19 results on '"Kalaska, Bartlomiej"'
Search Results
2. The methods for removal of direct oral anticoagulants and heparins to improve the monitoring of hemostasis: a narrative literature review
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Frackiewicz, Aleksandra, Kalaska, Bartlomiej, Miklosz, Joanna, and Mogielnicki, Andrzej
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- 2023
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3. Anionic and cationic block copolymers as promising modulators of blood coagulation
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Swieton, Justyna, Kaminski, Kamil, Miklosz, Joanna, Mogielnicki, Andrzej, and Kalaska, Bartlomiej
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- 2023
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4. Neurobehavioral effects of uremic toxin–indoxyl sulfate in the rat model
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Karbowska, Malgorzata, Hermanowicz, Justyna M., Tankiewicz-Kwedlo, Anna, Kalaska, Bartlomiej, Kaminski, Tomasz W., Nosek, Krzysztof, Wisniewska, Roza J., and Pawlak, Dariusz
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- 2020
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5. Monitoring of Anticoagulant Activity of Dabigatran and Rivaroxaban in the Presence of Heparins.
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Jakimczuk, Aleksandra, Kalaska, Bartlomiej, Kamiński, Kamil, Miklosz, Joanna, Yusa, Shin-Ichi, Pawlak, Dariusz, Szczubiałka, Krzysztof, and Mogielnicki, Andrzej
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ORAL medication , *RIVAROXABAN , *DABIGATRAN , *ANTICOAGULANTS , *HEPARIN , *NEUTRALIZATION tests - Abstract
The routine monitoring of direct oral anticoagulants (DOACs) may be considered in patients with renal impairment, patients who are heavily obese, or patients requiring elective surgery. Using the heparin-binding copolymer (HBC) and polybrene, we aimed to develop a solution for monitoring the anticoagulant activity of DOACs in human plasma in the interfering presence of unfractionated heparin (UFH) and enoxaparin. The thrombin time (TT) and anti-factor Xa activity were monitored in pooled plasma from healthy volunteers. In these tests, plasma with dabigatran or rivaroxaban was mixed with UFH or enoxaparin and then incubated with HBC or polybrene, respectively. HBC and polybrene neutralized heparins and enabled monitoring of anticoagulant activity of dabigatran in the TT test. Both agents allowed for accurate measurement of anti-factor Xa activity in the plasma containing rivaroxaban and heparins in the concentration range reached in patients' blood. Here, we present diagnostic tools that may improve the control of anticoagulation by eliminating the contamination of blood samples with heparins and enabling the monitoring of DOACs' activity. [ABSTRACT FROM AUTHOR]
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- 2022
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6. Kynurenine Pathway in Chronic Kidney Disease: What's Old, What's New, and What's Next?
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Mor, Adrian, Kalaska, Bartlomiej, and Pawlak, Dariusz
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CHRONIC kidney failure , *KYNURENINE , *BIOACTIVE compounds , *ARYL hydrocarbon receptors , *TRYPTOPHAN , *INFLAMMATION - Abstract
Impaired kidney function and increased inflammatory process occurring in the course of Chronic Kidney Disease (CKD) contribute to the development of complex amino-acid alterations. The essential amino-acid tryptophan (TRP) undergoes extensive metabolism along several pathways, resulting in the production of many biologically active compounds. The results of many studies have shown that its metabolism via the kynurenine pathway is potently increased in the course of CKD. Metabolites of this pathway exhibit differential, sometimes opposite, roles in several biological processes. Their accumulation in the course of CKD may induce oxidative cell damage which stimulates inflammatory processes. They can also modulate the activity of numerous cellular signaling pathways through activation of the aryl hydrocarbon receptor, leading to the disruption of homeostasis of various organs. As a result, they can contribute to the development of the systemic disorders accompanying the course of chronic renal failure. This review gathers and systematizes reports concerning the knowledge connecting the kynurenine pathway metabolites to systemic disorders accompanying the development of CKD. [ABSTRACT FROM AUTHOR]
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- 2020
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7. The neutralization of heparan sulfate by heparin-binding copolymer as a potential therapeutic target.
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Kalaska, Bartlomiej, Miklosz, Joanna, Kamiński, Kamil, Musielak, Bogdan, Yusa, Shin-Ichi, Pawlak, Dariusz, Nowakowska, Maria, Szczubiałka, Krzysztof, and Mogielnicki, Andrzej
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- 2019
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8. Elevated Levels of Peripheral Kynurenine Decrease Bone Strength in Rats with Chronic Kidney Disease.
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Kalaska, Bartlomiej, Pawlak, Krystyna, Domaniewski, Tomasz, Oksztulska-Kolanek, Ewa, Znorko, Beata, Roszczenko, Alicja, Rogalska, Joanna, Brzoska, Malgorzata M., Lipowicz, Pawel, Doroszko, Michal, Pryczynicz, Anna, and Pawlak, Dariusz
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KIDNEY disease diagnosis ,LABORATORY rats ,URIC acid ,CHRONIC kidney failure ,PARATHYROID hormone ,NITROGEN - Abstract
The diagnosis and treatment of bone disorders in patients with chronic kidney disease (CKD) represent a clinical challenge. CKD leads to mineral and bone complications starting early in the course of renal failure. Recently, we have observed the positive relationship between intensified central kynurenine turnover and bone strength in rats with subtotal 5/6 nephrectomy (5/6 Nx)-induced CKD. The aim of the present study was to determine the association between peripheral kynurenine pathway metabolites and bone strength in rats with 5/6 Nx-induced CKD. The animals were sacrificed 1 and 3 months after 5/6 Nx or sham operation. Nephrectomized rats presented higher concentrations of serum creatinine, urea nitrogen, and parathyroid hormone both 1 and 3 months after nephrectomy. These animals revealed higher concentrations of kynurenine and 3-hydroxykynurenine in the serumand higher gene expression of aryl hydrocarbon receptor (AhR) as a physiological receptor for kynurenine and AhR-dependent cytochrome in the bone tissue. Furthermore, nephrectomy significantly increased the number of osteoclasts in the bone without affecting their resorptive activity measured in serum. These changes were particularly evident in rats 1 month after 5/6 Nx. The main bone biomechanical parameters of the tibia were unchanged between nephrectomized and sham-operated rats but were significantly increased in older compared to younger animals. A similar trend was observed for geometrical parameters measured with calipers, bone mineral density based on Archimedes' method and image of bone microarchitecture obtained from micro-computed tomography analyses of tibial cortical bone. In nephrectomized animals, peripheral kynurenine levels correlated negatively with the main parameters of bone biomechanics, bone geometry, and bone mineral density values. In conclusion, our data suggest that CKD-induced elevated levels of peripheral kynurenine cause pathological changes in bone structure via AhR pathway. This finding opens new opportunities for the treatment/prevention of osteoporosis in CKD. [ABSTRACT FROM AUTHOR]
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- 2017
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9. The Toxicokinetic Profile of Dex40-GTMAC3--a Novel Polysaccharide Candidate for Reversal of Unfractionated Heparin.
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Sokolowska, Emilia, Kalaska, Bartlomiej, Pawlak, Dariusz, Mogielnicki, Andrzej, Kaminski, Kamil, Szczubialka, Krzysztof, Nowakowska, Maria, Lewandowska, Alicja, Kasacka, Irena, Blazejczyk, Agnieszka, and Wietrzyk, Joanna
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POLYSACCHARIDES ,TOXICOLOGY ,HEPARIN - Abstract
Though protamine sulfate is the only approved antidote of unfractionated heparin (UFH), yet may produce life threatening side effects such as systemic hypotension, catastrophic pulmonary vasoconstriction or allergic reactions.We have described 40 kDa dextrans (Dex40) substituted with glycidyltrimethylammonium chloride (GTMAC) as effective, immunogenically and hemodynamically neutral inhibitors of UFH. The aim of the present study was to evaluate in mice and rats toxicokinetic profile of the most promising polymer--Dex40-GTMAC3. Polymer was rapidly eliminated with a half-time of 12.5 ± 3.0 min in Wistar rats, and was mainly distributed to the kidneys and liver in mice. The safety studies included the measurement of blood count and blood biochemistry, erythrocyte osmotic fragility and the evaluation of the histological alterations in kidneys, liver and lungs of mice and rats in acute and chronic experiments. We found that Dex40-GTMAC3 is not only effective but also very well tolerated. Additionally, we found that protamine may cause overt hemolysis with appearance of permanent changes in the liver and kidneys. In summary, fast renal clearance behavior and generally low tissue accumulation of Dex40-GTMAC3 is likely to contribute to its superior to protamine biocompatibility. Intravenous administration of therapeutic doses to living animals does not result in the immunogenic, hemodynamic, blood, and organ toxicity. Dex40-GTMAC3 seems to be a promising effective and safe candidate for further clinical development as new UFH reversal agent. [ABSTRACT FROM AUTHOR]
- Published
- 2016
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10. Nonclinical Evaluation of Novel Cationically Modified Polysaccharide Antidotes for Unfractionated Heparin.
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Kalaska, Bartlomiej, Kaminski, Kamil, Sokolowska, Emilia, Czaplicki, Dominik, Kujdowicz, Monika, Stalinska, Krystyna, Bereta, Joanna, Szczubialka, Krzysztof, Pawlak, Dariusz, Nowakowska, Maria, and Mogielnicki, Andrzej
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POLYSACCHARIDES , *HEPARIN , *ANAPHYLAXIS , *BIOCOMPATIBILITY , *THROMBOPLASTIN - Abstract
Protamine, the only registered antidote of unfractionated heparin (UFH), may produce a number of adverse effects, such as anaphylactic shock or serious hypotension. We aimed to develop an alternative UFH antidote as efficient as protamine, but safer and easier to produce. As a starting material, we have chosen generally non-toxic, biocompatible, widely available, inexpensive, and easy to functionalize polysaccharides. Our approach was to synthesize, purify and characterize cationic derivatives of dextran, hydroxypropylcellulose, pullulan and γ-cyclodextrin, then to screen them for potential heparin-reversal activity using an in vitro assay and finally examine efficacy and safety of the most active polymers in Wistar rat and BALB/c mouse models of experimentally induced arterial and venous thrombosis. Efficacy studies included the measurement of thrombus formation, activated partial thromboplastin time, bleeding time, and anti-factor Xa activity; safety studies included the measurement of hemodynamic, hematologic and immunologic parameters. Linear, high molecular weight dextran substituted with glycidyltrimethylammonium chloride groups at a ratio of 0.65 per glucose unit (Dex40-GTMAC3) is the most potent and the safest UFH inhibitor showing activity comparable to that of protamine while possessing lower immunogenicity. Cationic polysaccharides of various structures neutralize UFH. Dex40-GTMAC3 is a promising and potentially better UFH antidote than protamine. [ABSTRACT FROM AUTHOR]
- Published
- 2015
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11. Monitoring of Cardiorespiratory Parameters in Rats—Validation Based on Pharmacological Stimulation.
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Miklosz, Joanna, Kalaska, Bartlomiej, Zajaczkowski, Stanislaw, Pawlak, Dariusz, and Mogielnicki, Andrzej
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BODY temperature , *BUTORPHANOL , *DIASTOLIC blood pressure , *OXYGEN in the blood , *OXYGEN saturation , *BLOOD pressure , *FEMORAL vein - Abstract
The methods used in preclinical studies should minimize the suffering and the number of animals but still provide precise and consistent results enabling the introduction of drug candidates into the phase of clinical trials. Thus, we aimed to develop a method allowing us to perform preliminary safety and toxicity studies of candidates for human medicines, while reducing the number of animals. We have devised a method based on a combination of two devices: Plugsys (Transonics System Inc., Ithaca, NY, USA) and PhysioSuite (Kent Scientific Corporation, Torrington, CT, USA), which allow simultaneous registration of nine circulatory and respiratory parameters, and body temperature. Vehicle and adrenaline, or nitroglycerin, as reference substances were administered into the right femoral vein of Wistar rats. Physiological conditions were registered over 60 min after drug administration by measuring systolic, diastolic and mean blood pressure, heart rate (HR), blood perfusion of paw vessels, blood oxygen saturation, respiratory rate, average and peak exhaled CO2, and body temperature. Blood pressure was measured by cannula placed in the left common carotid artery and connected to the pressure transducer (Plugsys). The other parameters were measured by the PhysioSuite. Adrenaline-induced immediate dose-related hypertension and nitroglycerin hypotension were correlated with the change in blood perfusion. They both increased HR. Adrenaline decreased blood oxygen saturation and slightly affected respiratory parameters, while nitroglycerin caused a progressive increase in respiratory rate and a decrease in the peak of exhaled CO2. Our method may become an inseparable part of the preliminary safety and toxicity studies of tested drugs, while being an important step towards improving animal welfare. [ABSTRACT FROM AUTHOR]
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- 2021
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12. Reversal Activity and Toxicity of Heparin-Binding Copolymer after Subcutaneous Administration of Enoxaparin in Mice.
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Swieton, Justyna, Miklosz, Joanna, Yusa, Shin-Ichi, Szczubialka, Krzysztof, Pawlak, Dariusz, Mogielnicki, Andrzej, and Kalaska, Bartlomiej
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ENOXAPARIN ,PROTAMINES ,MICE ,LUNGS ,SPLEEN ,HISTOPATHOLOGY - Abstract
Uncontrolled bleeding after enoxaparin (ENX) is rare but may be life-threatening. The only registered antidote for ENX, protamine sulfate (PS), has 60% efficacy and can cause severe adverse side effects. We developed a diblock copolymer, heparin-binding copolymer (HBC), that reverses intravenously administered heparins. Here, we focused on the HBC inhibitory activity against subcutaneously administered ENX in healthy mice. BALB/c mice were subcutaneously injected with ENX at the dose of 5 mg/kg. After 110 min, vehicle, HBC (6.25 and 12.5 mg/kg), or PS (5 and 10 mg/kg) were administered into the tail vein. The blood was collected after 3, 10, 60, 120, 360, and 600 min after vehicle, HBC, or PS administration. The activities of antifactors Xa and IIa and biochemical parameters were measured. The main organs were collected for histological analysis. HBC at the lower dose reversed the effect of ENX on antifactor Xa activity for 10 min after antidote administration, whereas at the higher dose, HBC reversed the effect on antifactor Xa activity throughout the course of the experiment. Both doses of HBC completely reversed the effect of ENX on antifactor IIa activity. PS did not reverse antifactor Xa activity and partially reversed antifactor IIa activity. HBC modulated biochemical parameters. Histopathological analysis showed changes in the liver, lungs, and spleen of mice treated with HBC and in the lungs and heart of mice treated with PS. HBC administered in an appropriate dose might be an efficient substitute for PS to reverse significantly increased anticoagulant activity that may be connected with major bleeding in patients receiving ENX subcutaneously. [ABSTRACT FROM AUTHOR]
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- 2021
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13. Preclinical Toxicity and Safety of MM-129—First-in-Class BTK/PD-L1 Inhibitor as a Potential Candidate against Colon Cancer.
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Hermanowicz, Justyna Magdalena, Kalaska, Bartlomiej, Pawlak, Krystyna, Sieklucka, Beata, Miklosz, Joanna, Mojzych, Mariusz, and Pawlak, Dariusz
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COLON cancer , *LABORATORY rats , *ZEBRA danio embryos , *BRACHYDANIO , *PHARMACOKINETICS , *PROGRAMMED death-ligand 1 - Abstract
MM-129 is a novel inhibitor targeting BTK/PI3K/AKT/mTOR and PD-L1, as it possesses antitumor activity against colon cancer. To evaluate the safety profile of MM-129, we conducted a toxicity study using the zebrafish and rodent model. MM-129 was also assessed for pharmacokinetics features through an in vivo study on Wistar rats. The results revealed that MM-129 exhibited favorable pharmacokinetics with quick absorption and 68.6% of bioavailability after intraperitoneal administration. No serious adverse events were reported for the use of MM-129, confirming a favorable safety profile for this compound. It was not fatal and toxic to mice at an anticancer effective dose of 10 μmol/kg. At the end of 14 days of administering hematological and biochemical parameters, liver and renal functions were all at normal levels. No sublethal effects were either detected in zebrafish embryos treated with a concentration of 10 μM. MM-129 has the potential as a safe and well-tolerated anticancer formulation for future treatment of patients with colon cancer. [ABSTRACT FROM AUTHOR]
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- 2021
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14. Cardiovascular and Respiratory Toxicity of Protamine Sulfate in Zebrafish and Rodent Models.
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Miklosz, Joanna, Kalaska, Bartlomiej, Podlasz, Piotr, Chmielewska-Krzesińska, Małgorzata, Zajączkowski, Miłosz, Kosiński, Adam, Pawlak, Dariusz, Mogielnicki, Andrzej, and Seong Lee, Eun
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PROTAMINES , *CARDIOTOXICITY , *BRACHYDANIO , *ZEBRA danio , *CARDIOLOGICAL manifestations of general diseases , *NITRIC-oxide synthases , *OXYGEN in the blood - Abstract
Protamine sulfate (PS) is the only available option to reverse the anticoagulant activity of unfractionated heparin (UFH), however it can cause cardiovascular and respiratory complications. We explored the toxicity of PS and its complexes with UFH in zebrafish, rats, and mice. The involvement of nitric oxide (NO) in the above effects was investigated. Concentration–dependent lethality, morphological defects, and decrease in heart rate (HR) were observed in zebrafish larvae. PS affected HR, blood pressure, respiratory rate, peak exhaled CO2, and blood oxygen saturation in rats. We observed hypotension, increase of HR, perfusion of paw vessels, and enhanced respiratory disturbances with increases doses of PS. We found no effects of PS on human hERG channels or signs of heart damage in mice. The hypotension in rats and bradycardia in zebrafish were partially attenuated by the inhibitor of endothelial NO synthase. The disturbances in cardiovascular and respiratory parameters were reduced or delayed when PS was administered together with UFH. The cardiorespiratory toxicity of PS seems to be charge–dependent and involves enhanced release of NO. PS administered at appropriate doses and ratios with UFH should not cause permanent damage of heart tissue, although careful monitoring of cardiorespiratory parameters is necessary. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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15. Modulation of the Paracrine Kynurenic System in Bone as a New Regulator of Osteoblastogenesis and Bone Mineral Status in an Animal Model of Chronic Kidney Disease Treated with LP533401.
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Mor, Adrian, Pawlak, Krystyna, Kalaska, Bartlomiej, Domaniewski, Tomasz, Sieklucka, Beata, Zieminska, Marta, Cylwik, Bogdan, and Pawlak, Dariusz
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BONES ,CHRONIC kidney failure ,TRYPTOPHAN ,ANIMAL models in research ,KYNURENINE - Abstract
An increase in the peripheral synthesis of serotonin and kynurenine, observed during the chronic kidney disease (CKD) course, is negatively associated with bone health. Serotonin and kynurenine are connected by the common precursor, tryptophan. LP533401 is an inhibitor of peripheral serotonin synthesis. This study aimed to establish if the inhibition of serotonin synthesis by LP533401 may affect the kynurenine pathway activity in bone tissue and its potential consequence with regard to osteogenesis and bone mineral status. Nephrectomized rats were treated with LP533401 at a dose of 30 and 100 mg/kg daily for eight weeks. Tryptophan and kynurenine concentrations were determined, and tryptophan 2,3-dioxygenase (TDO) expression was assessed. We discovered the presence of a TDO-dependent, paracrine kynurenic system in the bone of rats with CKD. Its modulation during LP533401 treatment was associated with impaired bone mineral status. Changes in TDO expression affecting the kynurenine pathway activity were related to the imbalance between peripheral serotonin and 25-hydroxyvitamin D. There were also close associations between the expression of genes participating in osteoblastogenesis and activation of the kynurenine pathway in the bones of LP53301-treated rats. Our results represent the next step in studying the role of tryptophan metabolites in renal osteodystrophy. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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16. The Inhibitory Effect of Protamine on Platelets is Attenuated by Heparin without Inducing Thrombocytopenia in Rodents.
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Miklosz, Joanna, Kalaska, Bartlomiej, Kaminski, Kamil, Rusak, Malgorzata, Szczubialka, Krzysztof, Nowakowska, Maria, Pawlak, Dariusz, and Mogielnicki, Andrzej
- Abstract
Protamine sulfate (PS) is a polycationic protein drug obtained from the sperm of fish, and is used to reverse the anticoagulant effect of unfractionated heparin (UFH). However, the interactions between PS, UFH, and platelets are still not clear. We measured the platelet numbers and collagen-induced aggregation, P-selectin, platelet factor 4, β-thromboglobulin, prostacyclin metabolite, D-dimers, activated partial thromboplastin time, prothrombin time, anti-factor Xa, fibrinogen, thrombus weight and megakaryocytopoiesis in blood collected from mice and rats in different time points.. All of the groups were treated intravenously with vehicle, UFH, PS, or UFH with PS. We found a short-term antiplatelet activity of PS in mice and rats, and long-term platelet-independent antithrombotic activity in rats with electrically-induced thrombosis. The antiplatelet and antithrombotic potential of PS may contribute to bleeding risk in PS-overdosed patients. The inhibitory effect of PS on the platelets was attenuated by UFH without inducing thrombocytopenia. Treatment with UFH and PS did not affect the formation, number, or activation of platelets, or the thrombosis development in rodents. [ABSTRACT FROM AUTHOR]
- Published
- 2019
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17. Studies on Antifungal Properties of Methacrylamido Propyl Trimethyl Ammonium Chloride Polycations and Their Toxicity In Vitro .
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Skóra M, Obłoza M, Tymecka M, Kalaska B, Gurgul M, and Kamiński K
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- Humans, Ammonium Chloride, Pandemics, Microbial Sensitivity Tests, Polymers pharmacology, Antifungal Agents toxicity, COVID-19
- Abstract
The biological activity of polycations is usually associated with their biocidal properties. Their antibacterial features are well known, but in this work, observations on the antifungal properties of macromolecules obtained by methacrylamido propyl trimethyl ammonium chloride (MAPTAC) polymerization are presented. The results, not previously reported, make it possible to correlate antifungal properties directly with the structure of the macromolecule, in particular the molecular mass. The polymers described here have antifungal activity against some filamentous fungi. The strongest effect occurs for polymers with a mass of about 0.5 mDa which have confirmed activity against the multidrug-resistant species Scopulariopsis brevicaulis, Fusarium oxysporum, and Fusarium solani, as well as the dermatophytes Trichophyton mentagrophytes, Trichophyton rubrum, Trichophyton interdigitale, and Trichophyton tonsurans. In addition, this publication describes the effects of these macromolecular systems on serum and blood components and provides a preliminary assessment of toxicity on cell lines of skin-forming cells, i.e., fibroblasts and keratinocytes. Additionally, using a Franz diffusion chamber, a negligibly low transport of the active polymer through the skin was demonstrated, which is a desirable effect for externally applied antifungal drugs. IMPORTANCE Infectious diseases are a very big medical, social, and economic problem. Even before the COVID-19 pandemic, certain infections were among of the most common causes of death. The difficulties in the treatment of infectious diseases concern in particular fungal diseases, against which we have only a few classes of drugs represented by a few substances. The publication presents the preliminary results of the in vitro antifungal activity studies of four MAPTAC polymers on different fungal species and their cytotoxicity to human cells (fibroblasts and keratinocytes). The paper also compares these properties with analogous ones of two commonly used antifungal drugs, ciclopirox and terbinafine., Competing Interests: The authors declare no conflict of interest.
- Published
- 2023
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18. Heparin-Binding Copolymer as a Complete Antidote for Low-Molecular-Weight Heparins in Rats.
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Kalaska B, Miklosz J, Kamiński K, Swieton J, Jakimczuk A, Yusa SI, Pawlak D, Nowakowska M, Szczubiałka K, and Mogielnicki A
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- Animals, Anticoagulants pharmacology, Anticoagulants therapeutic use, Antidotes pharmacology, Antidotes therapeutic use, Dose-Response Relationship, Drug, Factor Xa metabolism, Hemorrhage prevention & control, Heparin adverse effects, Heparin metabolism, Heparin, Low-Molecular-Weight adverse effects, Human Umbilical Vein Endothelial Cells drug effects, Human Umbilical Vein Endothelial Cells metabolism, Humans, Male, Protein Binding drug effects, Protein Binding physiology, Random Allocation, Rats, Rats, Wistar, Anticoagulants metabolism, Antidotes metabolism, Hemorrhage metabolism, Heparin, Low-Molecular-Weight metabolism
- Abstract
Bleeding resulting from the application of low-molecular-weight heparins (LMWHs) may be treated with protamine sulfate, but this treatment lacks efficiency; its action against antifactor Xa activity is limited to ∼60%. Moreover, protamine sulfate can cause life-threatening hypersensitivity reactions. We developed diblock heparin-binding copolymer (HBC), which can neutralize the anticoagulant activity of parenteral anticoagulants. In the present study, we explored the safety profile of HBC and its potential to reverse enoxaparin, nadroparin, dalteparin, and tinzaparin in human plasma and at in vivo conditions. HBC-LMWH complexes were characterized using zeta potential, isothermal titration calorimetry, and dynamic light scattering. The rat cardiomyocytes and human endothelial cells were used for the assessment of in vitro toxicity. Male Wistar rats were observed for up to 4 days after HBC administration for clinical evaluation, gross necropsy, and biochemistry and histopathological analysis. Rats were treated with LMWHs alone or followed by short-time intravenous infusion of HBC, and bleeding time and antifactor Xa activity were measured. HBC completely reversed antifactor Xa activity prolonged in vitro by all LMWHs with an optimal weight ratio of 2.5:1. The complexes of HBC-LMWHs were below 5 µm. We observed no effects on the viability of cardiovascular cells treated with HBC at concentrations up to 0.05 mg/ml. Single doses up to 20 mg/kg of HBC were well tolerated by rats. HBC completely reversed the effects of LMWHs on bleeding time and antifactor Xa activity in vivo after 20 minutes and retained ∼80% and ∼60% of reversal activity after 1 and 2 hours, respectively. Well-documented efficacy and safety of HBC both in vitro and in vivo make this polymer a promising candidate for LMWHs reversal. SIGNIFICANCE STATEMENT: Over the last decade, there has been significant progress in developing antidotes for the reversal of anticoagulants. Until now, there has been no effective and safe treatment for patients with severe bleeding under low-molecular-weight heparin therapy. Based on our in vitro and in vivo studies, heparin-binding copolymer seems to be a promising candidate for neutralizing all clinically relevant low-molecular-weight heparins., (Copyright © 2020 by The Author(s).)
- Published
- 2020
- Full Text
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19. A link between central kynurenine metabolism and bone strength in rats with chronic kidney disease.
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Kalaska B, Pawlak K, Oksztulska-Kolanek E, Domaniewski T, Znorko B, Karbowska M, Citkowska A, Rogalska J, Roszczenko A, Brzoska MM, and Pawlak D
- Abstract
Background: Disturbances in mineral and bone metabolism represent one of the most complex complications of chronic kidney disease (CKD). Serotonin, a monoamine synthesized from tryptophan, may play a potential role in bone metabolism. Brain-derived serotonin exerts a positive effect on the bone structure by limiting bone resorption and enhancing bone formation. Tryptophan is the precursor not only to the serotonin but also and primarily to kynurenine metabolites. The ultimate aim of the present study was to determine the association between central kynurenine metabolism and biomechanical as well as geometrical properties of bone in the experimental model of the early stage of CKD., Methods: Thirty-three Wistar rats were randomly divided into two groups (sham-operated and subtotal nephrectomized animals). Three months after surgery, serum samples were obtained for the determination of biochemical parameters, bone turnover biomarkers, and kynurenine pathway metabolites; tibias were collected for bone biomechanical, bone geometrical, and bone mass density analysis; brains were removed and divided into five regions for the determination of kynurenine pathway metabolites., Results: Subtotal nephrectomized rats presented higher serum concentrations of creatinine, urea nitrogen, and parathyroid hormone, and developed hypocalcemia. Several biomechanical and geometrical parameters were significantly elevated in rats with experimentally induced CKD. Subtotal nephrectomized rats presented significantly higher kynurenine concentrations and kynurenine/tryptophan ratio and significantly lower tryptophan levels in all studied parts of the brain. Kynurenine in the frontal cortex and tryptophan in the hypothalamus and striatum correlated positively with the main parameters of bone biomechanics and bone geometry., Discussion: In addition to the complex mineral, hormone, and metabolite changes, intensified central kynurenine turnover may play an important role in the development of bone changes in the course of CKD., Competing Interests: The authors declare there are no competing interests.
- Published
- 2017
- Full Text
- View/download PDF
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