Complement activation associated with polysorbate 80 in beagle dogs
Graphical abstract
Highlights
► Tween 80 can cause complement activation-related pseudoallergy in dogs. ► Tween 80 can activate the complement system through classical and alternative pathways. ► Tween® 80 changed the pulmonary and systemic circulation in dogs.
Introduction
Polysorbate 80 (Tween® 80) is an oleate ester of sorbitol and its anhydrides copolymerized with approximately 20 mol of ethylene oxide for each mole of sorbitol and sorbitol anhydrides. Due to its amphiphilic nature, it can reduce the interfacial tension of solvent systems and, in this way, disperse a variety of immiscible materials [1]. Tween® 80 is a solubilizing agent ubiquitously used in multiple medical preparations and as an accessory in various drugs administered as injections [2].
The use of Tween® 80 as a drug accessory has recently been implicated in adverse clinical effects, including acute hypersensitivity [3] and peripheral neuropathy [4]. Many traditional Chinese medicine injections (TCMIs), which incorporate Tween® 80, have resulted in severe non-immune anaphylaxis (pseudoallergy). Liang, et al. [5] concluded that Houttuynia cordata injections using Tween® 80 as a solubilizer produced non-immune anaphylactic reactions which were primarily attributable to Tween® 80. Non-immune anaphylactic reactions have also been reported in a number of medicines containing Tween® 80, including docetaxel [7], paclitaxel [8], omalizumab [9] and etoposide [10], [11]. Sun [6] evaluated the sensitization effect of Tween® 80 when injected in dogs, and concluded that the solubilization effect and safety of Tween® 80 could be achieved by limiting its concentration to levels below 0.25% or 0.30%.
Pseudoallergy has recently been re-titled “non-immune anaphylaxis”, which is the current term used by the World Allergy Organization [12]. Non-immune anaphylaxis [12], [13] can result from activation of inflammatory or anaphylactic mechanisms independent of antigen-specific immune responses [14] and is not initiated or mediated by pre-existing IgE antibodies [15]. The spectrum of non-immune anaphylactic reactions include direct (nonspecific) histamine release, direct activation of the C cascade, abnormal synthesis of eicosanoids and inhibition of bradykinin degradation [16].
The exact mechanisms of non-immune anaphylactic reactions in response to Tween® 80 remain to be elucidated. One possibility is that the activation of complement (C) may be involved with these adverse reactions [4], [17]. However, there is no consensus in the literature regarding this proposed role of C. In specific, two critical questions to be addressed include: 1) whether Tween® 80 can activate C in animals and which pathways are activated and 2) whether Tween® 80 can activate C via the same pathways when tested under in vivo and in vitro conditions. The aim of this study is to explore the possible role of C activation in Tween® 80-induced hypersensitivity. As one approach to accomplish this goal we examined the C activating effects of Tween® 80 in dog serum specimens as assessed in vivo and in vitro.
Section snippets
Drugs and reagents
Tween® 80 was obtained from Amerisco Inc. and zymosan from Sigma-Aldrich. ELISA kits for canine histamine, IgE, SC5b-9, C4d and Bb were purchased from USCNK Life Science Inc. (Wuhan, China). In these experiments, normal saline (NS) or 10 mM phosphate buffered saline (PBS), were used as control agents.
Animals
Seventeen female beagle dogs, weighing 10–12 kg, were purchased from Shanghai Xingang Laboratory Animal Company and were housed in individual cages in a large colony room. Experiments were performed
Effects of Tween® 80 on pulmonary and systemic circulation
Data obtained from in vivo experiments revealed that Tween® 80 produced significant hemodynamic changes in PAP, MAP, heart rate and ECG as compared with baseline values established during the 20 min before Tween® 80 administration. Fig. 1 contains a summary of PAP and MAP changes resulting from systemic administration of 25 mg/kg Tween® 80 (n = 4). PAP levels increased by 40%, changing from 22 to 30 mm Hg within 10 min. MAP initially increased by 10% changing from 90 to 100 mm Hg in first 5 min and then
Discussion
Recent experimental data [3] indicated that nonionic surfactants, such as Tween® 80 and Cremophor® EL (CrEL), are not inert vehicles, but are capable of exerting considerable biological and pharmacological activity by themselves. In particular, it has been reported that Tween® 80 can cause serious non-immune anaphylaxis shock reactions [2].
In this experiment, beagle dogs showed responses indicative of non-immune anaphylactic syndromes after infusion with Tween® 80. These reactions were major
Conclusion
Tween® 80-mediated C activation is an intrinsic property of its macromolecular components. We show here that C activation is prominently caused by Tween® 80 in vivo and in vitro. Similar changes in cardiopulmonary and C components were observed when examined under in vivo conditions. Such findings strongly suggest that CARPA may be a major cause for the cardiopulmonary distress produced by i.v. injected Tween® 80. The present study highlights a high risk potential for Tween® 80 to trigger
Acknowledgments
The authors acknowledge Dr. Shi Yanqiu and Dr. Tian Guoqiang for the helpful comments on the manuscript. This work was supported by a grant from the Key Projects in the National Science & Technology Pillar Program in the Eleventh Five-year Plan Period (no. 2009ZX09502-001), the Supporting Program of the Twelfth Five-year Plan for Science and Technology Research of China (no. 2012BAI22B01) and the National Natural Science Foundation of China (no. 30973934).
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