small vessel disease (cSVD), such as white matter hyperintensities (WMH) and cerebral microbleeds (CMB), are associated with an unfavorable clinical course in stroke patients on oral anticoagulation (OAC) for atrial fibrillation (AF). Here, we investigated whether similar findings can be observed for global cortical atrophy (GCA)., Methods: Registry-based prospective observational study of 320 patients treated with OAC following AF stroke. Patients underwent magnetic resonance imaging (MRI) allowing assessment of GCA. Using the simplified visual Pasquier scale, the severity of GCA was categorized as follows: 0: no atrophy, 1: mild atrophy; 2: moderate atrophy, and 3: severe atrophy. Using adjusted logistic and Cox regression analysis, we investigated the association of GCA using a composite outcome measure, comprising: (i) recurrent acute ischemic stroke (IS); (ii) intracranial hemorrhage (ICH); and (iii) death., Results: In our time to event analysis after adjusting for potential confounders (i.e., WMH, CMB, age, sex, diabetes, arterial hypertension, coronary heart disease, hyperlipidemia, and antiplatelet use), GCA was associated with an increased risk for the composite outcome in all three degrees of atrophy (grade 1: aHR 3.95, 95% CI 1.34-11.63, p = 0.013; grade 2: aHR 3.89, 95% CI 1.23-12.30, p = 0.021; grade 3: aHR 4.16, 95% CI 1.17-14.84, p = 0.028)., Conclusion: GCA was associated with our composite outcome also after adjusting for other cSVD markers (i.e., CMB, WMH) and age, indicating that GCA may potentially serve as a prognostic marker for stroke patients with atrial fibrillation on oral anticoagulation., (© 2022 The Author(s). Published by S. Karger AG, Basel.)

Dredged material dumping is an activity that causes some of the greatest changes in coastal waters. It results in the need to regularly monitor the properties of seawater related to water quality. In this study, we present the first wide-ranging attempt to correlate seawater turbidity and suspended particulate matter (SPM) concentrations within dumping sites and adjacent waters on the basis of in situ measurements. In the years 2019-2020, we examined four dumping sites, namely Darłowo, Gdynia, Gdańsk, and DCT, located in Polish coastal waters of the Baltic Sea, in the course of four measurement campaigns conducted in the spring, summer, autumn, and winter. The measurements were conducted using a turbidity sensor to determine the turbidity, in formazin turbidity units (FTU), a spectrophotometer to determine the concentrations of nutrients (total phosphorus (P-tot), phosphate phosphorus (P-PO 4 -3 ), total nitrogen (N-tot), ammonium nitrogen (N-NH 4 + ), and nitrate nitrogen (N-NO 3 - )), as well as glass microfiber filters to determine the concentrations of SPM. The analysis of the relationship between the turbidity and SPM within the dumping sites in comparison to reference points showed that the dumping sites are very complex waters and that the issue must be approached locally. The highest turbidity values were registered in the spring, and they correlated linearly with the SPM concentrations (R 2 = 0.69). Moreover, we performed a statistical cluster analysis to illustrate the similarities between sampling points in the four dumpsites based on nutrient concentrations. We conclude that the influence of the dumping sites on the local bio-optical and chemical properties significantly exceeds their borders and spreads to the adjacent waters. Nutrient concentrations in many cases exceeded the legal policy limits.

Research of the marine environment is still a huge challenge for humanity. Each survey campaign is a complex project, where research vessels and relevant survey equipment is used. One of the problems that limit the success of working at sea are failures of survey equipment. The aim of this paper was to identify the most common survey equipment failures during marine research, find their causes and analyze identified risks. The authors employ risk assessment methodology in maritime research at sea and present its practical utility and contribution in social and organizational development. For this purpose we based the analysis on the review of relevant project documentation (Daily Progress Reports, Observation Cards) and the questionnaire addressed to specialists who carry out their survey work on board research vessels and also people involved in the implementation of offshore projects. The research reveals that 76.3% respondents participated in a project which had to be stopped due to a failure of the survey equipment that required return to the port which highlights that the problem which was analyzed is of particular importance. The questionnaire form was designed to obtain as much information as possible on the types of failures with examples and also their causes according to three groups: human factors, technical factors and forces of nature. Twelve risks were identified and analyzed. The authors also stress the relationship between the quality of research project management and its implementation in the context of the failure rate of measuring equipment., Competing Interests: The authors have declared that no competing interests exist.

Many studies involving compounds that enhance histamine release, such as histamine H 3 receptor (H 3 R) antagonists, have shown efficacy in inhibiting weight gain, but none have passed clinical trials. As part of the search for H 3 receptor ligands that have additional properties, the aim of this study is to evaluate the activity in the reduction in weight gain in a rat model of excessive eating, as well as the impact on selected metabolic parameters, and the number and size of adipocytes of two new H 3 R antagonists, KSK-60 and KSK-74, which also exert a significant affinity at the sigma-2 receptor. Compounds KSK-60 and KSK-74 are homologues and the elongation of the distal part of the molecule resulted in an approximate two-fold reduction in affinity at H 3 R, but simultaneously an almost two-fold increase in affinity at the sigma-2 receptor. Animals fed palatable feed and receiving KSK-60 or KSK-74 both at 10 mg/kg b.w. gained significantly less weight than animals in the control obese group. Moreover, KSK-74 significantly compensated for metabolic disturbances that accompany obesity, such as an increase in plasma triglyceride, resistin, and leptin levels; improved glucose tolerance; and protected experimental animals against adipocyte hypertrophy. Furthermore, KSK-74 inhibited the development of inflammation in obesity-exposed adipose tissue. The in vivo pharmacological activity of the tested ligands appears to correlate with the affinity at the sigma-2 receptors; however, the explanation of this phenomenon requires further and extended research.

Schizophrenia is a serious mental disorder without a fully understood pathomechanism, but which involves dysregulation of neurotransmitters and their receptors. The best option for the management of schizophrenia comprises so-called multi-target ligands, similar to the third generation of neuroleptics. Dopamine type 2 receptors (D 2 Rs) are the main target in the treatment of schizophrenia, in particular for mitigation of the positive symptoms. Due to the high expression of 5-hydroxytryptamine type 3 receptors (5-HT 3 Rs) in human brain areas responsible for emotional behavior, motivation, and cognitive function, 5-HT 3 Rs represent a potential target for modulating the cognitive and negative symptoms of schizophrenia. Here we present the design, synthesis, and both in vitro and in vivo biological evaluation of 1,4-disubstituted aromatic piperazines. Screening of in vitro properties revealed the two most promising drug candidates (21 and 24) which were found to be potent D 2 Rs and moderate 5-HT 3 R antagonists, and which were forwarded to in vivo studies in Wistar rats. Considering toxicity, administration of the maximal feasible dose of 21 (2 mg/kg) did not produce any side effects. By contrast, the higher solubility of 24 led to revelation of mild and temporary side effects at the dose of 20 mg/kg. Importantly, both 21 and 24 showed facile crossing of the blood-brain barrier, even exerting higher levels in the brain in comparison to plasma. In a behavioral study using the acute amphetamine model of psychosis, we showed that compound 24 ameliorated both positive and negative effects of amphetamine including hyperlocomotion, social impairments, and disruption of prepulse inhibition. The effect of the highest dose (10 mg/kg) was comparable to the effect of the reference dose of aripiprazole (1 mg/kg)., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)

Coastal waters are the richest parts of ocean ecosystems characterised by dynamic changes in water biology, physical and chemical features. Establishing local relationships between water constituents and optical properties in these areas will help to develop successful ocean colour algorithms allowing a thorough understanding of complex coastal waters and improving water quality monitoring. In this paper, the authors present the use of optical and biogeochemical measurements in complex aquatic environments and aim to create a semi-empirical model of remote-sensing reflectance ( R rs ( λ i )) for four wavelengths ( λ i = 420 nm, 488 nm, 555 nm, and 620 nm) based on multiparameter algorithms of absorption ( a ( λ i )) and backscattering ( b b ( λ i )) coefficients. The bio-optical properties of water were determined based on empirical data gathered from aboard the r/v Oceania from April 2007 to March 2010 in chosen areas of the southern Baltic (Polish coast). The analyses reveal that R rs ( λ i ) in the studied area can be described with satisfactory accuracy using a five-parameter model. Positive results with a statistical error magnitude of R rs ( λ i ) of less than 50% were achieved for all four applied wavelengths. Bio-optical algorithms proposed by the authors enable evaluating biogeochemical characteristics of coastal areas in a broader context of ecosystem assessment and contribute significantly to the development of Earth and environmental sciences.

Small drug-like molecules that can block the function of serotonin 5-HT 2A receptors have garnered considerable attention due to their ability to inhibit platelet aggregation and the possible prevention of atherosclerotic lesions. Although clinical data provided compelling evidence for the efficacy of this approach in the prevention of various cardiovascular conditions, the chemical space of 5-HT 2A receptor antagonists is limited to ketanserin and sarpogrelate. To expand the portfolio of novel chemical motifs with potential antiplatelet activity, we evaluated the antiplatelet activity of a series of 6-fluorobenzo[d]isoxazole derivatives that possess a high affinity for 5-HT 2A receptor. Here we describe in vitro studies showing that 6-fluorobenzo[d]isoxazole derivatives exert promising antiplatelet activity in three various in vitro models of platelet aggregation, as well as limit serotonin-induced vasoconstriction. Compound AZ928 showed in vitro activity greater than the clinically approved drug sarpogrelate. In addition to promising antiplatelet activity, the novel series was characterized by a favorable safety profile. Our findings show that the novel series exerts promising antiplatelet efficacy while being deprived of potential side effects, such as hemolytic activity, which render these compounds as potential substances for further investigation in the field of cardiovascular research., (Copyright © 2021 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Background: Antiplatelet drugs have been used in the treatment of acute coronary syndromes and for the prevention of recurrent events. Unfortunately, many patients remain resistant to the available antiplatelet treatment. Therefore, there is a clinical need to synthesize novel antiplatelet agents, which would be associated with different pathways of platelet aggregation, to develop an alternative or additional treatment for resistant patients. Recent studies have revealed that 5-HT 2A receptor antagonists could constitute alternative antiplatelet therapy., Methods: Based on the structures of the conventional 5-HT 2A receptor ligands, two series of compounds with 4-phenylcyclohexane-5-spiro- or 5-methyl-5-phenyl-hydantoin core linked to various arylpiperazine moieties were synthesized and their affinity for 5-HT 2A receptor was assessed. Further, we evaluated their antagonistic potency at 5-HT 2A receptors using isolated rat aorta and cells expressing human 5-HT 2A receptors. Finally, we studied their anti-aggregation effect and compared it with ketanserin and sarpogrelate, the reference 5-HT 2A receptor antagonists. Moreover, the structure-activity relationships were studied following molecular docking to the 5-HT 2A receptor model., Results: Functional bioassays revealed some of the synthesized compounds to be moderate antagonists of 5-HT 2A receptors. Among them, 13, 8-phenyl-3-(3-(4-phenylpiperazin-1-yl)propyl)-1,3-diazaspiro[4.5]decane-2,4-dione, inhibited collagen stimulated aggregation (IC 50  = 27.3 μM) being more active than sarpogrelate (IC 50  = 66.8 μM) and comparable with ketanserin (IC 50  = 32.1 μM). Moreover, compounds 2-5, 9-11, 13, 14 inhibited 5-HT amplified, ADP- or collagen-induced aggregation., Conclusions: Our study confirmed that the 5-HT 2A antagonists effectively suppress platelet aggregation and remain an interesting option for the development of novel antiplatelet agents with an alternative mechanism of action., (© 2021. The Author(s).)

GPR18 is an orphan GPCR that is activated by the cannabinoid tetrahydrocannabinol (THC). Emerging evidence indicates its involvement in the control of cardiovascular functions, including heart rate, contractility, vascular tone, as well as blood pressure. Therefore, we investigated the effects of selective GPR18 receptor ligands, namely PSB-KD-107 (agonist) and PSB-CB-92 (antagonist), on blood pressure, electrocardiogram (ECG), and vascular dilatation in vitro and in vivo, as well as their anti-oxidative potential in in vitro ferric reducing antioxidant power (FRAP) and 2,2-diphenyl-1-picryl-hydrazyl-hydrate free radical (DPPH) assays. Our results clearly show that PSB-KD-107 dilates blood vessels. This effect is related to its activation of GPR18 as it can be blocked by the GPR18 antagonist PSB-CB-92. Moreover, our finding confirms the presence of GPR18 in blood vessels. The mechanism of the vasorelaxant activity of PSB-KD-107 is mainly related to endothelial nitric oxide generation; however, we cannot exclude additional nitric oxide-independent mechanisms or a direct influence on K + channels. PSB-KD-107 may affect blood pressure and heart function after a single administration; however, this effect was no longer observed after repeated administrations once daily for eight days. PSB-KD-107 does not affect platelet aggregation-an important feature considering the safety of its administration. PSB-KD-107 also shows a significant anti-oxidant effect and further studies of its antioxidant activity in vivo are justified.

Tiagabine is an antiepileptic drug used for the treatment of partial seizures in humans. Recently, this drug has been found useful in several non-epileptic conditions, including anxiety, chronic pain and sleep disorders. Since tachycardia-an impairment of cardiac rhythm due to cardiac ion channel dysfunction-is one of the most commonly reported non-neurological adverse effects of this drug, in the present paper we have undertaken pharmacological and numerical studies to assess a potential cardiovascular risk associated with the use of tiagabine. A chemical interaction of tiagabine with a model of human voltage-gated ion channels (VGICs) is described using the molecular docking method. The obtained in silico results imply that the adverse effects reported so far in the clinical cardiological of tiagabine could not be directly attributed to its interactions with VGICs. This is also confirmed by the results from the isolated organ studies (i.e., calcium entry blocking properties test) and in vivo (electrocardiogram study) assays of the present research. It was found that tachycardia and other tiagabine-induced cardiac complications are not due to a direct effect of this drug on ventricular depolarization and repolarization.

Background: Quinazoline α 1 -adrenoceptors antagonists have been shown to exert moderately favorable effects on the metabolic profile in hypertensive patients. However, based on AntiHypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) results, they are no longer recommended as a first line therapy of hypertension. Recent studies have shown that quinazoline-based α 1 -adrenoceptors antagonists (prazosin, doxazosin) induce the apoptosis and necrosis, which may be responsible for ALLHAT outcomes; however, these effects were proven to be independent of α 1 -adrenoceptor blockade and were associated with the presence of quinazoline moiety. MH-76 (1-[3-(2,6-dimethylphenoxy)propyl]-4-(2-methoxyphenyl)piperazine hydrochloride)) is a non-quinazoline α 1 -adrenoceptor antagonist which, in fructose-fed rats, exerted antihypertensive effect, and, contrary to prazosin, reduced insulin resistance and abdominal adiposity. In this study we aimed to further investigate and compare the effects of MH-76 and prazosin on inflammation in adipose tissue of fructose-fed rats., Methods: Abdominal adipose tissue was collected from four groups of fructose-fed rats (Control, Fructose, Fructose + MH-76 and Fructose + Prazosin) and subjected to biochemical, histopathological and immunohistochemical studies. Moreover, selected tissue distribution studies were performed., Results: Treatment with MH-76 but not with prazosin improved endothelial integrity, reduced adipose tissue inflammation and infiltration by immune cells, resulting in lowering leptin, MCP-1, IL-6, TNF-α and PAI-1 levels. In adipose tissue from Fructose + MH-76 animals, a higher amount of eosinophils accompanied with higher IL-4 concentration was observed. Treatment with MH-76 but not with prazosin markedly reduced phosphorylation of IRS-1 at Ser307., Conclusion: MH-76 may improve insulin signaling in adipose tissue by reducing the pro-inflammatory cytokine production and inhibiting the inflammatory cells recruitment. In contrast, in adipose tissue from animals treated with prazosin, the inflammatory effect was clearly enhanced.

GPR18 has been proposed to play a role in the progression of metabolic disease and obesity. Therefore, the aim of this study was to determine the effects of selective GRP18 ligands (the antagonists PSB-CB5 and PSB-CB27 and the agonist PSB-KK1415) on body mass and the development of metabolic disorders commonly accompanying obesity. Experiments were carried out on female Wistar rats. In order to determine the anorectic activity of the investigated ligands, their effect on food and water intake in a model of excessive eating was assessed. Lipid profile, glucose and insulin levels as well as alanine aminotransferase, aspartate aminotransferase, and γ-glutamyl transpeptidase activity in plasma were also evaluated. Potential side effects were examined in rat models of pica behavior and conditioned taste aversion. Animals treated with different ligands gained significantly less weight than rats from the obese control group. Effects of GPR18 antagonists on food intake and body weight were specific and unrelated to visceral illness, stress or changes in spontaneous activity. However, the GPR18 agonist is likely to affect body weight by inducing gastrointestinal disorders such as nausea. The presented preliminary data support the idea that the search for selective GPR18 antagonists for the treatment of obesity might be promising.

Anticonvulsant drugs are used to treat a wide range of non-epileptic conditions, including chronic, neuropathic pain. We obtained a phenoxyalkylaminoalkanol derivative, KM-416 which had previously demonstrated a significant anticonvulsant activity and had also been shown to bind to 5-HT 1A , α 2 -receptors and SERT and not to exhibit mutagenic properties. As KM-416 is a promising compound in our search for drug candidates, in the present study we further assessed its pharmacological profile (analgesic, local anesthetic, and antidepressant-like activities) accompanied with patch-clamp studies. Considering the importance of drug safety, its influence on the cardiovascular system was also evaluated. Moreover, KM-416 was subjected to forced degradation and pharmacokinetic studies to examine its stability and pharmacokinetic parameters. KM-416 revealed a significant antinociceptive activity in the tonic - the formalin test, neurogenic - the capsaicin test, and neuropathic pain model - streptozotocin-induced peripheral neuropathy. Moreover, it exerted a local anesthetic effect. In addition, KM-416 exhibited anti-depressant like activity. The results from the patch-clamp studies indicated that KM-416 can inhibit currents elicited by activation of NMDA receptors, while it also exhibited a voltage-dependent inhibition of Na + currents. KM-416 did not influence ventricular depolarization and repolarization. Following oral administration, pharmacokinetics of KM-416 was characterized by a rapid absorption in the rat. The brain-to-plasma AUC ratio was 6.7, indicating that KM-416 was well distributed to brain. The forced degradation studies showed that KM-416 was very stable under stress conditions. All these features made KM-416 a promising drug candidate for further development against neuropathic pain and epilepsy., (Copyright © 2020 Elsevier B.V. All rights reserved.)

The TiO 2 -Fe 3 O 4 composite materials were fabricated via the hydrothermal-assisted technique. It was determined how the molar ratio of TiO 2 to Fe 3 O 4 influences the crystalline structure and morphology of the synthesized composite materials. The effect of the molar ratio of components on the antibacterial activity was also analyzed. On the basis of XRD patterns for the obtained titanium(IV) oxide-iron(II, III) oxide composites, the two separate crystalline forms-anatase and magnetite -were observed. Transmission electron microscopy revealed particles of cubic and tetragonal shape for TiO 2 and spherical for Fe 3 O 4 . The results of low-temperature nitrogen sorption analysis indicated that an increase in the iron(II, III) oxide content leads to a decrease in the BET surface area. Moreover, the superparamagnetic properties of titanium(IV) oxide-iron(II, III) oxide composites should be noted. An important aim of the work was to determine the antibacterial activity of selected TiO 2 -Fe 3 O 4 materials. For this purpose, two representative strains of bacteria, the Gram-negative Escherichia coli and Gram-positive Staphylococcus aureus , were used. The titanium(IV) oxide-iron(II, III) oxide composites demonstrated a large zone of growth inhibition for both Gram-positive and Gram-negative bacteria. Moreover, it was found that the analyzed materials can be reused as antibacterial agents in three consecutive cycles with good results.

&lt;b&gt;Introduction&lt;/b&gt;: The ability to Reach quickly to changing external stimuli, to move the body quickly and precisely in any direction and to maintain the centre of gravity above the support base, all contribute to maintaining balance in dynamic conditions. The Limits of Stability Test (LOS) provides information on the state of dynamic equilibrium in a standing position.&lt;br&gt; &lt;b&gt;Aim&lt;/b&gt; : Assessment of dynamic postural control in developmental age.&lt;br&gt; &lt;b&gt;Material&lt;/b&gt; : 127 healthy children (65 girls and 62 boys) aged 6 - 17years. &lt;br&gt; &lt;b&gt;Methods&lt;/b&gt;: All children underwent LOS test (posturograph NeuroCom) with registration of reaction time (RT), movement velocity (MVL), directional control (DCL) , maximum excursion (MXE) and endpoint excursion (EPE).&lt;br&gt; &lt;b&gt;Results&lt;/b&gt;: At the age of 6-7 years, not fully developed jumping strategy and visual feedback mechanism in the control of movement were observed. All tested parameters were significantly worse in children aged 6 - 9 years. After this period, a significant improvement in TR and MVL was observed, with no significant changes in subsequent age groups while significant improvement in MXE up to 12 , EPE and DCL up to 13 years of age was noted. No significant gender differences were fund in the LOS test parameters. &lt;br&gt; &lt;b&gt;Conclusions&lt;/b&gt;: 1 The LOS test showed significantly lower dynamic balance development in children aged 6 - 7 years. 2 The study showed a significant improvement in all parameters of the LOS test up to 13 years of age, which supports the termination of the function at that time.

We investigated the therapeutic effect of MH-76 and MH-79, which are non-quinazoline α1-adrenoceptor antagonists with an additional ability to stimulate the nitric oxide (NO)/cyclic guanosine monophosphate (cGMP)/K + pathway, on deoxycorticosterone acetate (DOCA)-salt induced hypertension in rats. Prazosin was used as a reference compound, as quinazoline-based α1-adrenolytics may potentially exert unfavorable proapoptotic and necrotic effects. DOCA-salt hypertension was induced by DOCA (20 mg/kg s.c., twice weekly) administration plus 1% NaCl and 0.2% KCl solutions in drinking water for 12 weeks. The studied compounds MH-76, MH-79 (10 mg/kg i.p.) or prazosin (0.4 mg/kg i.p.) were administered to the DOCA-salt-treated rats, starting from the 6th week of DOCA-salt treatment and continuing for 6 weeks. This study showed that the administration of MH-79 and, to a lesser extent, MH-76 decreased elevated systolic blood pressure and heart rate, reduced heart and kidney hypertrophy, and reversed the histopathological alterations of the heart, kidney, and vessels in DOCA-salt hypertensive rats. MH-79 reversed endothelial dysfunction, which reduced inflammatory cell infiltration, arteriosclerotic alterations in renal and coronary arteries, and tubulointerstitial fibrosis. Prazosin showed a potent hemodynamic effect and reduced cardiac and renal fibrosis but exerted detrimental effects on blood vessels, potentiating fibroplasia of the media of the intrarenal artery and causing calcification of coronary arteries. Prazosin did not reverse endothelial dysfunction. Our results show the beneficial effect of non-quinazoline α1-adrenolytics on cardiac, vascular, and renal dysfunction in DOCA-salt hypertensive rats. Our findings also support the idea that targeting endothelial protection and endothelial integrity would yield beneficial effects against cardiac, blood vessel and renal injury related to hypertension.

Introduction: Proper development of postural control in children is connected with the maturation of the central nervous system, development of sensory organisation with appropriate use of proprioceptive, visual, vestibular information as well as reactions and postural strategy which allow the maintenance of balance in changeable environmental conditions. Developmental disturbances in this particular area is reflected in postural disfunctions and the assessment of these disfunctions and disturbances needs referring to normative values of the healthy population of children., Aim: Examination of postural control development in children aged 6-17 years., Material: 127 healthy children were tested (65 girls and 62 boys) aged 6-17 years., Method: Laryngological investigation, medical history interview, audiometry and tympanometry were conducted in all children. In the evaluation of postural control (mCTSIB-modified Clinical Test For The Sensory Interaction On Balance) a computer posturography system was used (Balance Master Neurocom). R esults: Further development of postural control was found in healthy children up to the age of 13 years of age. The development was not linear but showed transient characteristics with a faster development stage between the age of 6-7 and 8-9. Better postural control in girls, particularly the youngest, in comparison with boys was noticed. C onclusions: 1. The values of norm postural control in posturographic test mCTSIB in children aged 6-17 was established. In this test postural control development was completed in children before 13 year and it was not linear. 2. Due to gender differences it seems appropriate to use separate norms in order to evaluate the development of postural control in boys and girls.

Background and Aims: Metabolic syndrome associated with insulin resistance and hypertension is often caused by excessive fructose consumption. Treatment of hypertension in patients with metabolic syndrome is a difficult task as many antihypertensive drugs have adverse effects on the metabolic profile. We investigated if MH-76 and MH-79, non-quinazoline α 1 -adrenoceptor antagonists with an additional ability to stimulate NO/cGMP/K + pathway, ameliorates metabolic syndrome in fructose-fed rats. As reference compound prazosin was used., Methods and Results: Male rats were divided into 5 groups (n = 8) and studied for 18 weeks: group control: standard diet and drinking water; group Fructose: high-fructose diet (20% fructose in drinking water); groups Fructose + MH-76, Fructose + MH-79, Fructose + prazosin: high-fructose diet with subsequent MH-76, MH-79 (5 mg/kg/day ip) or prazosin (0.2 mg/kg/day ip) treatment 12 weeks later. In addition to their antihypertensive effect, the studied compounds reversed endothelial dysfunction, decreased hyperglycemia and hypertriglyceridemia, as well as prevented abdominal adiposity. Moreover, MH-76 reduced insulin resistance and decreased TNF-α concentration and lipid peroxidation in adipose tissue. Prazosin treatment exerted an antihypertensive effect, reduced hyperglycemia but did not improve endothelial dysfunction, insulin resistance, and abdominal adiposity. The lower efficacy of prazosin may be the result of its short half-time and the lack of described pleiotropic effects., Conclusions: α 1 -adrenoceptor blockade, endothelial protection, TNF-α suppressing and antioxidant activity together with favorable pharmacokinetic parameters determines high efficacy of MH-76, leading to the effective improvement of hemodynamic and metabolic disturbances in metabolic syndrome. The use of non-quinazoline, multiple-targeted α 1 -blockers may be an interesting option for treatment of hypertension with metabolic complications., (Copyright © 2019 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Despite the substantial clinical success of aspirin and clopidogrel in secondary prevention of ischemic stroke, up to 40% of patients remain resistant to the available antiplatelet treatment. Therefore, there is an urgent clinical need to develop novel antiplatelet agents with a novel mechanism of action. Recent studies revealed that potent alpha 2B-adrenergic receptor (alpha 2B-ARs) antagonists could constitute alternative antiplatelet therapy. We have synthesized a series of N-arylpiperazine derivatives of 4,4-dimethylisoquinoline-1,3(2H,4H)-dione as potential alpha 2B receptor antagonists. The most potent compound 3, effectively inhibited the platelet-aggregation induced both by collagen and ADP/adrenaline with IC 50 of 26.9 μM and 20.5 μM respectively. Our study confirmed that the alpha 2B-AR antagonists remain an interesting target for the development of novel antiplatelet agents with an alternative mechanism of action.

The aim of this study was to explore the α 1 -adrenoceptor-independent mechanisms involved in the vasorelaxant properties of two non-quinazoline α 1 -adrenoceptors antagonists (MH-76 and MH-79). Endothelium intact and endothelium denuded rat aorta was contracted with 1 μM phenylephrine to plateau, and the vasodilatory effect of MH-76 and MH-79 was examined in the absence or presence of inhibitors of the different signal transduction pathways. cGMP concetration was measured in rat aorta (enzyme immunoassay kit). In human aortic endothelial cells (HAEC) NO production was examined using a DAF-FM DA fluorescent indicator, whereas in human aortic smooth muscle cells the influence of the title compounds on K + efflux was evaluated. The vasorelaxant effect of MH-76 and MH-79 was attenuated by endothelium removal, N ω -Nitro-l-arginine methyl ester (L-NAME) and 1H-[1,2,4]Oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) pretreatment to the level characteristic for α 1 -adrenoreceptor blocking activity. In addition, the MH-76 and MH-79 induced relaxation was reduced by K + channels blockers. In endothelium intact rat aorta, MH-76 and MH-79 caused an increase in cGMP level, whereas in HAEC they increased NO generation. In contrast, the reference, quinazoline based α 1 -antagonist prazosin, did not influence NO production. Our findings suggest that the mechanisms underlying the vasodilatory properties of non-quinazoline based α 1 -adrenoceptors antagonists MH-76 and MH-79 involve not only α 1 -adrenoceptor blocking activity but also the activation of the endothelial NO-cGMP signalling pathway and the subsequent opening of K + channels. Our studies show that such double mechanism of action is superior to pure α 1 -adrenoceptor blockade, and may be considered as a promising alternative for the prevention and treatment of cardiovascular diseases., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

As a continuation of our search for novel histamine H 3 receptor ligands, a series of twenty four new tert-butyl and tert-pentyl phenoxyalkylamine derivatives (2-25) was synthesized. Compounds with three to four carbon atoms alkyl chain spacer were evaluated for their binding properties at human histamine H 3 receptor (hH 3 R). The highest affinities were observed for 4-pyridyl derivatives 4, 10, 16 and 22 (K i  = 16.0-120 nM). As it has been shown in docking studies, those specific heteroaromatic 4-N piperazine substituents might interact with one of the key receptor interacting amino acids. Moreover, the most promising compounds exhibited anticonvulsant activity in the maximal electroshock-induced seizure (MES) model in mice. Furthermore, the blood-brain barrier penetration, the functional H 3 R antagonist potency as well as the pro-cognitive properties in the passive avoidance test were demonstrated for compound 10. In order to estimate drug-likeness of compound 10,in silico and experimental evaluation of metabolic stability in human liver microsomes was performed. In addition, paying attention to the results obtained within this study, the 4-pyridyl-piperazino moiety has been established as a new bioisosteric piperidine replacement in H 3 R ligands., (Copyright © 2018. Published by Elsevier Masson SAS.)