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. 1985 Jan;84(1):157–163.

The influence of digoxin antibodies on digoxin disposition and effect: studies in guinea-pigs and HeLa cells.

N M Griffiths, D S Hewick, J F Lamb, I H Stevenson
PMCID: PMC1987214  PMID: 3978308

Abstract

Pretreatment of guinea-pigs with digoxin-specific Fab (fragment antigen binding) fragments reduced the cardiotoxicity of intravenously infused digoxin (the lethal doses in Fab-treated and control animals were 1.0 and 0.6 mgkg-1, respectively). At death the serum digoxin concentration was elevated 2 fold in the Fab-treated animals, while the tissue concentrations were generally lower. The 30-40% lower cardiac digoxin concentration (seen in whole homogenate and throughout the subcellular fractions examined) was surprising; presumably this reflects a difference from the controls in the proportion of pharmacologically active/inactive digoxin in this organ. Adding digoxin-specific immunoglobulin G or the Fab fragments to HeLa cells before incubation with digoxin, reduced specific digoxin binding (Na pump-bound) slightly more than the non-specific binding. Adding specific antibody after digoxin, however, did not reduce digoxin binding or effect a recovery in Na pump activity. It seems that the protective effect of digoxin-specific antibodies seen in the guinea-pig can to some extent be simulated using HeLa cells. However, this is apparently not so regarding the widely-reported ability of these antibodies to reverse the action of digoxin.

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Selected References

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  1. Aeberhard P., Butler V. P., Smith T. W., Haber E., Eng D. T., Brau J., Chalom A., Glatt B., Thébaut J. F., Delangenhagen B. Le traitement d'une intoxication digitalique massive (20 mg de digitoxine) par les anticorps anti-digoxine fractionnés (Fab). Arch Mal Coeur Vaiss. 1980 Dec;73(12):1471–1478. [PubMed] [Google Scholar]
  2. Aiton J. F., Lamb J. F. Effect of the serum concentration of the growth medium on the sodium pump site density of cultured HeLa cells. Q J Exp Physiol. 1984 Jan;69(1):97–115. doi: 10.1113/expphysiol.1984.sp002799. [DOI] [PubMed] [Google Scholar]
  3. Aiton J. F., Lamb J. F., Ogden P. Down-regulation of the sodium pump following chronic exposure of HeLa cells and chick embryo heart cells to ouabain. Br J Pharmacol. 1981 Jun;73(2):333–340. doi: 10.1111/j.1476-5381.1981.tb10426.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Boor P. J., Reynolds E. S., Moslen M. T. Neurotoxicity of digitoxin in adult and newborn rats: drug distribution. Arch Int Pharmacodyn Ther. 1976 Nov;224(1):4–12. [PubMed] [Google Scholar]
  5. Bossaller C. The effect of digitalis glycosides-specific antisera on the binding of the glycosides to (Na+ + K+)-ATPase. Arzneimittelforschung. 1981;31(4):625–628. [PubMed] [Google Scholar]
  6. Butler V. P., Jr Antibodies as specific antagonists of toxins, drugs, and hormones. Pharmacol Rev. 1982 Mar;34(1):109–114. [PubMed] [Google Scholar]
  7. Butler V. P., Jr, Schmidt D. H., Smith T. W., Haber E., Raynor B. D., Demartini P. Effects of sheep digoxin-specific antibodies and their Fab fragments on digoxin pharmacokinetics in dogs. J Clin Invest. 1977 Feb;59(2):345–359. doi: 10.1172/JCI108647. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Castle M. C., Lage G. L. Metabolism and distribution of digitoxin in the rat. Arch Int Pharmacodyn Ther. 1973 Jun;203(2):323–334. [PubMed] [Google Scholar]
  9. Doherty J. E., Kane J. J. Clinical pharmacology of digitalis glycosides. Annu Rev Med. 1975;26:159–171. doi: 10.1146/annurev.me.26.020175.001111. [DOI] [PubMed] [Google Scholar]
  10. Dutta S., Marks B. H. Distribution of ouabain and digoxin in the rat and guinea pig. Life Sci. 1966 May;5(10):915–920. doi: 10.1016/0024-3205(66)90200-1. [DOI] [PubMed] [Google Scholar]
  11. Gardner J. D., Kilno D. R., Swartz T. J., Butler V. P., Jr Effects of digoxin-specific antibodies on accumulation and binding of digoxin by human erythrocytes. J Clin Invest. 1973 Aug;52(8):1820–1833. doi: 10.1172/JCI107364. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Harrison C. E., Jr, Brandenburg R. O., Ongley P. A., Orvis A. L., Owen C. A., Jr The distribution and excretion of tritiated substances in experimental animals following the administration of digoxin-3H. J Lab Clin Med. 1966 May;67(5):764–777. [PubMed] [Google Scholar]
  13. Hess P., Müller P. Extracellular versus intracellular digoxin action on bovine myocardium, using a digoxin antibody and intracellular glycoside application. J Physiol. 1982 Jan;322:197–210. doi: 10.1113/jphysiol.1982.sp014032. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Hess T., Scholtysik G., Riesen W. The prevention and reversal of digoxin intoxication with specific antibodies. Am Heart J. 1978 Oct;96(4):486–495. doi: 10.1016/0002-8703(78)90160-6. [DOI] [PubMed] [Google Scholar]
  15. Hess T., Stucki P., Barandun S., Scholtysik G., Riesen W. Treatment of a case of lanatoside C intoxication with digoxin-specific F(ab')2 antibody fragments. Am Heart J. 1979 Dec;98(6):767–771. doi: 10.1016/0002-8703(79)90476-9. [DOI] [PubMed] [Google Scholar]
  16. Hoeschen R. J. The effect of digoxin antibody on the washout of tritiated digoxin and its inotropic effect from perfused rabbit hearts. Recent Adv Stud Cardiac Struct Metab. 1976;9:345–353. [PubMed] [Google Scholar]
  17. Hougen T. J., Lloyd B. L., Smith T. W. Effects of inotropic and arrhythmogenic digoxin doses and of digoxin-specific antibody on myocardial monovalent cation transport in the dog. Circ Res. 1979 Jan;44(1):23–31. doi: 10.1161/01.res.44.1.23. [DOI] [PubMed] [Google Scholar]
  18. LOWRY O. H., ROSEBROUGH N. J., FARR A. L., RANDALL R. J. Protein measurement with the Folin phenol reagent. J Biol Chem. 1951 Nov;193(1):265–275. [PubMed] [Google Scholar]
  19. Lamb J. F., Ogden P. Internalization of ouabain and replacement of sodium pumps in the plasma membranes of HeLa cells following block with cardiac glycosides. Q J Exp Physiol. 1982 Jan;67(1):105–119. doi: 10.1113/expphysiol.1982.sp002605. [DOI] [PubMed] [Google Scholar]
  20. Lloyd B. L., Smith T. W. Contrasting rates of reversal of digoxin toxicity by digoxin-specific IgG and Fab fragments. Circulation. 1978 Aug;58(2):280–283. doi: 10.1161/01.cir.58.2.280. [DOI] [PubMed] [Google Scholar]
  21. Mandel W. J., Bigger J. T., Jr, Butler V. P., Jr The electrophysiologic effects of low and high digoxin concentrations on isolated mammalian cardiac tissue: reversal by digoxin-specific antibody. J Clin Invest. 1972 Jun;51(6):1378–1387. doi: 10.1172/JCI106933. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. NERI R. O., TOLKSDORF S., BEISER S. M., ERLANGER B. F., AGATE F. J., Jr, LIEBERMAN S. FURTHER STUDIES ON THE BIOLOGICAL EFFECTS OF PASSIVE IMMUNIZATION WITH ANTIBODIES TO STEROID-PROTEIN CONJUGATES. Endocrinology. 1964 Apr;74:593–598. doi: 10.1210/endo-74-4-593. [DOI] [PubMed] [Google Scholar]
  23. Ochs H. R., Vatner S. F., Smith T. W. Reversal of inotropic effects of digoxin by specific antibodies and their Fab fragments in the conscious dog. J Pharmacol Exp Ther. 1978 Oct;207(1):64–71. [PubMed] [Google Scholar]
  24. PORTER R. R. The hydrolysis of rabbit y-globulin and antibodies with crystalline papain. Biochem J. 1959 Sep;73:119–126. doi: 10.1042/bj0730119. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Proppe D. Pharmacokinetics of tritiated ouabain, digoxin and digitoxin in guinea-pigs. Clin Exp Pharmacol Physiol. 1975 Nov-Dec;2(6):489–502. doi: 10.1111/j.1440-1681.1975.tb01854.x. [DOI] [PubMed] [Google Scholar]
  26. Russell J. Q., Klaassen C. D. Biliary excretion of cardiac glycosides. J Pharmacol Exp Ther. 1973 Sep;186(3):455–462. [PubMed] [Google Scholar]
  27. Smith T. W., Butler V. P., Jr, Haber E., Fozzard H., Marcus F. I., Bremner W. F., Schulman I. C., Phillips A. Treatment of life-threatening digitalis intoxication with digoxin-specific Fab antibody fragments: experience in 26 cases. N Engl J Med. 1982 Nov 25;307(22):1357–1362. doi: 10.1056/NEJM198211253072201. [DOI] [PubMed] [Google Scholar]
  28. Smith T. W., Haber E., Yeatman L., Butler V. P., Jr Reversal of advanced digoxin intoxication with Fab fragments of digoxin-specific antibodies. N Engl J Med. 1976 Apr 8;294(15):797–800. doi: 10.1056/NEJM197604082941501. [DOI] [PubMed] [Google Scholar]
  29. Smith T. W., Lloyd B. L., Spicer N., Haber E. Immunogenicity and kinetics of distribution and elimination of sheep digoxin-specific IgG and Fab fragments in the rabbit and baboon. Clin Exp Immunol. 1979 Jun;36(3):384–396. [PMC free article] [PubMed] [Google Scholar]
  30. Steinbuch M., Audran R. The isolation of IgG from mammalian sera with the aid of caprylic acid. Arch Biochem Biophys. 1969 Nov;134(2):279–284. doi: 10.1016/0003-9861(69)90285-9. [DOI] [PubMed] [Google Scholar]
  31. Watson J. F., Butler V. P., Jr Biologic activity of digoxin-specific antisera. J Clin Invest. 1972 Mar;51(3):638–648. doi: 10.1172/JCI106853. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Werdan K., Wagenknecht B., Zwissler B., Brown L., Krawietz W., Erdmann E. Cardiac glycoside receptors in cultured heart cells--I. Characterization of one single class of high affinity receptors in heart muscle cells from chick embryos. Biochem Pharmacol. 1984 Jan 1;33(1):55–70. doi: 10.1016/0006-2952(84)90370-8. [DOI] [PubMed] [Google Scholar]

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