RESUMO
OBJECTIVE: The purpose of this study was to determine whether an endogenous benzodiazepine receptor ligand (EBZ) was present in the arterial and portal blood of dogs with congenital portosystemic shunts (CPSS). STUDY DESIGN: The presence or absence of an EBZ was determined by the collection of systemic and portal blood from dogs with CPSS. ANIMALS: Fifteen client-owned dogs with a confirmed CPSS. All dogs had historical signs compatible with hepatic encephalopathy. Eight healthy dogs were used as controls. METHODS: In all dogs, systemic blood samples were collected after they were anesthetized. Portal blood samples were collected intraoperatively. EBZ was measured by radioreceptor assay. RESULTS: In 10 of 15 dogs, the portal blood concentration of EBZ was significantly elevated compared with normal dogs (mean, 13.2 +/- 18.55 ng/mL). Five dogs had elevated systemic blood EBZ levels (mean, 8.2 +/- 16.08 ng/mL). Eleven of 15 dogs had a higher portal than systemic blood concentration of EBZ. In contrast, control dogs had extremely low EBZ concentrations detected in their portal blood (mean, 0.16 +/- 0.3 ng/mL) and systemic blood (0 ng/mL). The mean portal and systemic blood concentrations in dogs with CPSS were significantly greater than in control dogs (P < .05). CONCLUSIONS: Elevated blood levels of EBZ were found in dogs with CPSS. The portosystemic gradient noted in 11 dogs suggests the gastrointestinal tract as a possible source for the endogenous ligand. CLINICAL RELEVANCE: Generalized motor seizures have been reported in dogs after surgical correction of CPSS. If the presence of a CPSS results in stimulation of brain receptors for benzodiazepines, post-CPSS ligation seizures may result from a withdrawal of EBZ after ligation of the portosystemic shunt.
Assuntos
Benzodiazepinas/sangue , Doenças do Cão/sangue , Doenças do Cão/congênito , Cães/anormalidades , Sistema Porta/anormalidades , Animais , Benzodiazepinas/análise , Química Encefálica , Anormalidades Congênitas/sangue , Anormalidades Congênitas/patologia , Anormalidades Congênitas/veterinária , Doenças do Cão/patologia , Feminino , Masculino , Sistema Porta/química , Ensaio Radioligante/veterinária , Receptores de GABA-A/análiseRESUMO
Attempting to forecast future trends in research is difficult enough in any area but is well nigh impossible with the volatile field of hepatic encephalopathy (HE). Undaunted in this review it is suggested that more frequent use of intact animal models of HE to probe the pathogenesis of HE will occur with newly developed pharmacological agents. This process would be greatly facilitated by wide acceptance of a discrete number of reproducible animal models of this syndrome. Brief comments are made on the current status on some of the current hypotheses. Greater utilization of patients with subclinical HE for clinical studies will occur. Continuing interest in nuclear magnetic resonance imaging and spectroscopy findings peculiar to HE will be seen over the next decade.
Assuntos
Encefalopatia Hepática/etiologia , Animais , Transtornos Cognitivos/etiologia , Transtornos Cognitivos/fisiopatologia , Modelos Animais de Doenças , Previsões , Encefalopatia Hepática/fisiopatologia , Humanos , Imageamento por Ressonância Magnética , Espectroscopia de Ressonância Magnética , Neurotoxinas/farmacologia , Neurotransmissores/farmacologia , Neurotransmissores/fisiologiaRESUMO
The portacaval shunt rat is often used as a model of human portal-systemic encephalopathy, but its relevance to human portal-systemic encephalopathy remains uncertain. Specifically, it has not been demonstrated that the behavioral changes seen in this model respond to measures known to improve portal-systemic encephalopathy in human subjects. Accordingly, the aim of this study was to establish whether neomycin (an effective treatment for portal-systemic encephalopathy in human beings) added to the drinking water of rats subjected to portacaval shunt reversed or ameliorated the reduction in spontaneous motor activity, which represents a measure of encephalopathy in this animal model. A randomized, placebo-controlled crossover design was used, with each animal serving as its own control. After establishment of baseline activities, 12 rats with portacaval shunt and 12 sham-operated rats were divided into two equal groups: Group A animals received neomycin for 1 wk; this was followed by 1 wk off neomycin; in group B rats, the sequence was reversed. Spontaneous intake of neomycin for 7 days at doses comparable to human usage (0.1 to 0.2 gm/kg/day) was associated with a significant increase in spontaneous motor activity in rats subjected to portacaval shunt (26.4% in group A, 66.3% in group B; p < 0.01 for each protocol) with no significant effect in sham-operated animals. Withdrawal of neomycin resulted in reversal of this effect in group A rats subjected to portacaval shunt. Similar significant improvements for exploratory activity as measured on the basis of nose-hole pokes was also seen in rats subjected to portacaval shunt and given neomycin.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Comportamento Animal/efeitos dos fármacos , Encefalopatia Hepática/tratamento farmacológico , Neomicina/uso terapêutico , Derivação Portocava Cirúrgica/efeitos adversos , Amônia/sangue , Animais , Nitrogênio da Ureia Sanguínea , Modelos Animais de Doenças , Encefalopatia Hepática/etiologia , Encefalopatia Hepática/psicologia , Masculino , Atividade Motora/efeitos dos fármacos , Distribuição Aleatória , Ratos , Ratos Sprague-DawleyRESUMO
As will be discussed by Dr E.A. Jones based on observations in animal models of hepatic encephalopathy (HE) in 1984 we commenced our studies on the possible role of "endogenous" benzodiazepines (BZs) in human HE in 1986. Unlike animals our initial studies in humans with HE were complicated by the frequent intake of prescription BZs by these patients. Re-education of our staff on the appropriate use of BZs in patients with liver disease and a carefully devised system to exclude patients who have received prescription BZs in the 3 months preceding hospital admission was instigated before our studies could commence. Initially, we examined CSF of patients with HE for the presence of BZ-like activity using a radiometric assay. Our findings of significantly increased activity have since been confirmed by other investigators. Subsequently we discovered fairly large quantities of BZs in blood and urine of these patients, the level of which correlated with the degree of severity of HE. The ultimate finding that this BZ-like activity was due to diazepam, desmethyldiazepam and some other 1-4 benzodiazepine compounds again raised the possibility that our findings were due to occult ingestion of commercially synthesized BZs even though similar findings were made in animal models of HE. Concurrently with this work it became apparent that the food cycle contains trace amounts of the same BZs. However, the levels of "natural BZs" in food cannot yet explain the high levels of BZs seen in patients with HE. The source for this high level of BZs is currently our main area of research.
Assuntos
Benzodiazepinas/metabolismo , Encefalopatia Hepática/metabolismo , Animais , Diazepam/metabolismo , Encefalopatia Hepática/etiologia , Humanos , Modelos Biológicos , Nordazepam/metabolismoRESUMO
Body fluids from patients with hepatic encephalopathy and from controls with no renal or hepatic disease were assayed for benzodiazepine immunoreactivity and benzodiazepine-receptor-binding activity. The subjects had taken no synthetic benzodiazepines for at least 3 months. Benzodiazepine receptor binding in cerebrospinal fluid was significantly higher in hepatic encephalopathy patients than in controls (210 [SE 50.2] vs 40.7 [7.3] oxazepam equivalents [ng/ml]). The severity of hepatic encephalopathy was directly and significantly correlated with the level of benzodiazepine activity by radioreceptor assay or radioimmunoassay in urine and in plasma. Benzodiazepine activity equivalent to levels of more than 900 ng/ml was found in patients with advanced encephalopathy. Although the chemical identity and source of this substance (or substances) are still unknown, its properties and the estimated levels of activity suggest it may have a role in the pathogenesis of the neural inhibition seen in hepatic encephalopathy.
Assuntos
Benzodiazepinas/metabolismo , Encefalopatia Hepática/metabolismo , Receptores de GABA-A/metabolismo , Benzodiazepinas/sangue , Benzodiazepinas/urina , Encefalopatia Hepática/sangue , Encefalopatia Hepática/líquido cefalorraquidiano , Encefalopatia Hepática/urina , Humanos , Radioimunoensaio , Ensaio Radioligante , Receptores de GABA-A/líquido cefalorraquidiano , Estudos de Amostragem , Índice de Gravidade de DoençaRESUMO
Based on the reversal of hepatic encephalopathy in animal models with administration of specific benzodiazepine receptor antagonists, it has been postulated that this syndrome may be mediated by an endogenous benzodiazepine-like compound. In this study using a radio-receptor assay, evidence for the existence of this substance has been demonstrated in cerebrospinal fluid but not sera of rabbits with hepatic encephalopathy due to galactosamine-induced hepature failure. Cerebrospinal fluid from rabbits with hepatic encephalopathy caused 36.1 +/- 5.03% displacement of 3H-Ro 15-1788 specific binding to cortical benzodiazepine receptors, compared to 11.7 +/- 0.76% in control animals (P less than 0.01). The benzodiazepine receptor binding activity has been shown to behave as a competitive inhibitor of radiolabeled benzodiazepine receptor binding. The finding of endogenous benzodiazepine binding activity affords a potential explanation for the amelioration of hepatic encephalopathy in this model with the administration of benzodiazepine receptor antagonists.