Skip to main content
Log in

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

  • Histamine and Kinins
  • Histamine Release
  • Published:
Agents and Actions Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. 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.

  2. 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).

    PubMed  Google Scholar 

  3. 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).

    PubMed  Google Scholar 

  4. 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).

    PubMed  Google Scholar 

  5. 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.

    Google Scholar 

  6. 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).

    PubMed  Google Scholar 

  7. 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).

    Article  PubMed  Google Scholar 

  8. A. Padfield andJ. Watkins,Allergy to diazepam, Br. Med. J.I, 575–576 (1977).

    Google Scholar 

  9. 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.

    Google Scholar 

  10. 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.

    Google Scholar 

  11. A. Doenicke (personal communication).

  12. 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.

    Google Scholar 

  13. 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).

    PubMed  Google Scholar 

  14. 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.

    Google Scholar 

  15. 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.

    Google Scholar 

  16. 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).

    PubMed  Google Scholar 

  17. 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.

    Google Scholar 

  18. 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).

    Google Scholar 

  19. 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).

    PubMed  Google Scholar 

  20. 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).

    PubMed  Google Scholar 

  21. G.W. Snedecor andW.G. Cochran,Statistical Methods, 6th edn. Iowa State University Press, Ames, Iowa 1967.

    Google Scholar 

  22. 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).

    PubMed  Google Scholar 

  23. 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).

    PubMed  Google Scholar 

  24. S.E. Lindell andK. Viske,A note on the distribution of [14C]-histamine added to blood, Br. J. Pharmacol.17, 131–136 (1961).

    Google Scholar 

  25. 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.

  26. R.J. Henry, Accuracy, precision and control charts. InClinical Chemistry—Principles and Techniques, pp. 122–143. Harper and Row, 1964.

  27. W. Lorenz,Histamine release in man, Agents and Actions5, 402 (1975).

    PubMed  Google Scholar 

  28. M.W. Brunden,The analysis of non-independent 2×2 tables from 2×C tables using rank sums, Biometrics28, 603–607 (1972).

    Google Scholar 

  29. 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.

    Google Scholar 

  30. R.C. Lewontin andJ. Felsenstein,The robustness of homogeneity tests in 2×N tables, Biometrics21, 19–33 (1965).

    Google Scholar 

  31. G.A. Lienert, Multiple Lokationsvergleiche zwischen unabhängigen Stichproben. InVerteilungsfreie Methoden in der Biostatistik, Bd. 1, pp. 292–318. Verlag Anton Hain, 1973.

  32. S. Siegel,Nonparametric Statistics for the Behavioral Sciences, pp. 175–179. McGraw-Hill Kogakuska Ltd, Tokyo 1956.

    Google Scholar 

  33. L.B. Lusted,Introduction to Medical Decision Making, pp. 1–248. Ch. C. Thomas, Springfield, Illinois 1968.

    Google Scholar 

  34. W. Lorenz andA. Doenicke, unpublished observations.

  35. H. Lennartz, R. Dudziak andW. Lorenz, unpublished observations.

  36. A. Doenicke andW. Lorenz,Histaminfreisetzung und anaphylaktische Reaktionen bei Narkosen. Biochemische und klinische Aspekte, Anaesthesist19, 413–417 (1970).

    PubMed  Google Scholar 

  37. 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).

    PubMed  Google Scholar 

  38. M.M. Fisher,Severe histamine mediated reactions to intravenous drugs used in anaesthesia, Anaesth. Intens. Care3, 180–197 (1975).

    Google Scholar 

  39. 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.

    Google Scholar 

  40. W. Lorenz andA. Doenicke,Histamine release in clinical conditions, Mount Sinai J. Med.45, 357–386 (1978).

    Google Scholar 

  41. J. Watkins,Anaphylactoid reactions to i.v. substances, Br. J. Anaesth.51, 51–60 (1979).

    PubMed  Google Scholar 

  42. A. Thornton,Adverse Reactions of Anaesthetic Drugs, pp. 1–348. Elsevier/North-Holland Biomedical Press, Amsterdam 1981.

    Google Scholar 

  43. J.A. Thornton andW. Lorenz,Histamine and anti-histamines in anaesthesia and surgery: report on symposium, Anaesthesia (in press).

  44. 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.

    Google Scholar 

  45. J.B. Glen,Report on polyethoxylated 12-hydroxystearic acid surfactant to BASF UK Ltd, February 1981.

  46. W. Schmutzler,Histamine release from human adenoidal mast cells induced by anti-human IgE, acetylcholine, Epontol ®,cremophor El and 12-hydroxystearic acid (in press).

  47. 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.

    Google Scholar 

  48. J. Watkins, A. Clark, T.N. Appleyard andA. Padfield,Immune-mediated reactions to althesin (alphaxalone), Br. J. Anaesth.48, 881–886 (1976).

    PubMed  Google Scholar 

  49. W. Lorenz andH.-J. Reimann, unpublished data.

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

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

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF01965109

Keywords

Navigation