Cremophors, direct histamine release

Acute hypersensitivity reactions were common during phase 1 trials of paclitaxel, and this caused delays in the completion of many trials. Reactions were mild to severe and consisted of cutaneous flushing, bronchospasm, bradycardia, and hypotension the reactions occurred after either the first or second dose (48). The mechanism of these reactions is uncertain, but they are thought to be non-immunologically mediated, and direct histamine release by mast cells is probably responsible. A large dose of Cremophor EL is used in the formulation of paclitaxel, and this may play an important part in these hypersensitivity reactions Cremophor EL induces similar reactions in dogs by direct release of histamine (4). 

Direct histamine release may be induced with many polymer substances (Paton 1957), but the link between this finding and the abnormal release of histamine from the leucocytes of susceptible individuals with Cremophor EL (also a polymer) is yet to be disclosed. Presumably, it is either a qualitative abnormality (idiosyncrasy) or a quantitative one (extreme exaggeration of the normal), thus possibly defined as intolerance . 

The mechanism of induction of histamine release by alphaxalone and alphadolone shown by the leucocyte test in susceptible individuals is not clear at present, but it appears to be like Cremophor EL. This means that it could be due either to an anaphylactic or anaphylactoid (direct histamine release) reaction. We did not find histamine release with these agents from the leucocytes of normal volunteers. We were unable to elicit a positive Prausnitz-Kiistner reaction in two patients in whom a reaction occurred after a second exposure to Althesin, and in whom the vehicle did not produce any response, either in the direct skin test or in the leucocyte test. 

The mechanism of paclitaxel-induced hypersensitivity reactions is uncertain. The symptoms suggest histamine release from mast cells to be a likely cause. Cremophor EL is thought to play a significant role in inducing hypersensitivity reactions. Cremophor EL causes similar reactions in dogs by direct release of histamine [17 ]. Hypersensitivity reactions have also been directly linked to complement activation secondary to binding of naturally occurring anticholesterol antibodies to the hydroxyl-rkh surface of Cremophor EL micelles [75 ]. However, there is evidence that paclitaxel alone, without the Cremophor EL vehicle, can also cause hypersensitivity reactions [76 ]. 

Cremophor EL has been implicated in several cases of adverse reactions to the compound present as a solubilizer in intravenous anaesthetic preparations. Adverse reactions may be due to direct pharmacological release of histamine, to immune-mediated mechanisms, or to activation of C3 complement leading to release of histamine [121]. It has been variously estimated that the incidence of reactions to Althesin which contains 20 % Cremophor EL is 1 in 14 000 to 19 000, 1 in 900 or 1 in 1900 [122]. 

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See also in sourсe #XX -- [ ]

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