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

Abstract

: Histamine release caused by drugs and/or their solvents is a well known phenomenon. In this study, both in vivo (anaesthetized and conscious dogs) and in vitro (isolated rat peritoneal, human and guinea-pig lung mast cells) models were used. Cremophor E1 and six derivatives of 12-hydroxystearic acid were compared for their histamine releasing abilities. Although the three types of isolated mast cells responded similarly, histamine release being observed with DH (the diester of 12-hydroxystearic acid with polyethylene glycol), TN (12-hydroxystearic acid polymerized with ethylene oxide) and ME (the monoester of 12-hydroxystearlc acid esterified with polyethylene glycol), the anaesthetized dog exhibited elevated blood histamine levels and clinical symptoms after administration of all the solubilizing agents, except TN and ME. The reasons for this discrepancy are not known. The addition of the drugs (Althesin or propanidid) to their solubilizing agents caused histamine release, which was not observed with the solubilizing agent alone. This is the first demonstration of an in vitro model, which copies the clinical situation, i.e. solvent does nothing but the solvent plus drug combination causes histamine release and hence adverse reactions.RESUMe : La hb6ration d'histamine, due h des produits anesth6si-ques et/ou ~ leurs solvants, est un ph6nom6ne bien connu. Deux mod61es ont 6t6 utihs6s au cours de cette 6tude : l'un in vivo (chez le chlen anesth6si6 ou 6veill6), l'autre in vitro (sur des mastocytes xsol6s de p6ritoine de rat, de poumon humain ou de cobaye). Les capacit6s histaminolib6ratrices du cr6mophor E1 et de six d6riv6s de l'aclde 12-hydroxyst6arique ont 6t6 compar6es. Quoique les trois types de mastocytes isol6s aient r6agi de fa~on analogue, l'histaminolib6ration 6tant observ6e avec le DH (diester de l'acide 12-hydroxyst6afique + poly6thyl~ne glycol), le TN (acide 12-hydroxyst6arique polym6ns6 avec de l'oxyde d'6thyl6ne) et le ME (monoester de l'aclde 12-hydroxyst6arique est6rifi6 avec du poly6thyl6ne glycol), le chien anesth6si6 pr6sente un taux d'histamine 61ev6 et des sympt6mes chniques apr~s administration de tousles agents solvants, sauf le TN et le ME. Les raisons de cette dxff6rence ne sont pas connues. L'adjonction d'Alfat6sine ou de propanidide aux agents solvants entralne une histaminolib6-ration, qui n'6talt pas observ6e avec le solvant seul. Cette 6tude est le premier exemple d'un mod61e in vitro, copiant la situation clinique : le solvant n'entralne pas de r6action, mals l'adjoncnon de prodmt ~t ce dernier provoque une histaminolib6ration et donc des effets secondaires.Adverse reactions to drugs used during anaesthesia and surgery are common. Although reported incidences vary considerably, using data obtained from 23 carefully controlled clinical trials, the following incidences were obtained: all reactions 20-30 %, systemic reactions 1-5 % and life-threatening reactions 0.1-0.5 % [8]. In many cases, these reactions appear to be caused not by the drug itself but by the combination of...

Vancomycin-induced release of histamine from rat peritoneal mast cells and a rat basophil cell line (RBL-1)

“…[26]. In addition, the rat peritoneal mast cell has been found to be useful in the study of a number of agents producing histamine release in man [27,28], and may, therefore, accurately represent vancomycin effects induced clinically.…”

The pharmacokinetics and pharmacodynamics of alfaxalone in cats after single and multiple intravenous administration of Alfaxan®at clinical and supraclinical doses

“…The solubilizing agent for Saffan Ò was a polyethoxylated castor oil, Cremophor Ò -EL, which caused histamine release in animals by stimulating mast cell degranulation. This histamine released caused unacceptable adverse events (Clarke et al, 1975;Fisher, 1975;Dodman, 1980;Ennis & Lorenz, 1985). Because alfaxalone has a wide margin of safety, a formulation containing no Cremophor Ò -EL has been a target of research for some years (Brewster et al, 1989).…”

Histamine in Anaesthesia and Surgery: Causality Analysis

“…1a,c, LORENZ et al 1976, 1977aLORENZ and DOENICKE, 1978a,b), patients (Figs. 1b,2b, LoRENZ et al 1976PHILBIN et al 1982a) and several animal species (LORENZ and DOENICKE 1978a;NEUGEBAUER and LORENZ 1981;Moss et al 1982) and isolated cells (ENNIS and Lorenz 1985a).…”

“…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.…”