Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Benzodiazepines”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 55 records · Page 3Linked to original sources
PubMed2005

Views of general practitioners and benzodiazepine users on benzodiazepines: a qualitative analysis.

Effectively assisting benzodiazepine users to cease use requires a greater understanding of general practitioners' (GPs) and benzodiazepine users' views on using and ceasing benzodiazepines. This paper reports the findings from a qualitative study that examined the views of 28 GPs and 23 benzodiazepine users (BUs) in Cairns, Australia. A semi-structured interview was conducted with all participants and the information gained was analysed using the Consensual Qualitative Research Approach, which allowed comparisons to be made between the views of the two groups of interviewees. There was commonality between GPs and BUs on reasons for commencing benzodiazepines, the role of dependence in continued use, and the importance of lifestyle change in its cessation. However, several differences emerged regarding commencement of use and processes of cessation. In particular, users felt there was greater need for GPs to routinely advise patients about non-pharmacological management of their problems and potential adverse consequences of long-term use before commencing benzodiazepines. Cessation could be discussed with all patients who use benzodiazepines for longer than 3 months, strategies offered to assist in management of withdrawal and anxiety, and referral to other health service providers for additional support. Lifestyle change could receive greater focus at all stages of treatment.

Adult↗
PubMed1999

[(3)H]-girisopam, a novel selective benzodiazepine for the 2, 3-benzodiazepine binding site.

Several members of the 2,3-benzodiazepine family, such as tofisopam (Grandaxin((R))) nerisopam (GYKI-52 322) [F. Andrási, K. Horváth, E. Sineger, P. Berzsenyi, J. Borsy, A. Kenessey, M. Tarr, T. Láng, J. Korösi, T. Hámori, Neuropharmacology of a new psychotropic 2, 3-benzodiazepine, Arzneim.-Forsch. Drug. Res., 37 (1987) 1119-1124.] [1] or girisopam (GYKI-51 189) [K. Horváth, F. Andrási, P. Berzsenyi, M. Pátfalusi, M. Patthy, G. Szabó, L. Sebestyén, J. Korösi, P. Botka, T. Hámori, T. Láng, A new psychoactive 5H-2, 3-benzodiazepine with a unique spectrum of activity, Arzneim.-Forsch. Drug. Res., 39 (1989) 894-899.] [2] proved anxiolytic in man and various animal models. Moreover, girisopam could also be characterized as an atypical neuroleptic agent. In spite of the structural similarity, their pharmacological profiles differ significantly from that of the 'classical' 1,4-benzodiazepines. Importantly, according to the data obtained so far these drugs do not have an addiction potential. The novel 2,3-benzodiazepine antagonist girisopam binds with high affinity (K(d)=10.3+/-1.21 nM) and limited capacity (B(max)=6.94+/-1.8 pmol/mg protein) to a single class of recognition sites in rat striatum [J.E. Horváth, J. Hudák, M. Palkovits, Zs. Lenkei, M.I.K. Fekete, P. Arányi, A novel specific binding site for homophthalazines (formerly 2, 3-benzodiazepines) in the rat brain, Eur. J. Pharmacol., 236 (1993) 151-153.]. This protocol describes the use of [(3)H]-girisopam as a specific radioligand for the 2,3-benzodiazepines receptor.

Adult↗
PubMed1998

Plasma and CSF benzodiazepine receptor ligand concentrations in cirrhotic patients with hepatic encephalopathy: relationship to severity of encephalopathy and to pharmaceutical benzodiazepine intake.

Increased plasma and CSF concentrations of substances which bind to brain benzodiazepine receptors have previously been reported in cirrhotic patients with hepatic encephalopathy (HE). However, their relationship to previous intake of pharmaceutical benzodiazepines has not been clearly established. In the present study, plasma levels of benzodiazepine receptor ligands (BZRLs) were measured using a sensitive radioreceptor assay in 12 control subjects with no evidence of hepatic, neurological or psychiatric illness, 11 cirrhotic patients without HE, 24 cirrhotic patients with moderate (grade I-II) HE and in 45 cirrhotic patients with severe (grade II-IV) HE. In addition, CSF concentrations of BZRLs were measured in 8 cirrhotic patients with HE and an equal number of age-matched controls. Recent intake (within 10 days) of pharmaceutical benzodiazepines was assessed by detailed review of medical files, and interviews with the patient, at least one family member as well as the pharmacist. Significantly increased plasma concentrations of BZRLs were observed in cirrhotic patients with severe encephalopathy (p < 0.02) compared to controls and to cirrhotic patients without (or with mild) neurological impairment. Increased plasma BZRLs could be accounted for by prior exposure to benzodiazepine medication in all cases. CSF concentrations of BZRLs in cirrhotic patients were not significantly different from control values. These findings do not support a role for "endogenous" benzodiazepines in the pathogenesis of HE in chronic liver disease but suggest that pharmaceutic benzodiazepines administered to cirrhotic patients as sedatives or as part of endoscopic work-up could have contributed to the neurological impairment in some patients.

Animals↗
PubMed1980

[Benzodiazepine dependence: addiction potential of the benzodiazepines is greater than previously assumed (author's transl)].

The position of benzodiazepine dependence among addiction diseases was studied retrospectively by analysing the case reports of in-patients at the Psychiatric Clinic, Göttingen. Addicts constitute the largest group of patients in this clinic, a situation probably true in general of psychiatric hospitals in the Federal Republic of Germany. Isolated alcoholism is the most frequent addiction, followed by combined alcohol-drug dependence and pure drug dependence. At present, benzodiazepines are the most commonly used addictive drugs. Although most of benzodiazepine dependents have changed to it from another drug, primary benzodiazepine dependence is increasing. Among the benzodiazepines, lorazepam seems to have a particularly high addiction potential. On withdrawal of benzodiazepines, symptoms were less marked than after stopping a combination of benzodiazepines and alcohol, and (or) barbiturates; they generally developed with some time delay.

Alcoholism↗
PubMed2005

Predictors of discontinuation of benzodiazepine prescription after sending a letter to long-term benzodiazepine users in family practice.

BACKGROUND: Predictors of benzodiazepine discontinuation after sending a discontinuation letter by the family practitioner have not been established sufficiently. OBJECTIVE: To identify predictors of short- and long-term discontinuation of benzodiazepine use and relapse in use after a minimal intervention with a discontinuation letter followed by an offer for an evaluation consultation. METHODS: Predictors of benzodiazepine discontinuation and relapse in use were studied by logistic regression analysis and survival analysis within a family practice population of long-term benzodiazepine users (n = 1707) addressed by a discontinuation letter and followed for 21 months. RESULTS: A lower baseline prescription, a shorter duration of use, male gender and use of an agent with a half-life time <24 hours were predictive of complete discontinuation in the short (6 months) and long term (21 months). Multiple agent use at baseline, use of antidepressants at 6 months and benzodiazepine type (anxiolytic/hypnotic) at baseline predicted relapse. Attendance at an evaluation consultation 3 months after the letter was sent was not predictive of discontinuation or relapse. CONCLUSIONS: Amount of baseline use and duration of use are the main determinative characteristics of successful discontinuation. The discontinuation letter intervention is suitable for use with a broad group of long-term benzodiazepine users in family practice and can be used as a first step within a stepped care approach to decrease long-term benzodiazepine use.

Adult↗
PubMed1989

Effects of benzodiazepines and non-benzodiazepine compounds on the GABA-induced response in frog isolated sensory neurones.

1. The effects of benzodiazepines and non-benzodiazepine compounds on the gamma-aminobutyric acid (GABA)-induced chloride current (ICl) were studied in frog isolated sensory neurones by use of a concentration-jump (termed 'concentration-clamp') technique, under single-electrode voltage-clamp conditions. The drugs used were classified into four categories as follows: full benzodiazepine receptor agonists (diazepam, clonazepam, nitrazepam, midazolam, clotiazepam and etizolam), partial agonists (CL 218,872, Ro 16-6028, Ro 17-1812 and Ro 23-0364), inverse agonists (Ro 15-3505, FG 7142 and beta-CCE) and a benzodiazepine receptor antagonist, Ro 15-1788 (flumazenil). 2. All full agonists at concentrations of 3 x 10(-6) M or less increased dose-dependently the peak amplitude of ICl elicited by 3 x 10(-6) M GABA to twice to three times larger than the control. However, no further augmentation of the GABA response was observed at concentrations of 1 x 10(-5) M or higher. Partial agonists also showed a dose-dependent augmentation of the GABA response at concentrations ranging from 3 x 10(-8) M to 3 x 10(-5) M, but their efficacies of augmentation of the GABA response were only about half or less of those of full agonists. Of the inverse agonists, beta-CCE had a unique dose-dependent effect on the GABA response. Beta-CCE reduced dose-dependently the GABA response at concentrations of less than 3 x 10(-6) M, but augmented it at concentrations of 3 x 10(-5) M and 6 x 10(-5) M. The inverse agonists reduced dose-dependently the GABA response. The benzodiazepine antagonist, flumazenil, slightly augmented the GABA response at concentrations between 3 x 10 7M and 3 x 10 5 M. 3. These results show clear differences in the effects on the GABA response between these four categories of compounds known to affect the benzodiazepine recognition site of the GABA/ benzodiazepine receptor-chloride channel complex. Our experimental system of frog isolated sensory neurones and a 'concentration-clamp' technique appears to be useful for evaluating efficacy of compounds on responses mediated by the GABA/benzodiazepine receptor-chloride channel complex.

Animals↗
PubMed2000

Fluorescent-labeled ligands for the benzodiazepine receptor. Part 1: Synthesis and characterization of fluorescent-labeled benzodiazepines.

Because radioactive labeled ligands in receptor assays have several disadvantages, we synthesized a number of fluorescent-labeled benzodiazepines. Several fluorophores were attached at different positions of 1,4-benzodiazepine molecules in order to assess the impact of the fluorophores and their coupling position on the affinity for the benzodiazepine receptor. Besides the 1,4-benzodiazepines, the 1,2-annelated 1,4-benzodiazepines were also used for labeling. A metabolite of flumazenil (18), desethylflumazenil (Ro15-3890, 19), was labeled with the fluorophore 4-bromomethyl-7-methoxycoumarin, with and without the incorporation of a spacer chain, yielding the methyl-methoxycoumarin (Mmc) derivatives Mmc-Ro15-3890 (20a) and Mmc-O-CO-(CH2)3-Ro15-3890 (20b), respectively. After the synthesis, the fluorescent-labeled benzodiazepines were purified by HPLC, using an analytical RP-C18 column. For the purification of 20b, the chromatographic system was optimized, using multi-criteria decision making (MCDM) techniques. The binding affinities for the benzodiazepine receptor and the fluorescence characteristics were determined for the resulting products.

Animals↗
PubMed1978

Benzodiazepine receptor binding: the interactions of some non-benzodiazepine drugs with specific [3H] diazepam binding to rat brain synaptosomal membranes.

The interaction of several non-benzodiazepine drugs with [3H] diazepam binding to benzodiazepine receptors in rat brain synaptosomal membranes was investigated. Baclofen, benzoctamine, hydroxyzine, chlorpromazine, haloperidol, imipramine, and amitriptyline displace specific [3H] diazepam binding, but the concentrations needed are too high to explain pharmacological effects of these drugs by an interaction with benzodiazepine receptors. The most potent non-benzodiazepine drug for inhibiting specific [3H] diazepam binding was methaqualone (IC50 value of 150 micrometer). It is suggested that interactions with benzodiazepine receptors may account for the anxiolytic and anticonvulsive side effects of this drug. The analeptic drug pentylenetetrazole interacts with benzodiazepine receptor binding with an IC50 value of about 1 mM, which is possibly too high to explain its convulsive properties by an antagonism at the benzodiazepine receptor.

Animals↗
PubMed1983

Benzodiazepine hypnotics: time course and potency of benzodiazepine receptor occupation after oral application.

Ex vivo benzodiazepine receptor occupation by six benzodiazepine hypnotics in the mouse brain was investigated with respect to the time course after oral administration and with respect to the in vitro potency as benzodiazepine receptor ligands. All drugs were administered as solutions. Receptor occupation, as indicated by the inhibition of specific [3H] flunitrazepam binding, occurs very rapidly after oral administration of all benzodiazepines tested with about 80% or even more of maximal inhibition already seen within 30 min after oral administration. However, the onset is somewhat faster with midazolam and temazepam than with the other four derivatives. The duration of benzodiazepine receptor occupation in the mouse brain differed markedly for the six benzodiazepines in agreement with their very different pharmacokinetics in this species. Except for midazolam, there was a good correlation between in vitro receptor affinity and ex vivo receptor occupancy, suggesting that all drugs except midazolam reach the receptor in the CNS similarly. Midazolam has a large first pass metabolism after oral administration which seems the reason for the lower ex vivo potency relative to the in vitro affinity. It is concluded that a fast onset of receptor occupation is a rather general property of benzodiazepines when administered orally as solutions.

Administration, Oral↗
PubMed1982

Distinction of benzodiazepine agonists from antagonists by photoaffinity labelling of benzodiazepine receptors in vitro.

When membranes of rat cerebellum are exposed to UV light in the presence of flunitrazepam this ligand can be incorporated into one of the assumed 4 benzodiazepine binding sites of the GABA-benzodiazepine receptor complex. This irreversible incorporation of flunitrazepam, in contrast to reversible binding of this substance, leads to conformational changes of the remaining 3 benzodiazepine binding sites which result in a decreased affinity of benzodiazepine agonists, but not of benzodiazepine antagonists. The investigation of the affinity of drugs for [3H]benzodiazepine antagonist binding before and after photoaffinity labelling of benzodiazepine receptors with flunitrazepam can therefore be used as a sensitive and simple test to distinguish between agonists and antagonists in vitro.

Animals↗
PubMed1997

Anticonvulsant activity of azirino[1,2-d][1,4]benzodiazepines and related 1,4-benzodiazepines in mice.

The anticonvulsant properties of several 1,4-benzodiazepine and azirino[1,2-d][1,4]benzodiazepine (ABDZ) derivatives were studied after intraperitoneal (IP) administration in DBA/2 mice (a strain genetically susceptible to sound-induced seizures) and in Swiss mice. The anticonvulsant effects were evaluated on seizures evoked by means of auditory stimulation (109 dB, 12-16 kHz) in animals placed singly under a hemispheric Perspex dome or on seizures induced by administration of pentylenetetrazole. The 1,4-benzodiazepines were generally more potent than the related ABDZ derivatives. The rank order of potency for anticonvulsant activity was flunitrazepam > diazepam > pinazepam > ABDZ5 > ABDZ4 > prazepam > halazepam > ABDZ1 > ABDZ3 > camazepam > ABDZ6 > ABDZ2. The impairment of locomotor performance following IP administration of these derivatives was also evaluated by means of the rotarod test. The rank order of potency for impairment of coordinated motor movements was pinazepam > flunitrazepam > diazepam > ABDZ5 > prazepam > halazepam > ABDZ4 > ABDZ3 > ABDZ1 > camazepam > ABDZ2 = ABDZ6. The potency of various 1,4-benzodiazepines and ABDZs as inhibitors of specific [3H]flumazenil binding to membranes from cerebellum or cortex was evaluated. In general, ABDZs were active as anticonvulsants and inhibited [3H]flumazenil binding in the micromolar range. Radioligand binding studies carried out in stable cell lines demonstrated that none of the ABDZs tested showed a particular subtype specificity. The pharmacological actions of ABDZ4 and ABDZ5, which appeared to be the most potent ABDZs as anticonvulsants, were significantly reduced by treatment with flumazenil (8.24 mumol/kg IP), suggesting a clear involvement of benzodiazepine mechanisms in the anticonvulsant activity of these compounds or their metabolites. The anticonvulsant activity of ABDZ4 and ABDZ5 was also evaluated against seizures induced in DBA/2 mice by two beta-carbolines: methyl-beta-carboline-3-carboxylate (beta-CCM) and methyl-6,6-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM). Both ABDZ4 and ABDZ5 give better protection against seizures induced by beta-CCM than DMCM, suggesting a preferential action on the benzodiazepine receptor subtype BDZ1.

Animals↗
PubMed2006

Enantioselective synthesis of diversely substituted quaternary 1,4-benzodiazepin-2-ones and 1,4-benzodiazepine-2,5-diones.

Benzodiazepines are privileged scaffolds in medicinal chemistry, but enantiopure examples containing quaternary stereogenic centers are extremely rare. We demonstrate that installation of the di(p-anisyl)methyl (DAM) group at N1 of 1,4-benzodiazepin-2-ones and 1,4-benzodiazepine-2,5-diones derived from enantiopure proteinogenic amino acids allows retentive replacement of the C3-proton via a deprotonation/trapping protocol. A wide variety of carbon and nitrogen electrophiles function well in this reaction, providing the corresponding quaternary benzodiazepines with excellent enantioselectivity. Deprotonation/trapping experiments on a pair of diastereomeric 1,4-benzodiazepine-2,5-diones provide evidence for a key role of conformational chirality in these enantioselective reactions. Acidic removal of the DAM group is fast and high-yielding and can be performed selectively in the presence of a N-Boc indole. Thus the synthesis of quaternary benzodiazepines with diverse N1 functionality can now be accomplished.

Alkylation↗
PubMed1984

Supersensitivity of benzodiazepine receptors in hepatic encephalopathy due to fulminant hepatic failure in the rat: reversal by a benzodiazepine antagonist.

Benzodiazepine receptors were studied in rats with hepatic encephalopathy due to fulminant hepatic failure induced by galactosamine. [3H]-Diazepam binding studies on brain synaptic membranes of rats with mild and severe encephalopathy show a significant increase in the number of receptors in both stages of coma. [3H]Diazepam binding to synaptic membrane preparations from rats in the mild or severe stage of encephalopathy hyper-responded to the stimulatory effect of gamma-aminobutyric acid (GABA) applied in vitro at doses which for control rat preparations were in a subthreshold range. The effect of GABA was shown to be specific, since it was blocked by bicuculline methiodide. The sensitivity of benzodiazepine receptors in hepatic encephalopathy to nanomolar concentrations of GABA, which induced a significant increase in their affinity, seems to indicate a functional supersensitivity of benzodiazepine receptors in vivo in both mild and severe stages of encephalopathy. The phenomena described may be attributed to a partial degeneration of nerve terminals in hepatic encephalopathy, leading to a supersensitivity of benzodiazepine receptors, which parallels the previously described denervation supersensitivity of GABA receptors present in this animal model of fulminant hepatic failure. These findings may account for the brain hypersensitivity to sedatives administered to patients with liver diseases. The administration in vivo of a benzodiazepine antagonist, 2-phenylpyrazolo[4,3-c]-quinolin-3(5H)-one, counteracted the hypersensitivity of benzodiazepine receptors in the mild stage of encephalopathy.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2002

The Benzodiazepine Withdrawal Symptom Questionnaire: psychometric evaluation during a discontinuation program in depressed chronic benzodiazepine users in general practice.

BACKGROUND: The Benzodiazepine Withdrawal Symptom Questionnaire (BWSQ, Tyrer et al. 1990) has been developed to measure distinct features of the benzodiazepine withdrawal syndrome. However, psychometric evaluations of this questionnaire are scarce. AIMS, SETTING: To evaluate the BWSQ during a discontinuation program carried out by general practitioners in 230 depressed chronic benzodiazepine users. FINDINGS: Reliability coefficients during the program were between 0.84 and 0.88 and the test-retest correlations were between 0.75 and 0.88 during withdrawal. Mean scores of the BWSQ during withdrawal differentiated between completers and failures (p = 0.036). The factor structure underlying the items consisted of perceptual and sensory disturbances, dysphoric mood, muscular pain and memory loss. Low scores during the last phase of tapering off predicted no, or limited, use of benzodiazepines in the first years following discontinuation (p = 0.003). CONCLUSIONS: We found the BWSQ to measure symptoms during benzodiazepine withdrawal in a reliable way. Our findings indicate some construct validity for BWSQ. Low scores during withdrawal predict more limited future use of benzodiazepines.

Adult↗
PubMed1994

Urinary screening for benzodiazepines with radioreceptor assay: comparison with EMIT d.a.u. benzodiazepine assay and high-performance liquid chromatography.

The radioreceptor assay (RRA) provides a total estimate of all pharmacologically active forms of benzodiazepines and their metabolites. We evaluated the method for urine drug screening. Detection limits of the most commonly used benzodiazepines and their major metabolites were determined. In all cases, the detection limits were lower than the cutoff values specified for the Syva EMIT d.a.u. benzodiazepine assay. Thirty-three urine samples for routine drug screening were tested for benzodiazepines by RRA and EMIT. Results were compared with those obtained by a highly specific high-performance liquid chromatographic (HPLC) method. Five commonly used benzodiazepines and their major metabolites were identified by use of a computerized multichannel photodetector. We obtained two false-negative results by RRA when compared with HPLC. These may be caused by conjugate formation. The inclusion of a simple enzymatic hydrolysis improves the detection of compounds excreted in the urine as glucuronide conjugates (e.g., oxazepam). We conclude that the combination of enzymatic hydrolysis and direct RRA provides a rapid and acceptable method for detection of the presence of benzodiazepines in urine samples.

Benzodiazepines↗
PubMedDate not supplied

[Plea for benzodiazepines or is there a future for benzodiazepines in psychiatry?].

Thirty years ago chlordiazepoxide was used in psychiatry for the first time. Benzodiazepines, a therapeutic class with a large spectrum of activities, are now used regularly by 5 to 15% of adults. In France 15% of prescriptions include at least 1 benzodiazepine and 5 compounds of this class appear among the 30 most frequently prescribed of state reimbursed medications. In a developing country like Tunisia sales of psychotropic drugs increased by 84% between 1984 and 1987, benzodiazepines representing half of the prescriptions. Criticisms were voiced as early as in the years 1970. Ralph Nader himself led a campaign against those drugs used in suicidal attempts, provoking car accidents and industrial injuries, memory deficits and dependence. Later, several side effects were pin-pointed: amnesia, which has been used with criminal intent in a few dramatic cases; in fact it should be differentiated from the cognitive troubles resulting from anxiety itself; tolerance: for instance in drug addicts using high doses; it concerns only some effects of the drug; dependence: which remains rare when contrasted with the large consumption of benzodiazepines; withdrawal reaction should be differentiated from teh relapse of anxiety once the drug has been discontinued. In the public opinion one is supposed to bear any pain--and never complain--when it is psychic and not somatic. Benzodiazepines that alleviate psychic pain were considered with spite and then grudge, to use the terminology of erotomania. Actually, benzodiazepine treatment should be a part of a larger therapeutic program taking into account the characteristics of each individual patient.(ABSTRACT TRUNCATED AT 250 WORDS)

Benzodiazepines↗
PubMed1999

Assessment of GABA(A)benzodiazepine receptor (GBzR) sensitivity in patients on benzodiazepines.

OBJECTIVES: To measure GABA(A) benzodiazepine receptor sensitivity in patients taking benzodiazepines and compare with matched controls. METHODS: Seven patients who were on prescribed benzodiazepines for an anxiety disorder or insomnia were recruited from general practice and an adult mental health service outpatient clinic. They were matched with seven volunteers. All subjects received an intravenous injection of midazolam 50 microgram/kg in 10 ml normal saline over 10 min. Objective responses to midazolam were assessed using saccadic eye movement velocity slowing and subjective assessments using visual analogue scales. Measurements were recorded for 120 min and plasma midazolam concentrations obtained at 15-min intervals post-infusion to 120 min. Ratios of pharmacodynamic/pharmacokinetic effects were obtained for each individual to estimate GABA(A) benzodiazepine receptor sensitivity. RESULTS: Patients had an attenuated response to midazolam on both subjective and objective measures. GABA(A) benzodiazepine receptor sensitivity was significantly reduced in the patient group. CONCLUSIONS: Chronic treatment with benzodiazepines was associated with reduced effects of midazolam. Saccadic eye movement velocity was especially sensitive as a measure of attenuated response.

Adult↗
PubMed1990

The involvement of the benzodiazepine receptor in hepatic encephalopathy: evidence for the presence of a benzodiazepine receptor ligand.

The involvement of GABAergic systems in the pathogenesis of HE was supported by electrophysiologic studies of single Purkinje neurons from rabbits with HE which demonstrated the hypersensitivity of these neurons to depression by GABA and BZ receptor agonists. In contrast, these neurons were excited by BZ receptor antagonists. At concentrations which had no effect on neuronal activity, BZ receptor antagonists also reversed the hypersensitivity of HE neurons to depression by muscimol. This combination of neuronal responses is consistent with an increase in the concentration or availability of a ligand for the BZ receptor with agonist properties in the brains of rabbits with HE. Subsequent neurochemical studies support these electrophysiologic observations. Autoradiographic techniques indicated the presence of a reversible inhibitor of [3H]Ro 15-1788 and [3H]flunitrazepam binding to the cerebral and cerebellar cortices of rabbits with HE. The ability of this substance to inhibit [3H]flunitrazepam binding to HE rabbit brain sections was further enhanced in the presence of NaCl and GABA. The autoradiographic studies suggested that the density and affinity of the components of the GABA-BZ receptor complex are unaltered in this animal model of HE. This inference is fully supported by the subsequent studies of radioligand binding to well-washed membrane preparations. Finally, extracts of HE rabbit brains yielded a family of substances with the properties of BZ receptor agonists. These substances may include, but are not limited to, diazepam, oxazepam and desmethyldiazepam, but do not include substances commonly elevated in the plasma and CSF of patients with HE4. The positive identification of these substances awaits confirmation by mass-spectroscopic analysis. However, the precedent for the presence of a family of benzodiazepines in animals that were not administered these drugs has been set. The origin of these substances is a matter of ongoing research. Several studies have shown the presence of benzodiazepines in plant and animal materials. It is possible that these "endogenous" benzodiazepines are the result of contamination of the food chain. A normally functioning liver would capture and metabolize these compounds after their absorption from the gut. This function of the liver would be impaired in liver failure, thus allowing sufficient levels of BZ receptor agonists to accumulate in the CNS, contributing to the pathogenesis of HE. However, studies by DeBlas and coworkers have reported that 1,4 benzodiazepines are present in human brains preserved prior to the commercial use of these compounds. Further, they have found benzodiazepines in cell lines cultured without potential exogenous sources of benzodiazepines.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗