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Biomedical subjects

M L Zeneroli

Publications and source records attributed to M L Zeneroli.

At least 19 recordsLinked to original sources
PubMed2005

Evaluation of rifaximin, placebo and lactulose in reducing the levels of benzodiazepine-like compounds in patients with liver cirrhosis: a pilot study.

Benzodiazepine-like compounds (BZDs), either taken with the diet or synthesized by intestinal bacterial flora, may represent a precipitating factor for hepatic encephalopathy (HE) in cirrhotic patients. We evaluated whether a diet and/or treatment with rifaximin or lactulose can reduce serum concentrations of BZDs in 18 cirrhotic patients without HE. Patients were given a standard diet for 7 days to keep the dietary intake of BZDs constant and were then randomized to a 7-day treatment with rifaximin 1,200 mg/day, lactulose 10-20 g three times daily, or placebo. Blood samples were collected at enrollment, at the end of the diet and drug treatment periods, and 7 days after the drug was stopped (follow-up). Serum concentrations of BZDs were measured by a radioligand binding technique after high-performance liquid chromatography extraction and purification and were expressed as diazepam equivalents (DE). No change in serum BZD concentrations was observed during the diet, while a statistically significant decrease from 105.6 +/- 66.5 to 63.5 +/- 49.5 pmol DE/ml was achieved in rifaximin-treated patients (p < 0.05) but not in patients treated with lactulose or placebo. During the followup, serum BZD concentrations returned to 104.5 +/- 74.0 pmol DE/ml in rifaximin-treated patients (p < 0.05 vs. end-treatment values), while no significant change was observed in the lactulose- and placebo-treated patients. These data indicate that control of bacterial flora with cyclic administration of rifaximin plays a pivotal role in avoiding increased plasma concentrations of BZDs, which represent a precipitating factor for HE inpatients with severe liver disease.

Adult↗
PubMed2001

Ammonia and endogenous benzodiazepine-like compounds in the pathogenesis of hepatic encephalopathy.

BACKGROUND: Ammonia and endogenous benzodiazepines (BDZs) are two of the most important agents among those taken into consideration in the pathogenesis of hepatic encephalopathy (HE). METHODS: Venous ammonia and endogenous BDZs sera levels were assayed in 58 liver cirrhosis patients (34 male, 24 female) free of commercial BDZs. Endogenous BDZs were measured by binding assay after high-performance liquid chromatography purification. Ammonia was assessed by colorimetric test. RESULTS: Endogenous BDZs and ammonia were significantly higher in Child-Pugh class C than in class B and class A (P < 0.05), correlating to the severity of the liver dysfunction but not with the degree of HE. A significant difference, in fact, was noted between degree 0 (no HE) versus III-IV of HE (P < 0.05), but not between degrees I-II versus III-IV. Regression analysis performed to find a correlation between the ammonia and BDZ levels in HE resulted negative. CONCLUSION: Clinical evidence is provided in cirrhotic patients that ammonia and endogenous BDZ levels do not correlate with each other in the outcome of HE.

Ammonia↗
PubMed1999

Increased expression of peripheral benzodiazepine receptors and diazepam binding inhibitor in human tumors sited in the liver.

The peripheral benzodiazepine receptor system triggers intracellular metabolic events and has been associated with cell proliferation. Its endogenous ligand, the diazepam binding inhibitor, contributes to steroidogenesis by promoting cholesterol delivery to the inner mitochondrial membrane. The present study was undertaken to verify whether this system is altered in tumors sited in the liver. Peripheral benzodiazepine receptors and diazepam binding inhibitor were studied using immunocytochemistry and in situ hybridization in 9 human tumors sited in the liver, in liver hyperplasia, cirrhotic nodular regeneration, intestinal adenocarcinoma and in surrounding non-tumoral tissue. Immunocytochemical staining and in situ hybridization demonstrated that peripheral benzodiazepine receptors and diazepam binding inhibitor were more prominently expressed in neoplastic cells than in non-tumoral tissue. They were present in the same cells, suggesting that diazepam binding inhibitor may act in an intracrine manner in these cells. Higher peripheral benzodiazepine receptors and diazepam binding inhibitor expression in tumor cells suggest an implication of this system in the metabolism of neoplastic cells. Furthermore the evaluation of peripheral benzodiazepine receptor and diazepam binding inhibitor expression might be useful in evaluating malignancy and in diagnostic approaches of tumors in liver tissue.

Aged↗
PubMed1999

Tryptophan metabolism and hepatic encephalopathy. Studies on the sedative properties of oxindole.

Oxindole administration (1-100 mg/kg i.p.) to mammals decreases locomotor activity, reduces muscular tone and blood pressure and at larger doses causes coma and death. Utilizing both HPLC and GC/MS, we showed that oxindole is present in the blood, brain and other organs of several animal species, including humans. We demonstrated that oxindole is a tryptophan metabolite able to significantly decrease neuronal excitability by modifying the function of voltage-operated sodium channels. Its synthesis requires the availability of indole, which is formed in the gut. When liver function is impaired, a sufficient amount of indole reaches systemic circulation and is oxidized into oxindole, which seems to be one of the responsible agents for the neurological symptoms found in the course of liver impairment.

Animals↗
PubMed1998

Diazepam binding inhibitor and total cholesterol plasma levels in cirrhosis and hepatocellular carcinoma.

Cholesterol is used by cells for biosynthetic processes and for steroid synthesis. Although the role of cholesterol in tumorigenesis is not clear it is known that steroids are important factors in human carcinogenesis. A polypeptide, diazepam binding inhibitor (DBI), which is an endogenous ligand for peripheral benzodiazepine receptors enhances steroidigenesis by promoting cholesterol delivery to the inner mitochondrial membrane which represents the rate-limiting step of steroid biosynthesis. We have assayed the total cholesterol (TC) and the DBI plasma concentrations in patients with liver cirrhosis complicated by hepatocellular carcinoma (HCC) in comparison with those of uncomplicated liver cirrhosis. TC and DBI levels have been studied in 73 cirrhotic patients and in 23 patients with HCC. Both TC and DBI levels were higher in HCC patients when compared with age, sex and Child-Pugh class matched cirrhotic controls. The values (mean+/-S.D.) in patients in Child-Pugh class B and C with and without HCC were respectively 128+/-30 mg/dl vs. 106+/-27 mg/dl (P < 0.01) and 2.05+/-0.78 pmol/ml vs. 0.78+/-0.84 pmol/ml (P < 0.0001). The data may be the result of the metabolic influence of tumors that enhances steroid biosynthesis during tumor proliferation.

Adult↗
PubMed1998

Up-regulation of peripheral benzodiazepine receptor system in hepatocellular carcinoma.

Increased number of peripheral benzodiazepine receptors (PBRs) have been found in some tumors outside the liver. The present study was to verify whether the PBR system is altered in hepatocellular carcinoma (HCC). The levels of endogenous benzodiazepine-like compounds (BZDs), measured by radioreceptor binding technique after HPLC purification and the endogenous ligand for PBRs, termed diazepam binding inhibitor (DBI), measured by radioimmunoassay utilizing a specific antibody for human DBI, were studied in the blood of 15 normal subjects, 12 liver cirrhosis and 10 patients with HCC. The levels of BZDs in serum were increased hundred fold in liver cirrhosis patients and slightly elevated in HCC patients. DBI was found to be increased in HCC patients. The binding recognition sites for PBRs (Bmax) were increased 4 to 7 fold in HCC tissue in comparison with that found in non-tumoral liver tissue (NTLT). On the contrary the concentrations of DBI were found to be significantly decreased in HCC tissue in comparison with the respective NTLT. These results seem to suggest an implication of PBRs and of their putative endogenous ligands in the metabolism of these neoplastic cells and possibly in their proliferation. The up-regulation of PBRs found in HCC tissue seems to indicate an increased functional activity of these receptors and opens up the possibility of new pharmacological and diagnostic approaches while the changes in the circulating endogenous ligands for the above receptors might be envisaged as early markers of tumorigenesis in liver cirrhosis.

Adult↗
PubMed1998

Benzodiazepine-like compounds in the plasma of patients with fulminant hepatic failure.

BACKGROUND: Benzodiazepine-like compounds have been implicated in the pathogenesis of encephalopathy after fulminant hepatic failure. METHODS: The levels and the nature of benzodiazepine-like compounds were determined in six cases of fulminant hepatic failure during the course of the disease. Blood samples were collected on admission and a few days later, when the neurologic status had improved in five cases and immediately before death in one case. The compounds were measured in sera with a binding technique after high-performance liquid chromatography purification and analyzed with mass spectrometry. RESULTS: Their levels were highly variable in those with severe encephalopathy and were still increased on awakening in some cases. Diazepam and N-desmethyldiazepam were inconsistently present. CONCLUSIONS: The inconsistent presence of benzodiazepine-like compounds in encephalopathy after fulminant hepatic failure and their persistence, in some cases, at high levels on awakening from coma seem to indicate that the encephalopathy is not strictly dependent on the levels of these compounds.

Adult↗
PubMed1998

Endogenous benzodiazepine-like compounds and diazepam binding inhibitor in serum of patients with liver cirrhosis with and without overt encephalopathy.

BACKGROUND/AIM: Despite some controversy, it has been suggested that endogenous benzodiazepine plays a role in the pathogenesis of hepatic encephalopathy. The aim of the present study was to evaluate the concentrations of endogenous benzodiazepines and the peptide, diazepam binding inhibitor, in the blood of patients with liver cirrhosis with and without overt encephalopathy, and to compare these levels with those of consumers of commercial benzodiazepines. SUBJECTS: Normal subjects (90), benzodiazepine consumers (14), and cirrhotic patients (113) were studied. METHODS: Endogenous benzodiazepines were measured by the radioligand binding technique after high performance liquid chromatography (HPLC) purification. The presence of diazepam and N-desmethyldiazepam was assayed by HPLC-electrospray tandem mass spectrometry. Diazepam binding inhibitor was studied in serum by radioimmunoassay. RESULTS: Endogenous benzodiazepines were below the limit of detection in 7% of patients with encephalopathy. When detectable, their levels were at least comparable with those of benzodiazepine consumers and correlated with the liver dysfunction but not the stage of encephalopathy. Serum levels of diazepam binding inhibitor tended to decrease when endogenous benzodiazepines levels increased. CONCLUSIONS: Endogenous benzodiazepines may accumulate in patients with liver cirrhosis during the course of the disease, and the phenomenon appears to be independent of the presence or absence of encephalopathy.

Aged↗
PubMed1997

Antibacterial activity of rifaximin reduces the levels of benzodiazepine-like compounds in patients with liver cirrhosis.

Benzodiazepine-like compounds are present in trace amounts in the blood of normal subjects and increase in liver cirrhotic patients with or without encephalopathy. Their increased presence may, however, represent an occasional precipitating factor of hepatic encephalopathy. The source of these compounds is still unknown, but they are constituents of our diet since benzodiazepine receptor ligands have been described in plants, vegetables and in animals. They may also be synthesized, at least in part, by intestinal bacterial flora. In this article we report that the level of these compounds in the blood decreased by 40% after therapy with rifaximin, which reduces the aerobic and anaerobic intestinal bacterial flora. This observation indicates that intestinal bacterial flora is involved in the production of these compounds and that repeated short-term medications with this non-absorbable antibiotic may be useful in reducing the levels of benzodiazepine-like compounds in patients with liver cirrhosis.

Aged↗
PubMed1997

Changes in endogenous benzodiazepine-like compound levels during the course of fulminant hepatic failure: potential effects of decreased renal function.

The pathogenetic agents which cause encephalopathy due to fulminant hepatic failure are still under debate. Ammonia and benzodiazepine-like compounds are two of the most important agents considered, so far. Herein, we report the levels of benzodiazepine-like compounds in serum and in urine and of venous ammonia measured during the course of the disease (30 days). The patient rapidly developed stage IV encephalopathy with high levels of ammonia and with only a slight increase of benzodiazepine-like compounds. At that moment, the levels of these compounds were similar to those recorded in the blood when the patient regained full consciousness 28 days later. During the course of the disease, there was a 10-fold increase of benzodiazepine-like compounds in serum which was recorded in parallel with an impaired excretion due to oliguria. This observation seems to indicate that encephalopathy may develop in the absence of significantly increased levels of these compounds and that their episodic increase during fulminant hepatic failure may be an epiphenomenon linked with several factors such as impaired renal function.

Adult↗
PubMed1996

Hepatic encephalopathy in liver transplant recipients precipitated by benzodiazepines present in transfused blood.

The observation that there are episodes of encephalopathy in liver cirrhosis patients after orthotopic liver transplantation, despite a well functioning graft and despite the lack of cerebral complications, prompted us to investigate the potential role of circulating benzodiazepine-like compounds in these episodes. The plasma levels of benzodiazepines were examined in 14 liver cirrhotic patients before and after transplantation. The benzodiazepines in the fluids infused during surgery and in individual bags of blood administered after surgery to 4 of these patients were also assayed. Herein we report that benzodiazepines accumulating in the blood of some transplanted patients appear to derive from blood transfusions utilized during surgery. The analysis of the types of benzodiazepines present in the blood utilized for transfusions suggests the use of commercial benzodiazepines by the donors. These compounds seem to be able to precipitate hepatic encephalopathy in patients with preexisting encephalopathy. Hence we suggest not using benzodiazepine consumers as blood donors, at least for patients with encephalopathy undergoing to liver transplantation.

Adult↗
PubMed1996

Evaluation of the efficacy and safety of flumazenil in the treatment of portal systemic encephalopathy: a double blind, randomised, placebo controlled multicentre study.

BACKGROUND: Portal systemic encephalopathy (PSE) is a complex neuropsychiatric syndrome associated with hepatic failure. Small scale studies have shown the benzodiazepine receptor antagonist flumazenil to be effective in ameliorating PSE. AIMS: To determine the efficacy of flumazenil in patients with non-comatous mild to moderate PSE (stages I to III) due to severe chronic liver disease. PATIENTS: 49 male and female adults without symptoms of severe bleeding and sepsis and who screened negative for benzodiazepine in both blood and urine, were included in the study. METHODS: Patients were randomised to receive either three sequential bolus injections of flumazenil (0.4, 0.8, and 1 mg) or placebo at one minute intervals, followed by intravenous infusions of either flumazenil (1 mg/h) or placebo for three hours. Clinical PSE grading and vital signs were assessed hourly during baseline and post-treatment periods and half hourly during treatment. The main outcome measures were improvement in group average PSE score and reduction of two points in individual PSE score (clinically relevant improvement). RESULTS: The mean average improvement in the PSE score in the subjects treated with flumazenil was not statistically significantly different from placebo. However, for patients showing clinically relevant improvement, the difference between flumazenil and placebo was statistically significant (seven of 28 v none of 21; p = 0.015). Flumazenil was well tolerated. CONCLUSIONS: A subgroup of patients with PSE resulting from chronic liver disease may benefit from the administration of flumazenil.

Chronic Disease↗
PubMed1991

Alterations of GABA-A and dopamine D-2 brain receptors in dogs with portal-systemic encephalopathy.

The binding characteristics of gamma-aminobutyric acid-A (GABA-A) receptors and the kinetic characteristics of the target enzyme of GABA synthesis in nerve terminals, glutamic acid decarboxylase (GAD), were studied in a dog model of portal-systemic encephalopathy obtained by porta-caval shunt performed in dimethylnitrosamine pretreated animals. Furthermore the properties of dopamine receptors and the levels of catecholamines of encephalopathic dogs were investigated. The mild stage of encephalopathy was characterized by an up-regulation of the inhibitory GABA-A receptors probably related to a decrese of GABA in nerve terminals since GAD was decreased and by a slight decrease of catecholamines and by an increased synthesis of octopamine associated with a decreased affinity of dopamine receptors. In the severe stage there was a selection of high affinity GABA-A receptors with an increased number of benzodiazepine recognition sites which were supersensitive to GABA stimulation, a decreased number of Dopamine D-2 receptors and a marked reduction of catecholamines. These data seem to suggest that the neurological disturbances of experimental portal-systemic encephalopathy might be the result of an imbalance between inhibitory and excitatory systems leading to a prevalence of the first one.

Animals↗
PubMed1991

Globus pallidus alterations and brain atrophy in liver cirrhosis patients with encephalopathy: an MR imaging study.

Brain magnetic resonance (MR) was performed in 29 liver cirrhosis patients without (N = 10) and with hepatic encephalopathy (HE) of chronic recurrent (N = 10) and of chronic persistent (N = 9) type. Sixty percent of the patients with chronic recurrent HE and 100% of the patients with chronic persistent HE showed a bilateral and symmetrical hyperintensity of the globus pallidus in the T1-weighted images while the T2-weighted images were normal, suggesting the possibility of the accumulation of a paramagnetic compound in this brain area during HE. Other findings of the study were evidence of brain atrophy of mild or moderate degree in 70% of patients with chronic recurrent HE and in 77% with chronic persistent HE and patients with liver cirrhosis without HE appeared normal on MR examination.

Adult↗
PubMed1990

Neurotransmission in hepatic encephalopathy.

After a careful characterization, a rat model of fulminant hepatic failure galactosamine-induced was utilized in order to evaluate the neurochemical changes and the histological alterations which occur during the developing of the encephalopathy. Following these studies, normal rats were treated with toxins claimed to be the primary agents of hepatic encephalopathy to recognize those which are able to mimic the behavioral, electrophysiological and neurochemical changes found in the rat model of fulminant hepatic failure. With the limit due to informations coming from an experimental model, the symptoms of HE seem to be attributable to neurotoxic agents such as ammonia. The toxicity of ammonia does not seem to be due to a mere decrease of general brain metabolism, but seems rather to be mediated by an increase, at least in some compartment, of neurotoxic amino acids such as glutamate. Both accumulation of ammonia and the neurotoxic effect of glutamate seem to be potentiated by the described zinc depletion (both in liver and in brain). Hence the final effect of these phenomena is the development of the symptoms of encephalopathy triggered by an imbalance between inhibitory and excitatory receptor systems in the brain associated with neuronal alterations which take place early and before the appearance of brain edema.

Animals↗
PubMed1990

Endogenous benzodiazepine receptor ligands in human and animal hepatic encephalopathy.

The role of endogenous benzodiazepine receptor ligands in the pathogenesis of hepatic encephalopathy was studied in humans and in rat models of hepatic encephalopathy. Endogenous benzodiazepine ligands were extracted from rat brain and human CSF by acid treatment and purification by HPLC. Detection and partial characterization of these endogenous benzodiazepine ligands were carried out using both radioreceptor binding assays and radioimmunoassays with anti-benzodiazepine antibodies. Four different benzodiazepine receptor ligands were identified in human and rat tissue, two of which may be diazepam and desmethyldiazepam, based on elution profiles and anti-benzo-diazepine antibody reactivity. Human CSF and serum from patients with hepatic encephalopathy contained approximately 10 times more endogenous benzodiazepine receptor ligand than CSF from controls or nonencephalopathic patients with liver disease. The levels of brain benzodiazepine receptor ligand compounds were also increased approximately 10-fold in rats suffering from fulminant hepatic failure, but not in rats with portacaval shunts, a model of chronic hepatic disease. The increased concentrations of these substances could be behaviorally significant and may contribute to the pathogenesis of hepatic encephalopathy.

Adult↗