Brain Tryptophan/Serotonin Perturbations in Metabolic Encephalopathy and the Hazards Involved in the Use of Psychoactive Drugs

Bengtsson, Finn

doi:10.1007/978-1-4615-4709-9_20

Cited by 12 publications

(5 citation statements)

References 94 publications

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“…It is important to recall that the amount of the drug given in the present study, a body weight adjusted dose‐equal treatment, led to the PCS rats being given a lower absolute amount of citalopram than controls, and yet they displayed over three times higher serum drug levels in steady‐state. This finding alone support the contention that liver impaired patients, when treated with this SSRI, and probably most other CNS active drugs, would benefit from applying therapeutic drug monitoring in clinical practice (Bengtsson et al 1997; Bengtsson 1999).…”

Section: Discussionsupporting

confidence: 74%

“…Notably, though, they found that psychometric test performance improved rather than worsened after fluvoxamine administration. Nevertheless, in order to adequately assess this complex problem when such psychoactive drugs are used in liver impaired subjects, it is important to consider and study both pharmacokinetic and pharmacodynamic parameters, especially since the 5‐HT system in the brain is likely to be perturbed per se in this situation (Bengtsson 1992 & 1999; Bengtsson et al 1997).…”

Section: Discussionmentioning

confidence: 99%

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Sustained Citalopram Treatment in Experimental Hepatic Encephalopathy: Effects on Entrainment to the Light‐Dark Cycle and Melatonin

Kugelberg

Apelqvist

Carlsson

et al. 2006

Basic Clin Pharma Tox

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Patients with chronic hepatic encephalopathy often display altered diurnal rhythm as well as other affective disturbances which motivate treatment with antidepressants. We investigated the effects of sustained treatment with citalopram (10 mg/kg daily, 10 days) on 24-hr behavioural open-field activities in portacaval-shunted (PCS) rats and shamoperated control rats. In addition, the daytime and nighttime serum melatonin levels, as well as the serum concentrations of the enantiomers of citalopram and its metabolites, were analyzed. Untreated PCS rats showed reduced locomotor and rearing activities during nighttime. Citalopram treatment resulted in elevated behavioural activity in the PCS rats during night, indicative of an improved entrainment to the light-dark cycle, whereas no behavioural effect could be observed in sham rats. Higher melatonin levels in both PCS and sham rats were observed during nighttime compared with daytime, but the untreated PCS rats also showed higher daytime melatonin level than the corresponding sham group. Citalopram treatment seemed not to have any major effect on the melatonin levels. Higher serum levels of both citalopram and metabolites were observed in PCS rats as compared to sham rats. An altered ratio between the S-and R-enantiomers could also be observed in the PCS rats. In conclusion, the present data support the contention of a disturbed diurnal rhythm, and that the melatonin activity may be altered, in chronic hepatic encephalopathy. The citalopram treatment resulted in similar behavioural performances and daytime serum melatonin levels in PCS rats and controls, although pharmacokinetic differences were present between the groups.

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Section: Discussionsupporting

confidence: 74%

Section: Discussionmentioning

confidence: 99%

Sustained Citalopram Treatment in Experimental Hepatic Encephalopathy: Effects on Entrainment to the Light‐Dark Cycle and Melatonin

Kugelberg

Apelqvist

Carlsson

et al. 2006

Basic Clin Pharma Tox

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“…Decarboxylation of Trp to tryptamine occurs in both the CNS and the periphery, and these, together with intestinal bacterial production of tryptamine and the ability of the latter to cross the blood-brain barrier, all account for the origin of brain tryptamine (Bender, 1982 and references cited therein). Tryptamine possesses a number of behavioural, physiological and pharmacological properties and has been implicated in a number of psychiatric conditions (Mousseau, 1993) and also in hepatic encephalopathy (Bengtsson, 1999). The transamination pathway leads, via an unstable intermediate, to the production of IPA, a metabolite shown to possess a variety of interesting behavioural, biochemical and pharmacological properties, including inhibition of liver TP activity, elevation of brain 5-HT and kynurenic acid levels, enhancement of melatonin turnover in the pineal gland, antioxidant and free-radical scavenging effects, antagonism of excitatory amino acid effects, anxiolytic effects, suppression of circulating glucocorticoid levels and inhibition of their damaging effects in the hippocampus (for reviews, see Politi et al 1996Politi et al , 1999.…”

Section: The Decarboxylation and Transamination Pathwaysmentioning

confidence: 99%

Tryptophan metabolism in alcoholism

Badawy

2002

NRR

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Acute and chronic alcohol (ethanol) intake and subsequent withdrawal exert major effects on tryptophan (Trp) metabolism and disposition in human subjects and experimental animals. In rats, activity of the ratelimiting enzyme of Trp degradation, liver Trp pyrrolase (TP), is enhanced by acute, but inhibited after chronic, ethanol administration, then enhanced during withdrawal. These changes lead to alterations in brain serotonin synthesis and turnover mediated by corresponding changes in circulating Trp availability to the brain. A low brain-serotonin concentration characterizes the alcohol-preferring C57BL/6J mouse strain and many alcoholpreferring rat lines. In this mouse strain, liver TP enhancement causes the serotonin decrease. In man, acute ethanol intake inhibits brain serotonin synthesis by activating liver TP. This may explain alcohol-induced depression, aggression and loss of control in susceptible individuals. Chronic alcohol intake in dependent subjects may be associated with liver TP inhibition and a consequent enhancement of brain serotonin synthesis, whereas subsequent withdrawal may induce the opposite effects. The excitotoxic Trp metabolite quinolinate may play a role in the behavioural disturbances of the alcohol-withdrawal syndrome. Some abstinent alcoholics may have a central serotonin deficiency, which they correct by liver TP inhibition through drinking. Further studies of the Trp and serotonin metabolic status in long-term abstinence in general and in relation to personality characteristics, alcoholism typology and genetic factors in particular may yield important information which should facilitate the development of more effective screening, and preventative and therapeutic strategies in this area of mental health.

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“…Due to ethical problems involved in clinical trials of liver-impaired humans, a model comprising the chronic portacaval shunted (PCS) rat 3 can be used for this purpose. 4 The antidepressant venlafaxine inhibits the reuptake of serotonin and noradrenaline and has some effect on the reuptake of dopamine. 5 The main venlafaxine metabolites in man are O-desmethylvenlafaxine (ODV) and N-desmethylvenlafaxine (NDV).…”

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confidence: 99%

Disposition of venlafaxine enantiomers in rats with hepatic encephalopathy after chronic drug treatment

et al. 2002

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Portacaval shunted (PCS) rats, a model of hepatic encephalopathy, and control animals were administered racemic venlafaxine for 14 days (10 mg/kg). The levels of the S- and R-enantiomers and the S/R-enantiomer ratios of venlafaxine and its metabolites were assessed by an enantiomer-selective chromatographic assay in serum, brain parenchyma, and brain dialysate of both groups. Higher levels of the S- and R-enantiomers of venlafaxine were found in serum and brain of PCS vs. normal rats (median values of S- and R-venlafaxine in serum: 290 and 201 nM in PCS; 97 and 66 nM in normal rats; median values of S- and R-venlafaxine in cortex: 956 and 939 nM in PCS; 357 and 318 nM in normal rats). Interestingly, similar S/R-venlafaxine ratios were observed in PCS and normal rats both in serum (S/R = 1.4) and brain compartments (S/R = l.0-1.1). These findings may have clinical relevance for the safety of venlafaxine in chronic hepatic encephalopathy.

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Brain Tryptophan/Serotonin Perturbations in Metabolic Encephalopathy and the Hazards Involved in the Use of Psychoactive Drugs

Cited by 12 publications

References 94 publications

Sustained Citalopram Treatment in Experimental Hepatic Encephalopathy: Effects on Entrainment to the Light‐Dark Cycle and Melatonin

Sustained Citalopram Treatment in Experimental Hepatic Encephalopathy: Effects on Entrainment to the Light‐Dark Cycle and Melatonin

Tryptophan metabolism in alcoholism

Disposition of venlafaxine enantiomers in rats with hepatic encephalopathy after chronic drug treatment

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