Meanwhile, drugs can cause anaphylactoid reaction which displays the same clinical manifestations as anaphylaxis. However, a different mechanism exists. Anaphylactoid reactions are non-IgE-mediated and do not require a history of exposure. In both IgE- and nonIgE-mediated reactions, mast cells and basophils rapidly release histamine, b-hexosaminidase and tryptase via different trigger mechanisms. Because anaphylaxis and anaphylactoid reactions are clinically indistinguishable, reports of anaphylactoid reactions and anaphylaxis are confused. The nature of the adverse reaction to VK1 injection is one example of this uncertainty. The anaphylaxis and anaphylactoid reactions induced by drugs are related to hereditary capacity, immune status, the drug delivery route, the identity of the drug, and metabolism, among other factors. Completely simulating these responses in vitro is difficult. Therefore, selecting and establishing the appropriate animal model is very important. Compared with other experimental animals, dogs and humans are more likely to experience similar symptoms, and dogs are more sensitive to anaphylactoid reactions than any other animals. The degranulation of basophils or mast cells is an important element in the study of anaphylaxis and anaphylactoid reactions. RBL-2H3, a continuous rat cell line that is useful for in vitro studies, has been used extensively to study signaling pathways Nutlin-3 involved in degranulation and IgE-FceRI interactions. Behavioristics is considered to be a vital, simple and intuitive method to determine the type of adverse reaction. The present study showed that dogs experienced serious multiorgan symptoms, increases in plasma histamine concentrations, and sharp decreases in blood pressure after the first intravenous VK1 injection. Undoubtedly, the results demonstrate that VK1 injection induces an anaphylactoid reaction. VK1 is a lipid-soluble substance. For preparation as an injection, the use of a solubilizer such as Tween-80 is required. When 1 mg/kg Tween-80 was administered to the dogs, anaphylactoid reactions appeared; these results are in agreement with previous reports. Other drugs that require solubilizers containing Tween-80, such as qingkailing injection, shengmai injection, the anti-neoplastic agent paclitaxel and the immunosuppressant cyclosporine, also cause obvious anaphylactoid reactions. However, it is the low dose of Tween-80 that did not lead to the significant changes in the plasma histamine concentration and blood pressure. The plasma histamine levels sharply increased in the dogs upon the administration of 25 mg/kg Tween-80. VK1-FE is a preparation in which VK1 is dissolved in lecithin and is a steady O/W emulsion without any solubilizer. This preparation can be used to help explain the effect of the solubilizer on adverse reactions. Abnormal behaviors were not observed in dogs administered VK1-FE without Tween-80. Furthermore, no significant change in plasma histamine was observed in these dogs. The results revealed that VK1-FE does not induce an anaphylactoid reaction. Therefore, VK1 is not the trigger that initiates the anaphylactoid reaction in response to VK1 injection.