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Dezsi L.,Semmelweis University | Rosivall L.,Semmelweis University | Rosivall L.,MTA SE Pediatrics and Nephrology Research Group | Hamar P.,Semmelweis University | And 4 more authors.
European Journal of Nanomedicine

Complement activation-related pseudoallergy (CARPA) is a hypersensitivity reaction to intravenous administration of nanoparticle-containing medicines (nanomedicines). This review focuses on CARPA in rodent models: rats, mice, guinea pigs and rabbits. Information on all aspects of hypersensitivity reactions caused by known complement activators (zymosan, cobra venom factor) and different nanomedicines (liposomes, other drug carrier nanocarriers) in these species has been compiled and analyzed, trying to highlight the similarities and differences. What is most common in all species' reactions to i.v. complement activators, liposomes and other nanoparticles is a dose-dependent hemodynamic and cardiopulmonary disturbance manifested in acute, reversible rise or fall of blood pressure and respiratory distress that can lead to shock. Other symptoms include heart rate changes, leukopenia followed by leukocytosis, thrombocytopenia, hemoconcentration due to fluid extravasation (rise of hematocrit) and rise of plasma thromboxane B2. The results of a recent rat study are detailed, which show that rats are 2-3 orders of magnitude less sensitive to liposome-induced CARPA than pigs or hypersensitive humans. It is concluded that CARPA can be studied in rodent models, but they do not necessarily mimic the human reactions in terms of symptom spectrum and sensitivity. © 2015 by De Gruyter. Source

Milosevits G.,Semmelweis University | Szebeni J.,Semmelweis University | Szebeni J.,SeroScience Ltd. | Krol S.,Fondazione Istituto Neurologico Carlo Besta
European Journal of Nanomedicine

Exosomes are nature's nanocarriers that transport biological information in humans. Their structural properties, origin and functions are making them interesting objects for the diagnosis of diseases, such as cancer, and also, as innovative tools for drug delivery. The interaction of exosomes with the immune system has been one of the focal points of interest; nevertheless their "stealth" properties helping to avoid adverse immune reactions are still not fully understood. In this review, after giving an overview of recent findings on the role of exosomes in disease pathogenesis and physiological functions, we focused on their interaction with the immune system and possibilities for clinical applications. The potential of exosomes of creating stealth nanoparticles that are better tolerated by the immune system than the presently available synthetic drug delivery systems represent a promising new approach in nanomedicine. © 2015 by De Gruyter 2015. Source

Bedocs P.,Defense and Veterans Center for Integrative Pain Management | Capacchione J.,Uniformed Services University of the Health Sciences | Potts L.,U.S. National Institutes of Health | Chugani R.,Washington University in St. Louis | And 4 more authors.
Anesthesia and Analgesia

BACKGROUND: Reports in the recent experimental literature have provided contradicting results in different animal species regarding the efficacy of IV lipid emulsion (ILE) in the reversal of cardiovascular and central nervous system symptoms of local anesthetic and other lipophilic drug overdoses. In particular, ILE seemed to be effective in rats, rabbits, dogs, and humans, but not in swine, for which it not only failed to reverse the adverse effects of anesthetics, but the animals also developed a generalized cutaneous mottling or a dusky appearance immediately after ILE, suggestive of another type of toxicity. The latter symptoms arise in complement (C) activation-related pseudoallergy, a hypersensitivity reaction to particulate drugs and agents. METHODS: Ten Yorkshire swine (15-20 kg) were sedated with ketamine and anesthetized with isoflurane. ILE 1.5 and 5 mL/kg 20% was administered via the ear vein while pulmonary arterial pressure, systemic arterial blood pressure, electrocardiogram, and end-tidal CO2 were recorded continuously. Thromboxane was measured in blood collected at baseline and 2 and 10 minutes after injections. Complement activation by lipid emulsion was also assessed in vitro with soluble terminal complement complex (SC5b-9) and sheep red blood cell assays. RESULTS: Significant increases were observed in the pulmonary pressure (median [interquartile range]) within minutes after the administration of ILE, both at doses 1.5 and 5 mL/kg (15 [12-16.5] to 18.5 [16-20] mm Hg, P = 0.0058 and 15.5 [13-17.25] to 39.5 [30.5-48.5], respectively). The systemic arterial blood pressure increased, and the heart rate decreased after both injections. Thromboxane B2 concentration (median [interquartile range]) in the blood plasma increased from a baseline of 617.3 [412.4-920] to 1132 [597.9-1417] pg/mL (P = 0.0055) and from 1276 [1200-2581] to 4046 [2946-8442] pg/mL (P = 0.0017) after the administration of 1.5 and 5 mL/kg ILE, respectively. Intralipid did not cause in vitro complement activation in human serum. CONCLUSIONS: ILE causes clinically significant hemodynamic changes in pigs, in concert with significant increases in the plasma thromboxane concentration. However, the in vitro tests did not confirm involvement of the complement system in human sera, leaving the underlying mechanism of these findings in doubt. Nonetheless, the observed hemodynamic and biochemical effects of ILE serve as a caveat that the pig is not an ideal model for the study of interventions involving ILE. Copyright © 2014 International Anesthesia Research Society. Source

Csukas D.,Semmelweis University | Urbanics R.,Semmelweis University | Urbanics R.,SeroScience Ltd. | Moritz A.,University of Mannheim | And 2 more authors.
Nanomedicine: Nanotechnology, Biology, and Medicine

Intra-operative and postoperative bleeding is a major concern in surgical procedures for patients taking anticoagulant medications, or where anticoagulants are used to prevent potential life-threatening embolic complications. Heparin is the anticoagulant used most frequently and has an immediate effect on blood clotting, lasting 4 to 6. h. Although synthetic self-assembling peptides have been shown to achieve rapid hemostasis in small animals, none have adequately addressed the potential for hemostasis in the presence of anticoagulant therapy in-vivo. Our goal was to investigate the hemostatic activity of a known synthetic self-assembling peptide in animals treated and untreated with heparin anticoagulation therapy. Using a rat liver puncture model, animals were treated with known synthetic peptide AC5 Surgical Hemostatic Device™, or saline controls. Time-to-hemostasis and coagulation times were recorded in both heparinized and non-heparinized animals. Here we show that AC5™ was able to achieve rapid hemostasis equivalently in both heparinized and non-heparinized animals. From the Clinical Editor: Intra-operative and postoperative bleeding is a major concern in surgical procedures for patients taking anticoagulant medications. In this work the effective hemostasis was demonstrated both in heparinized and non-heparinized animals using self-assembling peptides. © 2015 Elsevier Inc.. Source

Racz Z.,Semmelweis University | Nagy E.,Semmelweis University | Rosivall L.,Semmelweis University | Szebeni J.,Semmelweis University | And 2 more authors.

Intravenous immunoglobulin (IVIG) has a therapeutic potential in many autoimmune diseases. Based on its immune modulating and complement inhibiting effects, IVIG has been tested in systemic lupus erythematosus (SLE), but due to osmotic tubular injury caused by immunoglobulin-stabilizing sugar components, lupus nephritis had been accelerated in some patients, thus IVIG use in SLE has been abandoned. The availability of non-sugar-stabilized IVIG raised the possible re-evaluation of IVIG for SLE. We investigated high-dose, long-term non-sugar-stabilized IVIG treatment on skin and renal SLE manifestations in the MRL/lpr mouse model. Animals were treated once a week with glycine-stabilized IVIG or saline (0.2 ml/ 10 g BW) from 6 weeks until they were humanely killed at 5 months of age. IVIG diminished macroscopic cutaneous lupus compared with saline treated mice. Histology and complement-3 immunostaining also demonstrated a significant reduction of skin disease after IVIG treatment. However, renal histology and function were similar in both groups. Compared with typical osmotic tubular damage induced by 5% sucrose and 10% maltose (used for IVIG stabilization), we did not observe any osmotic tubular injury in the glycine-stabilized IVIG treated mice. Our data demonstrate a beneficial effect of IVIG on skin lupus without renal side-effects. Deeper understanding of the organ-specific pathomechanism may aid an individualized SLE therapy. © The Author(s), 2010. Source

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