Hemodynamic Changes Induced by Liposomes and Liposome-Encapsulated Hemoglobin in Pigs

Abstract

Background-Intravenous administration of some liposomal drugs can trigger immediate hypersensitivity reactions that include symptoms of cardiopulmonary distress. The mechanism underlying the cardiovascular changes has not been clarified. Methods and Results-Anesthetized pigs (nϭ18) were injected intravenously with 5-mg boluses of large multilamellar liposomes, and the ensuing hemodynamic, hematologic, and laboratory changes were recorded. The significant (PϽ0.01) alterations included 79Ϯ9% (meanϮSEM) rise in pulmonary arterial pressure, 30Ϯ7% decline in cardiac output, 11Ϯ2% increase in heart rate, 236Ϯ54% increase in pulmonary vascular resistance, 71Ϯ27% increase in systemic vascular resistance, and up to a 100-fold increase in plasma thromboxane B 2 . These changes peaked between 1 and 5 minutes after injection, subsided within 10 to 20 minutes, were lipid dose-dependent (ED 50 ϭ4.5Ϯ1.4 mg), and were quantitatively reproducible in the same animal several times over 7 hours. The liposome-induced rises of pulmonary arterial pressure showed close quantitative and temporal correlation with elevations of plasma thromboxane B 2 and were inhibited by an anti-C5a monoclonal antibody (GS1), by sCR1, or by indomethacin. Liposomes caused C5a production in pig serum in vitro through classic pathway activation and bound IgG and IgM natural antibodies. Zymosan-and hemoglobin-containing liposomes and empty liposomes caused essentially identical pulmonary changes. Conclusions-The intense, nontachyphylactic, highly reproducible, complement-mediated pulmonary hypertensive effect of minute amounts of intravenous liposomes in pigs represents a unique, unexplored phenomenon in circulation physiology. The model provides highly sensitive detection and study of cardiopulmonary side effects of liposomal drugs and many other pharmaceutical products due to "complement activation-related pseudoallergy" (CARPA).

Pharmacokinetics, Toxicities, and Efficacies of Sodium Stibogluconate Formulations after Intravenous Administration in Animals

“…The adverse effects caused by this include a rise in pulmonary arterial pressure, a decline in cardiac output, increased heart rate, increased pulmonary vascular resistance, increased systemic vascular resistance, and up to a 100-fold increase in plasma thromboxane B 2 levels. These may have caused some of the effects observed in the SSG-NIV-dextran-treated dogs, since they can occur rapidly postdosing (peak, 1 to 5 min after administration) and they have been shown to be lipid dose dependent (28,29,30). In addition, liposome-induced complement activation and its consequences show significant interspecies and interindividual variations, which may explain the interspecies variability observed in this study.…”

“…Blood samples were collected with disposable syringes that contained sodium heparin from a catheter placed contralateral to the infusion cephalic vein. After each administration, blood sampling was carried out at 5,10,20,30,40,60,80, and 100 min and 2, 2.5, 3, 4, 5, 6, 8, and 24 h after administration. Blood samples (3 ml) were kept refrigerated until they were centrifuged (2,000 ϫ g).…”

Pilot Trial of Intravenous Lipid Emulsion Treatment for Severe Nifedipine-Induced Shock

“…Anaphylactoid reactions have been observed after infusion of specific liposomes and fat-containing nanoparticles [32][33][34]. These so-called CARPA reactions (compliment activation-related pseudoallergy) have been reported in various animal models including dogs, rats, and swine and may result in hypotension, hypertension, tachycardia, bradycardia, flushing, and rash.…”

Cerebrovascular Involvement in Liposome—Induced Cardiopulmonary Distress in Pigs

“…However, a common side effect after injection of liposomes is a poorly understood immediate hypersensitivity reaction in a 4 M. Bodo et al relatively large percentage of patients (3-45%) (Laverman et al, 2001;Yee et al, 1998). The physiological signs of shock, including transient hemodynamic changes, hypotension, bradycardia, and cardiac arrhythmias, were shown recently to be reproducible in pigs by intravenous injection of minute amounts of liposomes including Doxil (Szebeni et al, 1999.…”