Persisting benzodiazepine metabolites responsible for the reaction to the benzodiazepine antagonist flumazenil in patients with hepatic encephalopathy

Meier, Rémy; Gyr, K.; Scholer, Anthony

doi:10.1016/0016-5085(91)90501-b

Cited by 8 publications

(4 citation statements)

References 7 publications

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“…Most are reports of uncontrolled studies. Most often, intake of synthetic benzodiazepines by the patients could not be ruled out with certainty; therefore the antagonist could have simply reversed benzodiazepine-induced neurological symptoms (21,22). In some cases, favorable outcome was reported hours after flumazenil treatment; this is not consistent with the drug's known half-life.…”

Section: Discussionmentioning

confidence: 99%

“…The clinical response in these studies was very rapid (within minutes), was spectacular and was associated with marked improvement in EEG tracings. Since that time, the results of several uncontrolled clinical trials have been published demonstrating that the drug was efficient in nearly 70% of patients with HE associated with fulminant liver failure or cirrhosis (13)(14)(15)(16)(17)(18)(19)(20)(21)(22). Results of two placebo-controlled trials with opposite results have been published so far, both in abstract form.…”

Section: Discussionmentioning

confidence: 99%

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Flumazenil in cirrhotic patients in hepatic coma: A randomized double-blind placebo-controlled crossover trial

et al. 1994

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Previous reports have suggested that "endogenous" benzodiazepines could contribute to neural inhibition in hepatic encephalopathy. RO 15-1788 (flumazenil), a specific antagonist of brain benzodiazepine receptors, could thus reverse the neurological symptoms of hepatic encephalopathy. To test this possibility, we conducted a double-blind, placebo-controlled crossover trial of the efficacy of flumazenil in cirrhotic patients in hepatic coma. Seventy-seven cirrhotic patients in hepatic coma were evaluated. Fifty-six were excluded from the trial because of multiorgan failure or because coma was precipitated by prior use of benzodiazepines, and 21 patients were randomly assigned to the flumazenil group (11 patients) or the placebo group (10 patients). Treatment was administered intravenously as a 20-ml solution (placebo or 2 mg flumazenil); seven patients were crossed over. Clinical status was assessed blindly by two observers, using a modified Glasgow scale, every 15 min for 6 hr. Electroencephalogram tracings obtained before and after drug administration were evaluated blindly by two independent observers. Serum concentrations of benzodiazepines before treatment were measured by means of a fluorescence polarization immunoassay. Improvement in neurological symptoms was observed in six patients treated with flumazenil, whereas none in the placebo group showed improvement (p < 0.05; Fisher's exact test). Improvements in electroencephalogram tracings were demonstrated in four patients treated with flumazenil, compared with two patients in the placebo group (p = NS). Benzodiazepines were found in the serum of four patients treated with flumazenil (two responders and two nonresponders); all of these patients had received pharmaceutical benzodiazepines 4 to 6 days before the trial.(ABSTRACT TRUNCATED AT 250 WORDS)

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Flumazenil in cirrhotic patients in hepatic coma: A randomized double-blind placebo-controlled crossover trial

et al. 1994

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“…There is uncertainty about the possible role of endogenous benzodiazepine-like substances in the pathogenesis of HE [62]. Furthermore, the results with flumazenil in HE are very controversial [71], and the improvement in HE achieved in some reports after treatment with flumazenil might be related to antagonizing exogenous benzodiazepine drugs but not endogenous benzodiazepine-like substances [72]. Moreover, doubleblind crossover trials did not show significant improvement of HE with flumazenil [73].…”

Section: The Benzodiazepine Theorymentioning

confidence: 99%

Pathogenesis of hepatic encephalopathy: the tumour necrosis factor-? theory

Odeh

2007

Eur J Clin Invest

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Hepatic encephalopathy (HE) is a major complication for acute and chronic liver failure. Despite several decades of intensive clinical and basic research, the pathogenesis of HE is still incompletely understood, and the precise mechanisms causing brain dysfunction in liver failure are still not fully established. Several theories concerning the pathogenesis of HE have been previously suggested, including the ammonia theory, which received the most attention. These theories are not mutually exclusive and the validity of none of them has been definitely proved experimentally. In this review article, an attractive theory concerning the pathogenesis of HE, the tumour necrosis factor-alpha (TNF) theory, is presented and comprehensively discussed after accumulation of sufficient data which indicate that the pro-inflammatory cytokine, TNF, is strongly involved in the pathogenesis of HE associated with both acute and chronic liver failure. This theory seems to be superior to all other previous theories in the pathogenesis of HE, and may induce development of other beneficial therapeutical modalities for HE directed towards inhibition of TNF production and/or action, and towards enhancement of its degradation.

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“…The origin of the increased concentrations of benzodiazepine-like substances in the brain and cerebrospinal fluid of some animals and human patients with HE remains unknown. In human beings, it is difficult to rule out pharmaceutical origin (1, 9,34).…”

Section: Discussionmentioning

confidence: 99%

Increased benzodiazepine-like activity is neither necessary nor sufficient to explain acute hepatic encephalopathy in the thioacetamide-treated rat

Widler

1993

Hepatology

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Increased levels of natural benzodiazepine receptor agonists, produced in the body (endogenous) or ingested with food (exogenous) have been proposed as one of the factors causing hepatic encephalopathy in both experimental animals and human subjects. However, the divergent response of hepatic encephalopathy to benzodiazepine antagonists sheds doubt on this attractive hypothesis. Acute liver failure was induced in male Sprague-Dawley rats (n = 17) with intraperitoneal thioacetamide (600 mg/kg/day for 3 days) while 14 control rats received vehicle only. Acute liver failure developed in all treated rats (AST: 1,898 +/- 1,359 IU/L vs. controls, 45 +/- 5 IU/L, p < 0.005; bilirubin: 36 +/- 27 mumol/L vs. controls, 1.5 +/- 0.5 mumol/L, p < 0.005; centrizonal necrosis) and grade 3 or 4 hepatic encephalopathy (neurologic assessment and activity monitoring). However, benzodiazepine receptor ligand activity, measured in the supernatant of whole-brain homogenates with a [3H]flumazenil binding competition assay, was clearly increased in only 1 of 17 rats with acute liver failure compared with controls (52.7 +/- 34.1 vs. 44.3 +/- 18.9 ng diazepam equivalents/gm; NS). To evaluate whether the reported increase in benzodiazepine receptor ligand activity could be due to prolonged residence of exogenous benzodiazepine-like substances, additional rats with acute liver failure and controls were treated with diazepam (five doses of 0.5 mg/kg at 12-hr intervals by gavage). Benzodiazepine receptor ligand activity was greater in animals with acute liver failure than in controls (223 +/- 65 vs. 103 +/- 23 ng diazepam equivalents/gm; p < 0.002) 1 to 3 hr after the last diazepam dose.(ABSTRACT TRUNCATED AT 250 WORDS)

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Persisting benzodiazepine metabolites responsible for the reaction to the benzodiazepine antagonist flumazenil in patients with hepatic encephalopathy

Cited by 8 publications

References 7 publications

Flumazenil in cirrhotic patients in hepatic coma: A randomized double-blind placebo-controlled crossover trial

Flumazenil in cirrhotic patients in hepatic coma: A randomized double-blind placebo-controlled crossover trial

Pathogenesis of hepatic encephalopathy: the tumour necrosis factor-? theory

Increased benzodiazepine-like activity is neither necessary nor sufficient to explain acute hepatic encephalopathy in the thioacetamide-treated rat

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