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Flumazenil does not improve hepatic encephalopathy associated with acute ischemic liver failure in the rabbit

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Abstract

The effect of flumazenil, a benzodiazepine antagonist, on hepatic encephalopathy was studied in rabbits with acute hepatic failure induced by a two-stage liver devascularization procedure. The rabbits were randomized for treatment with 5 mg/kg of flumazenil or the placebo. The drug was administered at two easily recognizable time points in the course of the encephalopathy: first, when the righting reflex was disturbed, and second, when the animal could no longer achieve to the sitting position. The response after flumazenil did not differ from that after the placebo, as measured by clinical evaluation and automated EEG analysis. Furthermore, the progression of the encephalopathy, as measured by the survival time after the first injection, was not affected by flumazenil.

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References

  • Bansky, G., Meier, P. J., Ziegler, W. H., Walser, H., Schmid, M., and Huber, M. (1985). Reversal of hepatic coma by benzodiazepine antagonist Rol5-1788.Lancet 1: 1324–1325.

    Google Scholar 

  • Bansky, G., Meier, P. J., Riederer, E., Walser, H., Ziegler, W. H., and Schmid, M. (1989). Effects of the benzodiazepine receptor antagonist flumazenil in hepatic encephalopathy in humans.Gastroenterology 97: 44–50.

    Google Scholar 

  • Baraldi, M., and Zeneroli, M. L. (1982). Experimental hepatic encephalopathy: Changes in the binding of gamma-aminobutyric acid.Science 216: 427–429.

    Google Scholar 

  • Baraldi, M., Zeneroli, M. L., Ventura, E., Penne, A., Pinelli, G., Ricci, P., and Santi, M. (1984). Super-sensitivity of benzodiazepine receptors in hepatic encephalopathy due to fulminant hepatic failure in the rat: Reversal by a benzodiazepine antagonist.Clin. Sci. 67: 167–175.

    Google Scholar 

  • Basile, A. S., and Gammal, S. J. (1988). Evidence for the involvement of the benzodiazepine receptor complex in hepatic encephalopathy. Implications for treatment with benzodiazepine receptor antagonists.Clin. Neuropharm. 11: 401–422.

    Google Scholar 

  • Bassett, M. L., Mullen, K. D., Skolnick, P., and Jones, E. A. (1987). Amelioration of hepatic encephalopathy by pharmacologic antagonism of the GABA-A-benzodiazepine receptor complex in a rabbit model of fulminant hepatic failure.Gastroenterology 93: 1069–1077.

    Google Scholar 

  • Bitterman, H., Lefer, D. J., and Lefer, A. M. (1987). Beneficial actions of Ro 15-1788, a benzodiazepine receptor antagonist, in hemorrhagic shock.Meth. Find. Exp. Clin. Pharmacol. 9: 341–347.

    Google Scholar 

  • Brachtel, D., and Wernze, H. (1988). Renin-angiotensin system, blood pressure homeostasis and renal function in galactosamine-induced fulminant hepatic failure in the guinea pig.Clin. Physiol. Biochem. 6: 95–105.

    Google Scholar 

  • Braestrup, C., Nielsen, M., Honoré, T., Jensen, L.H., and Petersen, E. N. (1983). Benzodiazepine ligands with positive and negative efficacy.Neuropharmacology 22: 1451–1457.

    Google Scholar 

  • Burke, D.A. (1988). Reversal of hepatic coma with flumazenil with improvement in visual evoked potentials.Lancet 2: 505–506.

    Google Scholar 

  • Butterworth, R. F., Lavoie, J., Giguère, J. F., and Pomier-Layrargues, G. (1988). Affinities anddensities of high-affinity [3H]muscimol (GABA-A) binding sites and of central benzodiazepine receptors are unchanged in autopsied brain tissue from cirrhotic patients with hepatic encephalopathy.Hepatology 8: 1084–1088.

    Google Scholar 

  • Ferenci, P., Zieve, L., Ebner, J., Zimmermann, Ch., and Rzepczynski, D. (1987). Postsynaptic gammaaminobutyric acid receptors in hepatic coma following portacaval shunt and hepatic artery ligation in the rat.Metab. Brain Dis. 2: 195–200.

    Google Scholar 

  • Ferenci, P., Grimm, G., Meryn, S., and Gangl, A. (1989). Successful long-term treatment of portalsystemic encephalopathy by the benzodiazepine antagonist flumazenil.Gastroenterology 96: 240–243.

    Google Scholar 

  • Fick, T. E., Schalm, S. W., and De Vlieger, M. (1987). A surgical model of fulminant hepatic failure in the rabbit: Different effects of end-to-side versus small-diameter side-to-side portacaval shunt.Eur. Surg. Res. 19: 276–282.

    Google Scholar 

  • Gammal, S. H., Jones, E. A., Bassett, M. L., Mullen, K. D., Geller, D., and Skolnick, P. (1988). Antagonists of the GABA/benzodiazepine receptor complex ameliorate hepatic encephalopathy in two models of fulminant hepatic failure. In Soeters, P. B., Wilson, J. H. P., Meijer, A. J., and Holm, E. (eds.),Advances in Ammonia Metabolism and Hepatic Encephalopathy, Proceedings of the 6th International Symposium on ammonia, Vaalsbroek Castle, The Netherlands, 27–29 April 1987, Elsevier, Amsterdam, pp. 325–332.

    Google Scholar 

  • Gogolàk, G., Stumf, Ch., and Huck, S. (1985). Differentiation of drug-induced rhythmical activities in the rabbit's brain by a benzodiazepine antagonist.Arzneim-Forsch. 35: 233–236.

    Google Scholar 

  • Grimm, G., Katzenschlager, R., Schneeweiss, B., Lenz, K., Ferenci, P., Madl, C., Laggner, A. N., and Gangl, A. (1988). Improvement of hepatic encephalopathy treated with flumazenil.Lancet 2: 1392–1394.

    Google Scholar 

  • Grün, M., Liehr, H., and Rasenack, U. (1976). Significance of endotoxaemia in experimental “galactosamine-hepatitis” in the rat.Acta Hepato-Gastroenterol. 23: 64–81.

    Google Scholar 

  • Jones, E. A., Schafer, D. F., Ferenci, P., and Pappas, S. C. (1984). The GABA hypothesis of the pathogenesis of hepatic encephalopathy: Current status.Yale J. Biol. Med. 57: 301–316.

    Google Scholar 

  • Jones, E. A., Mullen, K. D., and Gammal, S. H. (1987). Hepatic encephalopathy. In Arias, I. M., Frenkel, M., and Wilson, J. H. P. (eds.),The Liver Annual 6, Elsevier, Amsterdam, pp. 396–415.

    Google Scholar 

  • Klotz, U., and Walker, S. (1989). Flumazenil and hepatic encephalopathy.Lancet 1: 155–156.

    Google Scholar 

  • Maddison, J. E., Dodd, P. R., Morrison, M., Johnston, G. A. R., and Farrell, G. C. (1987a). Plasma GABA, GABA-like activity and the brain GABA-benzodiazepine receptor complex in rats with chronic hepatic encephalopathy.Hepatology 7: 621–628.

    Google Scholar 

  • Maddison, J. E., Dodd, P. R., Johnston, A. R., and Farrell, G. C. (1987b). Brain gamma-aminobutyric acid receptor binding is normal in rats with thioacetamide-induced hepatic encephalopathy despite elevated plasma gamma-aminobutyric acid-like activity.Gastroenterology 93: 1062–1068.

    Google Scholar 

  • Pappas, S. C., Levy, G., Gordon, V. P., Nakatsukasa, H., and Martin, P. (1988). The GABA hypothesis of hepatic encephalopathy: Further studies in multiple animal models. In Soeters, P. B., Wilson, J. H. P., Meijer, A. J., and Holm, E. (eds.),Advances in Ammonia Metabolism and Hepatic Encephalopathy, Proceedings of the 6th International Symposium on ammonia, Vaalsbroek Castle, The Netherlands, 27–29 April 1987, Elsevier, Amsterdam, pp. 259–264.

    Google Scholar 

  • Rössle, M., Deckert, J., and Jones, E. A. (1989). Autoradiographic analysis of GABA-benzodiazepine receptors in an animal model of acute hepatic encephalopathy.Hepatology 10: 143–147.

    Google Scholar 

  • Roy, S., Pomier-Layrargues, G., Butterworth, R. F., and Huet, P. M. (1988). Hepatic encephalopathy in cirrhotic and portacaval shunted dogs: lack of changes in brain GABA uptake, brain GABA levels, brain glutamic acid decarboxylase activity and brain postsynaptic GABA receptors.Hepatology 8: 845–849.

    Google Scholar 

  • Rzepczynski, D., Zieve, L., Lindblad, S., and LaFontaine, D. (1986). In vivo studies of GABAergic effects in experimental hepatic encephalopathy.Hepatology 6: 902–905.

    Google Scholar 

  • Schafer, D. F., Fowler, J. M., Munson, P. J., Thakur, A. K., Waggoner, J. G., and Jones, E. A. (1983). Gamma-aminobutyric acid and benzodiazepine receptors in an animal model of fulminant hepatic failure.J. Lab. Clin. Med. 102: 870–880.

    Google Scholar 

  • Scollo-Lavizzari, G., and Steinmann, E. (1985). Reversal of hepatic coma by benzodiazepine antagonist Ro15-1788.Lancet 1: 1324.

    Google Scholar 

  • Sutherland, L. R., and Minuk, G. Y. (1988). Ro15-1788 and hepatic failure.Ann. Intern. Med. 108: 158.

    Google Scholar 

  • Svedberg, A., Maddock, S., and Drury, D. D. (1938). The effect of total removal of the liver in the rabbit.Am. J. Physiol. 121: 209–214.

    Google Scholar 

  • Thompson, J. S., Schafer, D. F., Schafer, G. J., and Hodgson, F. E. (1985). Gamma-aminobutyric acid plasma levels and brain binding in eck fistula dogs.J. Surg. Res. 38: 143–148.

    Google Scholar 

  • Van der Rijt, C. C. D., Schalm, S. W., De Groot, G. H., and De Vlieger, M. (1984). Objective measurement of hepatic encephalopathy by means of automated EEG analysis.Electroenceph. Clin. Neurophysiol. 57: 423–426.

    Google Scholar 

  • Van der Rijt, C. C. D., Schalm, S. W., Meulstee, J., and Stijnen, Th. (1989). Flumazenil therapy for hepatic encephalopathy: A double-blind cross-over study.Hepatology 10: 590 (abstract).

    Google Scholar 

  • Walker, J. E. (1983). Glutamate, GABA and CNS disease: a review.Neurochem. Res. 8: 521–550.

    Google Scholar 

  • Zeneroli, M. L., and Baraldi, M. (1988). Increased functional activity of the GABA-benzodiazepine receptor unit in a rat model of hepatic encephalopathy: Pharmacological evidence.Hepatology 8: 1388.

    Google Scholar 

  • Zieve, L., Ferenci, P., Rzepczynski, D., Ebner, J., and Zimmermann, C. (1987). A Benzodiazepine antagonist does not alter the course of experimental hepatic encephalopathy or neural gamma-aminobutyric acid (GABA) binding.Metab. Brain Dis. 2: 201–205.

    Google Scholar 

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van der Rijt, C.C.D., de Knegt, R.J., Schalm, S.W. et al. Flumazenil does not improve hepatic encephalopathy associated with acute ischemic liver failure in the rabbit. Metab Brain Dis 5, 131–141 (1990). https://doi.org/10.1007/BF00999840

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  • DOI: https://doi.org/10.1007/BF00999840

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