Benzodiazepine-receptor ligands and hepatic encephalopathy: A causal relationship?

Rothstein, Jeffrey D.

doi:10.1002/hep.1840190135

Cited by 12 publications

(5 citation statements)

References 38 publications

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“…Some studies have attributed this syndrome to the production of factors acting on the benzodiazepine receptors (BZ-like factors) whose origin is still debated [12]. Hence, depression in chronic hepatitis patients may be related to the presence of these BZ-like factors and this hypothesis could partially explain the mild pretreatment depression seen in our patients.…”

Section: Discussionsupporting

confidence: 52%

Interferon Alpha-Induced Depression in Chronic Hepatitis C Patients: Comparison between Different Types of Interferon Alpha

Malaguarnera¹,

Fazio²,

Restuccia³

et al. 1998

Neuropsychobiology

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IFN alpha treatment is able to produce dose-related side effects, such as depression, in the central nervous system. We assessed the effects on depression of four different types of IFN alpha (recombinant IFN alpha 2a, recombinant IFN alpha 2b, lymphoblastoid IFN alpha, leukocyte IFN alpha), administered at the same doses in four homogeneous groups of chronic hepatitis C patients (96 patients; 24 patients for each group). A group of 18 untreated hepatitis C patients was considered as a control group. Depression was measured using Zung’s self-rating depression scale (SDS scale) before starting IFN alpha therapy and at the 1st, 3rd and 6th month of treatment. In all patients evaluated, mean SDS values increased from mild to moderate depression, but never attained severe depression (SDS >70). More elevated SDS values were observed in the 1st month of treatment, with a progressive decrease during the end points above-mentioned. The recombinant IFN alpha 2a and lymphoblastoid IFN alpha arms presented higher SDS mean scores compared to the recombinant IFN alpha 2b and leukocyte IFN alpha arm. Only in the leukocyte IFN alpha arm SDS values returned to basal values at the 6-month end point. Leukocyte IFN alpha seemed to present a more elevated tolerability than other IFN alpha types available for clinical practice. A very careful selection of hepatitis C patients is required before starting IFN alpha therapy.

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Section: Discussionsupporting

confidence: 52%

Interferon Alpha-Induced Depression in Chronic Hepatitis C Patients: Comparison between Different Types of Interferon Alpha

Malaguarnera¹,

Fazio²,

Restuccia³

et al. 1998

Neuropsychobiology

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“…The observation that NBZDs are present in human brain samples stored since 1940 [30], when benzodiazepines were not yet synthesized, clearly indicates that NBZDs do not derive from environmental pollution by synthetic benzodiazepines, which entered the market only in 1959. Several attempts to find out the endogenous biosynthetic pathways of NBZD production have been made [31][32][33][34]. However, an endogenous biochemical pathway of NBZDs has not yet been identified in mammalian cells [33] while it has been found that microorganisms like Streptomyces and Penicillium can synthesize molecules like anthramycin and cyclopeptine, respectively, both containing the basic 1,4-benzodiazepine structure [35].…”

Section: Natural Benzodiazepinesmentioning

confidence: 99%

“…NBZDs such as diazepam and nordiazepam and other unknown benzodiazepine-like compounds are naturally present in several plants and vegetables [25][26][27][28], in different animal species and in humans [29][30][31]. Moreover, both plasma and brain contain other compounds with benzodiazepine-like activity called 'endozepines' apparently produced in mammalian cells [32,33]. The observation that NBZDs are present in human brain samples stored since 1940 [30], when benzodiazepines were not yet synthesized, clearly indicates that NBZDs do not derive from environmental pollution by synthetic benzodiazepines, which entered the market only in 1959.…”

Section: Natural Benzodiazepinesmentioning

confidence: 99%

“…Several attempts to find out the endogenous biosynthetic pathways of NBZD production have been made [31][32][33][34]. However, an endogenous biochemical pathway of NBZDs has not yet been identified in mammalian cells [33] while it has been found that microorganisms like Streptomyces and Penicillium can synthesize molecules like anthramycin and cyclopeptine, respectively, both containing the basic 1,4-benzodiazepine structure [35]. Moreover, evidence has been provided that some gut bacteria, such as Acinetobacter lwoffi, can produce precursors of benzodiazepine receptor ligands [36].…”

Section: Natural Benzodiazepinesmentioning

confidence: 99%

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Management of Hepatic Encephalopathy: Role of Rifaximin

Zeneroli

Avallone²,

Corsi³

et al. 2005

Chemotherapy

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Hepatic encephalopathy (HE) is a neuropsychiatric syndrome, which develops in patients with acute or chronic liver failure. It is widely accepted to be due to impairment of hepatic clearance of toxic products from the gut such as ammonia. Accumulation of ammonia induces a glutamate neurotoxicity leading to an increased tone of the γ-aminobutyric acid A (GABA-A) receptor system in the brain which results in HE. Factors either increasing the ammonia levels (protein load, constipation, sepsis, or gastrointestinal bleeding) or potentiating the functional activity of the GABAergic system [natural benzodiazepine-like compounds (NBZDs) or exogenous benzodiazepines] may act as precipitating factors of HE. NBZDs are present in trace amounts in the blood of normal subjects and have been found to be increased in the blood of patients with liver cirrhosis, with or without HE. These compounds may derive either from the diet since they have been found in plants, vegetables and animals or from gut bacteria. The observation that intestinal bacterial flora is involved in the production of both primary agent of HE (ammonia) and precipitating factors (NBZDs) suggests that the use of nonabsorbable antibiotics such as rifaximin may be useful in preventing episodes of HE in patients with liver cirrhosis.

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“…Increased amounts of ligands to the benzodiazepine receptor (BZR) have been demonstrated in the brain of cirrhotic patients (Basile et al, 1991a). There is evidence that these ligands may contribute to the symptoms of hepatic encephalopathy (Mullen et al, 1988;Rothstein, 1994). Chronic exposure to ligands to the BZR leads to changes in gene expression (Mhatre et al, 1993;Zhao et al, 1994) and binding to the BZR population in the brain (Hu and Ticku, 1994) in animal models.…”

Section: Introductionmentioning

confidence: 99%

Brain uptake of iomazenil in cirrhotic patients: a single photon emission tomography study

Kapczinski

Quevedo²,

Curran³

et al. 1999

J Psychopharmacol

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Brain uptake of 123I-iomazenil was studied in seven cirrhotic patients and eight normal controls using single photon emission computerized tomography. The highest concentration of the ligand was found in the occipital cortex, which corresponds to the brain region with the highest concentration of benzodiazepine receptors. The peak uptake was delayed in patients across all brain regions. The uptake in occipital cortex was higher in low albumin cirrhotics. Patients with low albumin also presented a more delayed peak uptake in occipital cortex and a higher volume of distribution of iomazenil in plasma, compared to patients with normal albumin levels and controls. The changes in brain uptake (delayed peak uptake and increased maximal uptake in occipital cortex) appears to reflect changes in the pharmacokinetics of the ligand, particularly in cirrhotics with low levels of plasma albumin. The curve of brain uptake of the tracer was modelled into a two compartments equation, which seems to provide a practical and reliable method to calculate the slopes of acquisition and decay, time to peak and maximal acquisition.

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Benzodiazepine-receptor ligands and hepatic encephalopathy: A causal relationship?

Cited by 12 publications

References 38 publications

Interferon Alpha-Induced Depression in Chronic Hepatitis C Patients: Comparison between Different Types of Interferon Alpha

Interferon Alpha-Induced Depression in Chronic Hepatitis C Patients: Comparison between Different Types of Interferon Alpha

Management of Hepatic Encephalopathy: Role of Rifaximin

Brain uptake of iomazenil in cirrhotic patients: a single photon emission tomography study

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