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

Abstract

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.

Definition and classification of the histamine-release response to drugs in anaesthesia and surgery: Studies in the conscious human subject

“…However, this communication illustrates by one intensely studied example with one clinically used histamine releaser (experiments in animals and human subjects for more than /0 years [29-32, 34, 39, 40, 44, 54] that the classical symptoms of anaphylaxis are rare in histamine-release responses in general and only more common ("classical") in grade III reactions. Increasing experience, however, in animals [6,25,42,49,50,60] and in man [61] is forming the suggestion that even this may not be true: Clinical pictures of severe heart attack or arrhythmias may be caused by histaminerelease responses which clearly have to be classified as grade III reactions.…”

Modulation of histamine release by fatty acids. A new in vitro model investigating adverse drug reactions in various species

“…Of the hydrophobic components (composed of 80 % derivatives of ricinoleic acid, 5 % derivatives of oleic acid), only the derivatives of oleic acid released histamine [11]. Further experimentation indicated that the derivatives of 12-hydroxystearic acid were the least dangerous in this test system [13]. In the first part of the study here presented, cremophor E1 and six derivatives of 12-hydroxystearic acid were compared using two models : the anaesthetized dog and isolated mast cells.…”

“…There has been much work published on the histamine releasing ability of cremophor and its derivatives using in vivo models [11][12][13]. Cremophor El, produced by the oxethylation of castor oil at elevated temperatures in an alkaline medium, is a mixture of hydrophilic and hydrophobic components [12].…”

“…Anaesthetized mongrel dogs (both sexes) were prepared as previously described [13]. Briefly the dogs were anaesthetized with pentobarbitone, two catheters were inserted and 20 min allowed to elapse for stabilization.…”

Histamine in Anaesthesia and Surgery: Causality Analysis

“…It is, however, not widely known that cyclosporin A is dissolved using cremophor El as a solubilizer. This mixture of fatty acids and its chemically modified derivatives (LORENZ et al 1982b) was demonstrated in a whole series of articles as a histamine releaser (LORENZ et al 1971a(LORENZ et al , 1977b(LORENZ et al , 1981a(LORENZ et al , 1982b and as a potentiator of histamine release responses (ENNIS and LORENZ 1985a. This may explain unexpected cardiovascular reactions and very high plasma histamine levels at certain times after transplantation (LORENZ and DOENICKE 1985a) Finally, histamine is involved in wound healing.…”