TY - GEN AU - Szénási, Gábor AU - Bakos, Tamás AU - Őrfi, Erik AU - Mészáros, Tamás AU - Hricisák, László AU - Rosivall, László AU - Hamar, Péter AU - Benyó, Zoltán AU - Szebeni, János AU - Dézsi, László TI - COMPARISON OF LIPOSOMAL DRUG-INDUCED BLOOD PRESSURE CHANGES IN MICE AND RATS PY - 2023 SP - 73 EP - 73 PG - 1 UR - https://m2.mtmt.hu/api/publication/34747635 ID - 34747635 AB - Introduction: Liposomal drugs administered intravenously (i.v.) can induce IgEindependent side effects known as infusion reaction, and also termed as complement activation-related pseudoallergy (CARPA). Aim: We aimed to reveal the basic mechanisms of blood pressure changes after i.v. injection of amphotericin B-containing liposomes (Abelcet, rats: 10 mg/kg; mice: 30 mg/kg). Methods: Male NMRI mice, and wild type or thromboxane prostanoid receptor deficient (TP KO) mice on C57Bl/6 background, as well as male Wistar rats (anesthetized with pentobarbital) were used (n=6-8/group). Mean arterial blood pressure was continuously monitored. Blood was collected at 0, 1, 3 10 and 30 min in rats, and from separate groups of mice at 3-5 min after treatment. Plasma C3a and thromboxane B2 (TXB2) concentrations were assayed using ELISA. Blood count was obtained using a hematology analyzer (Abacus Vet5). Results: Abelcet caused transient hypertension in mice (10-15 min) and transient hypotension in rats (20-40 min). Abelcet resulted in leucopenia and thrombocytopenia, and increased plasma complement C3a and TXB2 concentrations in both species. Complement depletion with cobra venom factor (CVF) lengthened the hypertensive effect in mice and abolished the hypotensive effect in rats. Pretreatment with DF2593A (10 mg/kg, i.v.), a C5a receptor (C5aR) antagonist, lengthened the hypertensive effect of Abelcet in mice and elicited a small decrease in the hypotensive effect in rats. Inhibition of C3a receptors with SB290157 (10 mg/kg) attenuated the hypertension in mice and enhanced the hypotension in rats, but both effects were rather small. Macrophage depletion with clodronate liposomes in mice lengthened the hypertensive effect similarly to CVF. Pre-treatment with GdCl3 to inhibit macrophages slightly attenuated the hypotensive effect of Abelcet in rats. Inhibition of mast cell activation by cromolyn or C48/80, decreased the hypotensive response in rats, but induced delayed hypotension in mice, respectively. Inhibition of platelet activation using eptifibatide, a platelet glycoprotein IIb/IIIa (GPIIb/IIIa) receptor inhibitor, lengthened the hypertensive effect in mice, but hardly affected the responses in rats. Abelcet did not change blood pressure in TP KO mice and led to a delayed hypertension after pretreatment with CVF. Conclusion: Our results suggest that complement activation has a small contribution to liposomal drug-induced hypotension, and both macrophages and mast cells contribute to the release of vasoactive mediators in rats. The early hypertensive effect of TXA2 release in mice wasindependent from complement activation, and wasreversed with some delay mainly by the activation of C5aR. Both macrophages and platelets are substantially implicated in the latter effect. LA - English DB - MTMT ER - TY - THES AU - Őrfi, Erik TI - Nano-gyógyszerek kórélettana, különös tekintettel a keringési vonatkozásokra PY - 2023 DO - 10.14753/SE.2023.2859 UR - https://m2.mtmt.hu/api/publication/34590726 ID - 34590726 LA - Hungarian DB - MTMT ER - TY - JOUR AU - Őrfi, Erik AU - Hricisák, László AU - Dézsi, László AU - Hamar, Péter AU - Benyó, Zoltán AU - Szebeni, János AU - Szénási, Gábor TI - The Hypertensive Effect of Amphotericin B-Containing Liposomes (Abelcet) in Mice: Dissecting the Roles of C3a and C5a Anaphylatoxins, Macrophages and Thromboxane JF - BIOMEDICINES J2 - BIOMEDICINES VL - 10 PY - 2022 IS - 7 PG - 12 SN - 2227-9059 DO - 10.3390/biomedicines10071764 UR - https://m2.mtmt.hu/api/publication/33022184 ID - 33022184 N1 - Funding Agency and Grant Number: Semmelweis University; European Union [825828, 952520]; National Research, Development, and Innovation Office (NKFIH) of Hungary [2020-1.1.6-JOVO-2021-00013]; Applied Materials and Nanotechnology Center of Excellence, Miskolc University, Miskolc, Hungary; New National Excellence Program of the Ministry for Innovation and Technology, NKFIH [UNKP-19-3-III, OTKA K-101775, K-115623, K-113164, K-125174] Funding text: Open access funding was provided by Semmelweis University. The financial support by the European Union Horizon 2020 projects 825828 "Expert" and 952520 "Biosafety" are acknowledged. This project was also supported by a grant from the National Research, Development, and Innovation Office (NKFIH) of Hungary (2020-1.1.6-JOVO-2021-00013). JS thanks the support by the Applied Materials and Nanotechnology Center of Excellence, Miskolc University, Miskolc, Hungary. E.O. was supported by the UNKP-19-3-III New National Excellence Program of the Ministry for Innovation and Technology, NKFIH OTKA K-101775, K-115623, K-113164, and K-125174 grants. LA - English DB - MTMT ER - TY - JOUR AU - Bakos, Tamás AU - Őrfi, Erik AU - Mészáros, Tamás AU - Milosevits, Gergely AU - Csukás, Domokos AU - Rosivall, László AU - Hamar, Péter AU - Dézsi, László AU - Szebeni, János AU - Szénási, Gábor TI - Complement Activation-Related Pseudoallergy (CARPA) in Rats; The Example of Liposomal Amphotericin-B (AmBisome) JF - ACTA PHARMACEUTICA HUNGARICA J2 - ACTA PHARM HUNG VL - 91 PY - 2021 IS - 3-4 SP - 175 EP - 176 PG - 2 SN - 0001-6659 UR - https://m2.mtmt.hu/api/publication/32509180 ID - 32509180 LA - English DB - MTMT ER - TY - JOUR AU - Milosevits, Gergely AU - Mészáros, Tamás AU - Őrfi, Erik AU - Bakos, Tamás AU - Garami, Miklós AU - Kovács, Gábor AU - Dézsi, László AU - Hamar, Péter AU - Győrffy, Balázs AU - Szabó, András AU - Szénási, Gábor AU - Szebeni, János TI - Complement-mediated hypersensitivity reactions to an amphotericin B-containing lipid complex (Abelcet) in pediatric patients and anesthetized rats: Benefits of slow infusion JF - NANOMEDICINE: NANOTECHNOLOGY BIOLOGY AND MEDICINE J2 - NANOMED: NANOTECHNOL VL - 34 PY - 2021 PG - 7 SN - 1549-9634 DO - 10.1016/j.nano.2021.102366 UR - https://m2.mtmt.hu/api/publication/31864261 ID - 31864261 N1 - * Megosztott szerzőség LA - English DB - MTMT ER - TY - GEN AU - Szénási, Gábor AU - Őrfi, Erik AU - Mészáros, Tamás AU - Fülöp, Tamás AU - Hricisák, László AU - Hamar, Péter AU - Rosivall, László AU - Dézsi, László AU - Benyó, Zoltán AU - Szebeni, János TI - A tromboxán szerepe a komplement aktiválók és liposzómák hipertenzív hatásában, egérben PY - 2019 UR - https://m2.mtmt.hu/api/publication/33154104 ID - 33154104 LA - Hungarian DB - MTMT ER - TY - GEN AU - Kerkovits, Nóra Melinda AU - Őrfi, Erik AU - Ruisanchez, Éva AU - Szénási, Gábor AU - Benyó, Zoltán TI - The C3a-induced vasoconstriction is mediated by thromboxane A2 in mouse thoracic aorta PY - 2019 UR - https://m2.mtmt.hu/api/publication/31262400 ID - 31262400 N1 - Poszter 14 LA - English DB - MTMT ER - TY - GEN AU - Kerkovits, Nóra Melinda AU - Janovicz, Anna AU - Ruisanchez, Éva AU - Őrfi, Erik AU - Gál, Péter AU - Szénási, Gábor AU - Benyó, Zoltán TI - Vascular effects and signal transduction of activated complement protein C3 in mice PY - 2019 SP - 2 UR - https://m2.mtmt.hu/api/publication/31262380 ID - 31262380 LA - English DB - MTMT ER - TY - JOUR AU - Kerkovits, Nóra Melinda AU - Janovicz, Anna AU - Ruisanchez, Éva AU - Őrfi, Erik AU - Gál, Péter AU - Szénási, Gábor AU - Benyó, Zoltán TI - Anaphylatoxin C3a induces vasoconstriction and hypertension mediated by thromboxane A2 in mice JF - FASEB JOURNAL J2 - FASEB J VL - 33 PY - 2019 IS - 51 SP - lb510 SN - 0892-6638 DO - 10.1096/fasebj.2019.33.1_supplement.lb510 UR - https://m2.mtmt.hu/api/publication/30871886 ID - 30871886 LA - English DB - MTMT ER - TY - JOUR AU - Dézsi, László AU - Mészáros, Tamás AU - Őrfi, Erik AU - Fülöp, Tamás AU - Hennies, Mark AU - Rosivall, László AU - Hamar, Péter AU - Szebeni, János AU - Szénási, Gábor TI - Complement Activation-Related Pathophysiological Changes in Anesthetized Rats: Activator-Dependent Variations of Symptoms and Mediators of Pseudoallergy JF - MOLECULES J2 - MOLECULES VL - 24 PY - 2019 IS - 18 PG - 12 SN - 1420-3049 DO - 10.3390/molecules24183283 UR - https://m2.mtmt.hu/api/publication/30799114 ID - 30799114 N1 - * Megosztott szerzőség AB - Complement (C) activation can underlie the infusion reactions to liposomes and other nanoparticle-based medicines, a hypersensitivity syndrome that can be partially reproduced in animal models. However, the sensitivities and manifestations substantially differ in different species, and C activation may not be the only cause of pathophysiological changes. In order to map the species variation of C-dependent and -independent pseudoallergy (CARPA/CIPA), here we used known C activators and C activator liposomes to compare their acute hemodynamic, hematological, and biochemical effects in rats. These C activators were cobra venom factor (CVF), zymosan, AmBisome (at 2 doses), its amphotericin B-free vehicle (AmBisombo), and a PEGylated cholesterol-containing liposome (PEG-2000-chol), all having different powers to activate C in rat blood. The pathophysiological endpoints measured were blood pressure, leukocyte and platelet counts, and plasma thromboxane B2, while C activation was assessed by C3 consumption using the Pan-Specific C3 assay. The results showed strong linear correlation between C activation and systemic hypotension, pointing to a causal role of C activation in the hemodynamic changes. The observed thrombocytopenia and leukopenia followed by leukocytosis also correlated with C3 conversion in case of C activators, but not necessarily with C activation by liposomes. These findings are consistent with the double hit hypothesis of hypersensitivity reactions (HSRs), inasmuch as strong C activation can fully account for all symptoms of HSRs, but in case of no-, or weak C activators, the pathophysiological response, if any, is likely to involve other activation pathways. LA - English DB - MTMT ER -