Cremophor induced histamine release

Cremophor-induced histamine release in dogs. Individual data (ng/ml histamine) obtained in 30 dogs, treated orally with solvent (S) or with different doses of R 35 443 (D) 4 h before the cremophor injection. 

Active doses of oxatomide with respect to ACF-reactions, histamine reactions and Cremophor-induced histamine release are of the same order. It appears therefore likely that the antiallergic activity of oxatomide is the result of two simultaneously occurring actions, a reduction of the amount of mediators set free from sensitized mast cells and an effective antagonism of whatever released histamine is going to act on smooth muscle. 

Histamine release was induced by Cremophor but with neither alphaxalone nor alphadolone separately. Each of these steroids when added to Cremophor led to a reduction in the Cremophor-induced histamine release, even to levels well below the control value (spontaneous histamine release in the presence of the medium used, Tyrode solution). When both alphaxalone and alphadolone were added to the vehicle they produced a paradoxical increase in 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). 

Oxatomide has been selected from a new chemical series of benzimidazolones and benzimidazoles on the basis of its activity on hypersensitivity and histamine-induced reactions in three species, the guinea-pig, the rat and the dog. In a well-known model, the guinea-pig anaphylaxis, oxatomide was at least as effective on the anaphylactic shock as on the histamine oedema induced in the same animals. In the rat, the new compound was an orally active inhibitor of PCA-reactions. Compound 48/80-induced lethal shock was prevented at doses of the same order as those required to inhibit histamine skin reactions. In the dog inhibition of allergic reactions, induced by Ascaris allergens in the skin of hypersensitive dogs, inhibition of histamine skin reactions and reduction of circulating histamine released by Cremophor EL were obtained by virtually the same oral doses. 

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 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 ]. 

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