Skip to main content

Advertisement

SpringerLink
Log in

Pharmacokinetics of natural mistletoe lectins after subcutaneous injection

  • Pharmacokinetics and Disposition
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

Knowledge of natural mistletoe lectins (nML) pharmacokinetics can be regarded as essential for further rational studies with mistletoe preparations. Studies with intravenous application of a recombinant type II ribosome inactivating protein (rML) analogous to nML revealed a short half-life of about 13 min in cancer patients. This open-label, phase I, monocenter clinical trial was performed in order to describe the pharmacokinetics of nML.

Methods

In 15 healthy male volunteers aged 18–42 years, nML were detected with a modified sandwich immuno-polymerase chain reaction (PCR) technique (Imperacer®, Chimera Biotec) after single subcutaneous injection of a mistletoe extract (abnobaVISCUM® Fraxini 20 mg) with marketing authorization containing about 20 µg nML/ml. Secondary objectives were safety and the number of activated natural killer cells (CD54+/CD94+).

Results

In none of the volunteers were nML detectable before the injection, and in all volunteers, nML were detected in serum samples after injection. Individual variability, however, was large. Mean and median peak concentrations were reached 1 and 2 h after injection, respectively. In some volunteers, nML were still detectable at the final investigation 2 weeks after injection. The injection resulted in fever and flu-like symptoms in all volunteers, but no serious adverse events occurred. All symptoms and local reactions at the injection site completely disappeared within a range of 4–95 days. The number of activated natural killer (NK) cells did not change.

Conclusions

Natural ML from abnobaVISCUM® Fraxini 20 mg are detectable in serum after a single subcutaneous injection. Detectability is considerably longer compared with intravenously administered rML. The subcutaneous injection of this preparation without usual pretreatment with lower doses results in short-lasting fever and other flu-like symptoms.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Horneber MA, Bueschel G, Huber R, Linde K, Rostock M (2008) Mistletoe therapy in oncology. Cochrane Database Syst Rev (2):CD003297

  2. Ribéreau-Gayon G, Jung ML, Frantz M, Anton R (1997) Modulation of cytotoxicity and enhancement of cytokine release induced by Viscum album L. extracts or mistletoe lectins. Anticancer Drugs 8(Suppl 1):S3–S8

    Article  PubMed  Google Scholar 

  3. Rostock M, Huber R, Greiner T, Fritz P, Scheer R, Schueler J, Fiebig HH (2005) Anticancer activity of a lectin-rich mistletoe extract injected intratumorally into human pancreatic cancer xenografts. Anticancer Res 25(3B):1969–1975

    CAS  PubMed  Google Scholar 

  4. Huber R, Rostock M, Goedl R, Lüdtke R, Urech K, Buck S, Klein R (2005) Mistletoe treatment induces GM-CSF-and IL-5 production by PBMC and increases blood granulocyte-and eosinophil counts: a placebo controlled randomized study in healthy subjects. Eur J Med Res 10(10):411–418

    CAS  PubMed  Google Scholar 

  5. Franz H (1985) Inhaltsstoffe der Mistel (Viscum album L.) als potentielle Arzneimittel. Pharmazie 40:97–104

    CAS  PubMed  Google Scholar 

  6. Franz H (1991) Mistletoe lectins (2). In: Franz H (ed) Advances in lectin research. Springer Berlin, pp 33–50

  7. Franz H, Friemel H, Buchwald S, Plantikow A, Kopp J, Körner IJ (1990) The A chain of lectin 1 from European mistletoe (Viscum album) induces interleukin-I and interleukin-II in human mononuclear cells. In: Kocourek J, Freed DLJ (eds) Lectins: biology, biochemistry, clinical biochemistry, Vol. 7. Sigma Chemical Company, St. Louis, pp 247–250

    Google Scholar 

  8. Stirpe F, Barbieri L, Batteli MG, Soria M, Lappi DA (1992) Ribosome-inactivating proteins from plants: present status and future prospects. Bio Technology 10:405–412

    CAS  PubMed  Google Scholar 

  9. Büssing A (2000) Biological and pharmacological properties of Viscum album L. In: Büssing A (ed) Mistletoe, the Genus Viscum. Amsterdam

  10. Klein R, Franz M, Wacker R, Classen K, Scheer R, Von Laue HB, Stoeva S, Voelter W (2004) Demonstration of antibodies to the chitin-binding mistletoe lectin (cbML) in tumor patients before and during therapy with an aqueous mistletoe extract. Eur J Med Res 9(6):316–322

    CAS  PubMed  Google Scholar 

  11. Adler M, Langer M, Witthohn K, Eck J, Blohm D, Niemeyer CM (2003) Detection of rViscumin in plasma samples by immuno-PCR. Biochem Biophys Res Comm 300:757–763

    Article  CAS  PubMed  Google Scholar 

  12. Schöffski P, Riggert S, Fumoleau P, Campone M, Bolte O, Marreaud S, Lacombe D, Baron B, Herold M, Zwierzina H, Wilhelm-Ogunbiyi K, Lentzen H, Twelves C (2004) Phase I trial of intravenous aviscumine (rViscumin) in patients with solid tumors: a study of the European Organization for Research of Cancer New Drug Development Group. Ann Oncol 15:1816–1824

    Article  PubMed  Google Scholar 

  13. Krause SW, Gastpar R, Andreesen R, Gross C, Ullrich H, Thonigs G, Pfister K, Multhoff G (2004) Treatment of colon and lung cancer patients with ex vivo heat shock protein 70-peptide-activated, autologous natural killer cells: a clinical phase I trial. Clin Cancer Res 10(11):3699–3707

    Article  CAS  PubMed  Google Scholar 

  14. Samtleben R, Kiefer M, Luther P (1985) Characterization of the different lectins from Viscum album L. (mistletoe) and their structural relationships with the agglutinins from Abrus precaratorius and Ricinus communis. In: Kocourek J, Freed DLJ (eds) Lectins: biology, biochemistry, clinical biochemistry Vol. 4. Sigma Chemical Company, St. Louis, pp 617–626

    Google Scholar 

  15. Franz M, Vollmer S, Wacker R, Jäger S, Scheer R, Stoeva S, Lehmann R, Tsitsilonis R, Voelter W (2005) Isolation and quantification of the chitin-binding mistletoe lectins (cbMLs) from mistletoe extracts and the validation of this method. In: Scheer R, Bauer R, Becker H, Fintelmann V, Kemper FH, Schilcher H (eds) Fortschritte in der Misteltherapie, KVC Verlag, pp 69–81

  16. Adler M, Wacker R, Niemeyer CM (2008) Sensitivity by combination: immuno-PCR and related technologies. Analyst 133(6):702–718

    Article  CAS  PubMed  Google Scholar 

  17. Eck J, Langer M, Möckel B, Witthohn K, Zinke H, Lentzen H (1999) Characterization of recombinant and plant-derived mistletoe lectin and their B-chains. Eur J Biochem 265(2):788–797

    Article  CAS  PubMed  Google Scholar 

  18. Elsässer-Beile U, Voss M, Schühle R, Wetterauer U (2000) Biological effects of natural and recombinant mistletoe lectin and an aqueous mistletoe extract on human monocytes and lymphocytes in vitro. J Clin Lab Anal 14(6):255–259

    Article  PubMed  Google Scholar 

  19. ADVINUS Therapeutics Private Limited (2009) Mistletoe extract AbnobaViscum Fraxini 20 mg: 90 day study in Sprague-Dawley rats by subcutaneous route with toxicokinetics and 4 week recovery period. ADVINUS report-No. G5087-90R-SC, Bangalore, India

  20. Klein R, Classen K, Berg PA, Lüdtke R, Werner M, Huber R (2002) In vivo-induction of antibodies to mistletoe lectin-1 and viscotoxin by exposure to aqueous mistletoe extracts: a randomised double-blinded placebo controlled phase I study in healthy individuals. Eur J Med Res 7(4):155–163

    CAS  PubMed  Google Scholar 

  21. Jacobs CA, Lynch DH, Roux ER, Miller R, Davis B, Widmer MB, Wignall J, VandenBos T, Park LS, Beckmann MP (1991) Characterization and pharmacokinetic parameters of recombinant soluble interleukin-4 receptor. Blood 77(11):2396–2403

    CAS  PubMed  Google Scholar 

  22. Hayashi N, Kinoshita H, Yukawa E, Higuchi S (1998) Pharmacokinetic analysis of subcutaneous erythropoietin administration with nonlinear mixed effect model including endogenous production. Br J Clin Pharmacol 46(1):11–19

    Article  CAS  PubMed  Google Scholar 

  23. Mabed M, El-Helw L, Shamaa S (2004) Phase II study of viscum fraxini-2 in patients with advanced hepatocellular carcinoma. Br J Cancer 90(1):65–69

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgment

The study was sponsored by Abnoba GmbH, Pforzheim, Germany.

Author information

Authors and Affiliations

  1. Department of Environmental Health Sciences, University Hospital Freiburg, Breisacher Str. 115b, 79106, Freiburg, Germany

    Roman Huber

  2. Abnoba GmbH, Pforzheim, Germany

    Jürgen Eisenbraun & Rainer Scheer

  3. CenTrial GmbH, Tübingen/Ulm, Germany

    Barbara Miletzki & Christoph H. Gleiter

  4. Chimera Biotec GmbH, Dortmund, Germany

    Michael Adler

  5. Department of Internal Medicine II, University of Tübingen, Tübingen, Germany

    Reinhild Klein

Authors
  1. Roman Huber
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jürgen Eisenbraun
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Barbara Miletzki
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Michael Adler
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Rainer Scheer
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Reinhild Klein
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Christoph H. Gleiter
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Roman Huber.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Huber, R., Eisenbraun, J., Miletzki, B. et al. Pharmacokinetics of natural mistletoe lectins after subcutaneous injection. Eur J Clin Pharmacol 66, 889–897 (2010). https://doi.org/10.1007/s00228-010-0830-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00228-010-0830-5

Keywords

Search

Navigation