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Doenicke, A.; Koenig, U. D.; Doenicke, Stephanie

doi:10.1007/978-3-642-95430-6_22

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“…In agreement with this concept were findings in patients that a variety of compounds with very different chemical constitution and either no or only a very weak basieity elicited adverse responses if they were solubilized with cremophor El, but were ineffective if they were dissolved in polyglycol. Examples of this phenomenon were propanidid [2], althesin [3], diazepam [8], lormetazepam [9], flunitrazepam [10] and etomidate [ 11 ]. However, in isolated human adenoidal mast cells [42] and in skin testing in human subjects [43] cremophor E1 and 12-hydroxystearic acid were shown to be effective without the addition of any drug and on first exposure to the solubilizing agents.…”

Section: Discussionmentioning

confidence: 98%

Histamine release and hypotensive reactions in dogs by solubilizing agents and fatty acids: Analysis of various components in cremophor El and development of a compound with reduced toxicity

et al. 1982

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Anaphylactoid reactions in man following administration of drugs solubilized with cremophor El (polyethylenglycolglycerol riconoleate) are a considerable clinical problem. Since these reactions occur in dogs on first exposure and in pigs on second exposure, the 'dog model' was used in this communication to analyse components and chemical modifications of cremophor El and its components for their clinical effects, their hypotensive actions and their histamine-releasing capacity. Two series of experiments in 1978 and 1980 were performed in 144 adult mongrel dogs of both sexes. In these studies histamine release was not related to the effect of the solubilizing agents as tensides and was elicited by rather low doses (about 10--100 mg/kg i.v.). The effect of these substances on blood pressure and on blood histamine levels was connected with distinct chemical features: the most potent compounds were oxethylated and additionally esterified unsaturated or hydroxylated fatty acids. Several phases in hypotensive reactions were observed, including an immediate response, a delayed blood pressure response and a late response about 15--20 min after injection. Only the delayed response was associated with histamine release. The combination of cardiovascular effects and histamine release was fatal on some occasions indicating that histamine release can be dangerous. Compared to cremophor El, the tenside effect was equal, but the toxicity was reduced in oxethylated 12-hydroxystearic acid. It is recommended that this solubilizer should be used in further extended studies in animals and - if these are successful - in clinical trials.

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