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 wasnot 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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W. Lorenz, R. Meyer, A. Doenicke, A. Schmal, H.-J. Reimann, M. Hutzel andE. Werle,On the species specificity of the histamine release from mast cell stores by cremophor El, Naunyn-Schmiedeberg's Arch. Pharmak.269, 417.
W. Lorenz, A. Doenicke, R. Meyer, H.-J. Reimann, J. Kusche, H. Barth, H. Geesing, M. Hutzel andB. Weissenbacher,Histamine release in man by propanidid and thiopentone: pharmacological effects and clinical consequences, Br. J. Anaesth.44, 355–369 (1972).
A. Doenicke, W. Lorenz, R. Beigl, H. Bezecny, G. Uhlig, L. Kalmar, B. Praetorius andG. Mann,Histamine release after intravenous application of short-acting hypnotics: a comparison of etomidate althesin (CT 1341) and propanidid, Br. J. Anaesth.45, 1097–1104 (1973).
M.S. Hüttel, A. Schou Olesen andE. Stoffersen,Complement-mediated reactions to diazepam with cremophor as solvent (Stesolid MR), Br. J. Anaesth.52, 77–79 (1980).
W. Lorenz, A. Doenicke, B. Schöning andE. Neugebauer, The role of histamine in adverse reactions to intravenous agents. InAdverse Reactions of Anaesthetic Drugs, pp. 169–238 (Ed.A. Thornton). Elsevier/North-Holland Biomedical Press, Amsterdam 1980.
W. Lorenz, H.-J. Reimann, A. Schmal, P. Dormann, B. Schwarz andE. Neugebauer,Histamine release in dogs by cremophor El and its derivatives: oxethylated oleic acid is the most effective constituent, Agents and Actions7, 63–67 (1977).
W. Lorenz, A. Doenicke, R. Meyer, H.-J. Reimann, J. Kusche, H. Barth, H. Geesing, M. Hutzel andB. Weissenbacher,An improved method for the determination of histamine release in man: Its application in studies with propanidid and thiopentone, Eur. J. Pharmacol.19, 180–190 (1972).
A. Padfield andJ. Watkins,Allergy to diazepam, Br. Med. J.I, 575–576 (1977).
A. Doenicke, Pseudo-allergic reactions due to histamine release during intravenous anaesthesia. InPseudo-Allergic Reactions. Involvement of Drugs and Chemicals, vol. 1, pp. 224–250 (EdsP. Dukor, P. Kallos, H.D. Schlumberger andG.B. West). Karger, Basel 1980.
W. Lorenz andA. Doenicke, Anaphylactoid reactions and histamine release by intravenous drugs used in surgery and anaesthesia. InAdverse Response to Intravenous Drugs, pp. 83–112 (EdsJ. Watkins andA.M. Ward). Academic Press, London, Grune and Stratton, New York 1978.
A. Doenicke (personal communication).
J.B. Glen, G.E. Davies, D.S. Thomson, S.C. Scarth andA.V. Thompson, Adverse reactions to intravenous anaesthetics in animals. InAdverse Response to Intravenous Drugs, pp. 129–135 (EdsJ. Watkins andA.M. Ward). Academic Press, London 1978.
J.B. Glen, G.E. Davies, D.S. Thomson, S.C. Scarth andA.V. Thompson,An animal model for the investigation of adverse responses to i.v. anaesthetic agents and their solvents, Br. J. Anaesth.51, 819–827 (1979).
J. Watkins, Mechanisms and factors predisposing towards adverse response to intravenous anaesthetic substances. InAdverse Reactions of Anaesthetic Drugs, pp. 137–167 (Ed.J.A. Thornton). Elsevier/North-Holland Biomedical Press, Amsterdam 1981.
R.T. Garrett, The clinical manifestations of adverse reactions following althesin and thiopentone. InAdverse Response to Intravenous Drugs, pp. 37–40 (EdsJ. Watkins andA.M. Ward). Academic Press, London 1978.
A.R. Johnson andN.C. Moran,Selective release of histamine from rat mast cells by compound 48/80 and antigen, Am. J. Physiol.216, 453–459 (1969).
W. Lorenz, J.V. Parkin, H. Rohde, H. Barth, H. Troidl, K. Thon, E. Hinterlang, D. Weber, R. Albrecht andH. Röher, Histamine in gastric secretory disorders: Questions about the relevance of the mucosal histamine content and about the origin of histamine in gastric aspirate. InGastric secretion: Basic and Clinical Aspects, pp. 29–51. (EdsS.J. Konturck andW. Donischke). Geog-Thieme, Stuttgart 1981.
W. Lorenz, H.-J. Reimann, A. Schmal, R. Tauber andR. Uhlig,Histamine release from typical and atypical mast cell stores by cremophor El, Naunyn-Schmiedeberg's Arch. Pharmak. Suppl.274, R75 (1972).
K.W. Batchelor andD.R. Stanworth,The effects of nonidet P 40 on the function of rat peritoneal mast cells in vitro, Br. J. Pharmacol.72, 95–100 (1981).
W. Lorenz, M. Thermann, K. Messmer, A. Schmal, P. Dormann, J. Kusche, H. Barth, R. Tauber, M. Hutzel, G. Mann andR. Uhlig,Evaluation of histamine elimination curves in plasma and whole blood of several circulatory regions: A method for studying kinetics of histamine release in the whole animal, Agents and Actions4, 336–356 (1974).
G.W. Snedecor andW.G. Cochran,Statistical Methods, 6th edn. Iowa State University Press, Ames, Iowa 1967.
W. Lorenz, H.-J. Reimann, H. Barth, J. Kusche, R. Meyer, A. Doenicke andM. Hutzel,A sensitive and specific method for the determination of histamine in human blood and plasma, Hoppe-Seyler's Z. Physiol Chem.353, 911–920 (1972).
W. Lorenz, H. Barth, M. Thermann, A. Schmal, P. Dormann andI. Niemeyer,Fluorometric histamine determination in canine plasma under normal conditions, following application of exogenous histamine and during histamine release by Haemaccel ®, Hoppe-Seyler's Z. Physiol. Chem.355, 1097–1111 (1974).
S.E. Lindell andK. Viske,A note on the distribution of [14C]-histamine added to blood, Br. J. Pharmacol.17, 131–136 (1961).
W. Lorenz, K. Mohri, H.-J. Reimann, H. Troidl, H. Rohde andH. Barth, Intramucosal mechanisms: relevance of the mast cell concept. InAdvances in Ulcer Disease, International Congress Series No. 357, pp. 176–194. Excerpta Medica, 1981.
R.J. Henry, Accuracy, precision and control charts. InClinical Chemistry—Principles and Techniques, pp. 122–143. Harper and Row, 1964.
W. Lorenz,Histamine release in man, Agents and Actions5, 402 (1975).
M.W. Brunden,The analysis of non-independent 2×2 tables from 2×C tables using rank sums, Biometrics28, 603–607 (1972).
B.S. Everitt, r × c contingency tables. InThe Analysis of Contingency Tables, Monographs on Applied Probability and Statistics pp. 38–48 (EdsM.S. Bartlett andD.R. Cox). Chapman and Hall, London 1977.
R.C. Lewontin andJ. Felsenstein,The robustness of homogeneity tests in 2×N tables, Biometrics21, 19–33 (1965).
G.A. Lienert, Multiple Lokationsvergleiche zwischen unabhängigen Stichproben. InVerteilungsfreie Methoden in der Biostatistik, Bd. 1, pp. 292–318. Verlag Anton Hain, 1973.
S. Siegel,Nonparametric Statistics for the Behavioral Sciences, pp. 175–179. McGraw-Hill Kogakuska Ltd, Tokyo 1956.
L.B. Lusted,Introduction to Medical Decision Making, pp. 1–248. Ch. C. Thomas, Springfield, Illinois 1968.
W. Lorenz andA. Doenicke, unpublished observations.
H. Lennartz, R. Dudziak andW. Lorenz, unpublished observations.
A. Doenicke andW. Lorenz,Histaminfreisetzung und anaphylaktische Reaktionen bei Narkosen. Biochemische und klinische Aspekte, Anaesthesist19, 413–417 (1970).
R.S.J. Clarke, J.W. Dundee, R.T. Garrett, G.K. McArdle andJ.A. Sutton,Adverse reactions to intravenous anaesthetics, Br. J. Anaesth.47, 575–585 (1975).
M.M. Fisher,Severe histamine mediated reactions to intravenous drugs used in anaesthesia, Anaesth. Intens. Care3, 180–197 (1975).
J. Watkins andA.M. Ward,Adverse response to Intravenous Drugs, pp. 1–188. (EdsJ. Watkins andA.M. Ward). Academic Press, London, Grune and Stratton, New York, 1978.
W. Lorenz andA. Doenicke,Histamine release in clinical conditions, Mount Sinai J. Med.45, 357–386 (1978).
J. Watkins,Anaphylactoid reactions to i.v. substances, Br. J. Anaesth.51, 51–60 (1979).
A. Thornton,Adverse Reactions of Anaesthetic Drugs, pp. 1–348. Elsevier/North-Holland Biomedical Press, Amsterdam 1981.
J.A. Thornton andW. Lorenz,Histamine and anti-histamines in anaesthesia and surgery: report on symposium, Anaesthesia (in press).
W. Lorenz, M. Thermann, H. Hamelmann, A. Schmal, D. Maroske, H.-J. Reimann, J. Kusche, F. Schingale, P. Dormann andP. Keck, Influence of H1- and H2-receptor antagonists on the effects of histamine in the circulatory system and on plasma histamine levels. InSymposium on Histamine H 2-Receptor Antagonists, p. 151 (EdsC.J. Wood andM.A. Simkins). Deltakos (UK), Ltd, London 1973.
J.B. Glen,Report on polyethoxylated 12-hydroxystearic acid surfactant to BASF UK Ltd, February 1981.
W. Schmutzler,Histamine release from human adenoidal mast cells induced by anti-human IgE, acetylcholine, Epontol ®,cremophor El and 12-hydroxystearic acid (in press).
M. Werner andE. Wolff, Klinisch-experimentelle Untersuchungen zur Frage der Propanidid-Allergie. InIntravenöse Narkose mit Propanidid. Anaesthesiology and Resuscitation, vol. 74, pp. 217–223 (Eds.M. Zindler, H. Yamamura andW. Wirth). Springer Verlag, Berlin 1973.
J. Watkins, A. Clark, T.N. Appleyard andA. Padfield,Immune-mediated reactions to althesin (alphaxalone), Br. J. Anaesth.48, 881–886 (1976).
W. Lorenz andH.-J. Reimann, unpublished data.
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Lorenz, W., Schmal, A., Schult, H. et al. 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. Agents and Actions 12, 64–80 (1982). https://doi.org/10.1007/BF01965109
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DOI: https://doi.org/10.1007/BF01965109