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Naloxone (Narcan) treatment in depression: clinical observations and effects on CSF endorphins and monoamine metabolites.

Various dysphoric states are seen both in mood depression and on taking opiates. On the hypothesis that opiate antagonists would alter mood level, naloxone (Narcan), 0.4--0.8 mg t.i.d., was given to five depressed patients in six trials for a duration of 6--12 days. The CSF endorphin and monoamine metabolite content was analyzed before and after naloxone treatment. We observed no positive effect on mood level. However, an abrupt worsening of symptoms was noted in two cases on discontinuation of treatment. Decreasing values of endorphin Fraction I as a result of treatment was noted as a general trend. Fraction II, although elevated, showed no distinct trend. 5HIAA increased in four of the six trials. The results suggest that naloxone treatment changes endorphin and serotonin activity, though not to a clinically observable extent.

Adult

Selected ion monitoring assay for biogenic amine metabolites and probenecid in human lumbar cerebrospinal fluid.

Details are presented of an improved selected ion monitoring assay for the major biogenic amine metabolites and probenecid in human lumbar cerebrospinal fluid (CSF). The metabolites and probenecid are simultaneously extracted with ethyl acetate from an acidified aqueous phase, and are simultaneously converted to pentafluoropropionyl esters by reaction with pentafluoropropionic anhydride and pentafluoropropanol. The esters of the metabolites are analyzed following a single injection of the derivatized sample onto the gas chromatographic column, while the ester of probenecid is analyzed following a separate injection onto the gas chromatographic column. Quantitation is achieved using for internal standards dueterated analogues of the metabolites and a chemical analogue of probenecid. Data are presented on the concentration of free and conjugated forms of the metabolites in lumbar CSF taken from healthy volunteers.

Biogenic Amines

Biogenic amines in 47, XYY syndrome.

47, XYYs represent a high percentage of patients admitted in security settings for aggressiveness. By using a polygraphic technique and amine metabolite estimation in the cerebrospinal fluid (CSF), an attempt was made to evaluate the functional activity of the central aminergic system of these patients. No drastic change was observed in sleep patterns of XYYs. The estimation of CSF amine metabolites revealed a normal value for homovanillic acid, but a significant decrease of 5-hydroxyindoleacetic acid turnover.

Adult

Treatment of depression with tricyclic drugs--pharmacokinetic and pharmacodynamic aspects.

A series of studies on the pharmacokinetic and pharmacodynamic properties of some tricyclic antidepressants is reviewed. During treatment with the same oral dose of these drugs, patients develop widely differing plasma levels. The importance of this variability for the clinical effects has been studied in detail for the monomethylated compound, nortriptyline. There is an association between side-effects and high plasma levels of this drug. In endogenously depressed patients, the relationship between plasma level and effect appears to be curvilinear. The tricyclic antidepressants differ in their capacity to inhibit transmitter uptake into noradrenaline- and serotonin neurons respectively. Nortriptyline is a preferential noradrenaline uptake inhibitor, while the dimethylated compound, chlorimipramine also has a profound influence on serotonin neurons. These differential effects are also reflected in changes in the levels of the transmitter metabolites in cerebrospinal fluid (CSF). The CSF studies have also supported the hypothesis of a biochemical heterogeneity of the depressive syndrome. The levels of the serotonin metabolite, 5-HIAA were bimodally distributed in CSF. In patients with a low level of 5-HIAA there was a significant correlation between the CSF metabolite level and the severity of the depression, and these patients also appeared to be more suicide-prone than those with higher 5-HIAA levels. These patients seemed to be less amenable to treatment with nortriptyline. The effect of chlorimipramine treatment in this subgroup of depressives is presently being explored.

Antidepressive Agents, Tricyclic

Cerebrospinal fluid monoamine metabolites and cyclic nucleotides in chronic schizophrenic patients with tardive dyskinesia or drug-induced tremor.

Lumbar CSF HVA, MHPG, 5HIAA, cAMP, and cGMP were measured in 12 chronic schizophrenics with tardive dyskinesia before and 3 weeks after sodium valproate (VPA) or cyproheptadine treatment. HVA levels significantly decreased and cAMP and cGMP levels significantly increased during the administration of VPA or cyproheptadine. There were no significant correlations between the degree of improvement in tardive dyskinesia and the changes of amine metabolities or cyclic nucleotides. None of the pretreatment values for CSF amine metabolites or cyclic nucleotides were different from those of 15 chronic schizophrenics without tardive dyskinesia as controls. Decrease of HVA and increase of cGMP during the treatment might indicate the normalization of dopaminergic-cholinergic imbalance in the brain. Furthermore, significantly low levels of 5HIAA were observed in the patients with drug-induced tremor. It is suggested that neuroleptic-induced tremor may be attributed to serotonergic dysfunction in the brain.

Adult

Effect of peripheral decarboxylase inhibition on HVA and 5HIAA in cerebrospinal fluid of depressed patients.

The effects of benserazide on the level of homovanillic acid and 5-hydroxyindoleacetic acid in CSF have been investigated in 1 manic and 11 depressed patients. Benserazide induced no change on both metabolites. This negative result supports the view that monoamine metabolites in CSF, in the absence of loading with an exogenous precursor, originate mostly from brain parenchyma, without significant contribution of the metabolism in capillary walls.

Adult

Cerebrospinal fluid amine metabolites after combined amitriptyline-triiodothyronine treatment of depressed women.

Levels of 5-hydroxyindoleacetic acid and homovanillic acid were measured in cerebrospinal fluid from 33 depressed women with no clinical response to amitriptyline, before and after combination treatment with triiodothyronine. Although the latter showed significant clinical improvement, changes in CSF amine metabolites did not differ significantly from a control group of 16 therapy-resistant depressed women receiving higher doses of amitriptyline. Possible explanations for the mechanism of action of triiodothyronine are discussed.

Adult

Alterations in plasma and CSF amino acids, amines and metabolites in hepatic coma.

The dog with an end-to-side portacaval shunt (PCS) has been extensively used as a model to investigate hepatic encephalopathy (HE) as it demonstrates a plasma amino acid pattern similar to patients with chronic liver disease. In adult mongrel dogs, the effect of PCS on plasma and CSF amino acids, octopamine (OCT), phenylethanolamine (PEA) and CSF 5-hydroxyindolacetic acid (5-HIAA), were studied. Moreover, the effect of correction of plasma amino acids by infusional techniques was investigated.Tyrosine, tryptophan and phenylalanine levels increased dramatically during the development of HE in plasma and CSF, while valine, leucine and isoleucine decreased in plasma only, but CSF levels remained stable. Plasma and CSF octopamine and phenylethanolamine and CSF 5-HIAA increased markedly as clinical features in the dogs' behavior, characteristic of hepatic encephalopathy occurred, including hypersalivation, ataxia, flapping tremor, somnolence and finally coma. Once in coma, the dogs were infused with an amino acid mixture (F080) calculated to normalize the plasma amino acid pattern. After one to eight hours, the dogs began to awake. Simultaneously, blood, and CSF aromatic amino acids returned to their control values, as did OCT, PEA and CSF 5-HIAA. If F080 infusion was stopped, biochemical alterations would appear within one week, again accompanied by clinical hepatic encephalopathy.The results indicate that the altered levels of aromatic and branched chain amino acids, octopamine and PEA in plasma and CSF correlate well with the development of HE and that correction of the plasma amino acid abnormalities improves encephalopathy simultaneously with correction of neurotransmitter derangements in CSF.

Amines

Metabolic control of respiratory neuronal activity and the accompanying changey-expiratory neurons.

Expiratory-related neurons have been classified according to their phase relation within the respiratory cycle, their response to lung distension and collapse (alpha- and beta-type), and to hyperventilation (tonic firing denoted by "+", cessation of activity by "-"). The dorsal surface of the medulla oblongata was superfused with a metabolite-containing CSF solution and the activity of expiratory (E) and inspiratory-expiratory (IE) neurons was extracellulary recorded. The neuronal sub-types established by their functional behaviour could equally be distinguished by their differential response to one or several metabolites. In contrast to inspiratory (I) neurons, Ealpha- Ebeta-, Ebeta- and IEbeta- neurons are inhibited by 3.5 mM AMP, but are activated by 10 mM citrate (with the exception of Ebeta+ units). Furthermore I cells are activated by ATP, while Ealpha and Ebeta units become inhibited. Vagotomy in some instances affected the response of some IEbeta units. An increase in spike density of IEbeta+ and Ealpha- cells is paralleled by a reduction of both the respiratory rate and the tidal volume, while a lower spike density in IEbeta+, IEbeta- and Ealpha- units is accompanied by increases in respiratory rate and tidal volume. In the case of Ebeta+ and Ebeta- cells lower activity is associated with an increased tidal volume. No metabolite-induced changes could be obtained with cardiovascular or unspecific reticular neurons.

Adenosine Monophosphate

Metabolic control of respiratory neuronal activity and the accompanying changes in breathing movements of the rabbit. 1. Mainpulation of inspiratory and expiratory-inspiratory neurons.

The property of the neuronal membrane to be permeable to metabolic modifiers of two regulatory enzymes has been utilized to manipulate the spike activity of inspiratory (I) and expiratory-inspiratory (EI) neurons of the bulbar respiratory centre. The neurons have been classified according to their response to lung distention or collapse (alpha- or beta-type) and to hyperventilation (tonic firing denoted by "+", cessation of activity by "-"). Using extracellular microelectrodes for single unit recording, the medulla oblongata was superfused with a metabolite-containing CSF. The various neuronal sub-types exhibited a differential activating or inhibitory response to one or several metabolic effectors. For example Ialpha+ units were activated by 5 mM glucose-6-phosphatase (G-6-P) and 3.5 mM 3-phosphoglycerate (3-PGA), which both inhibited Ibeta+ neurons, while 5 mM AMP inhibited Ialpha+ much more strongly than Ibeta+ cells. The spike density of Ialpha- and Ibeta- neurons was increased in the presence of 2.5 mM fructose-6-phosphate and 3.5--5 mM AMP, but became reduced by G-6-P. In contrast, 3 mM fructose-1,6-diphosphate and 5 mM 3-PGA activated the Ialpha- but inhibited the Ibeta- neurons. The EIbeta units were characteristically activated by 10 mM citrate, which inhibited all I-type neurons. Activations of the Ialpha and Ibeta neurons led to an accelerated respiratory rate and a higher tidal volume, while the opposite was true for EIbeta neurons. Intravenous injection of metabolites could not duplicate the striking effects under local applications.

Animals

Comparative study of the effect of ethyl apovincaminate and xantinol nicotinate in cerebrovascular diseases. Immediate drug effects on the concentrations of carbohydrate metabolites and electrolytes in blood and CSF.

Randomly selected 34 cerebrovascular patients were treated with ethyl apovincaminate (RGH-4405, Cavinton) and 109 with xanitinol nicotinate. The effects of drugs given in slow i.v. infusions on the concentration of carbohydrate metabolites and electrolytes in serum and CSF were observed. Cavinton improved the paresis in 60.6% of patients while xantinol nicotinate did so only in 47.1%. On the basis of the biochemical changes it can be concluded that Cavinton enhances both the glycolytic and the oxidative glucose breakdown in CNS.

Brain

A mass fragmentographic method for the determination of chlorpromazine and two of its active metabolites in human plasma and CSF.

A mass fragmentographic method for the quantitation of chlorpromazine (CPZ), mono-demethyl-chlorpromazine (nor1-CPZ), and 7-hydroxy-chlorpromazine (7-OH-CPZ) in plasma, cerebrospinal fluid, and tissues has been developed. The deuterated analogues of the compounds are used as internal standards. The high specificity was ascertained by multiple ion determination. The experimental error is below 10%. The sensitivity allows determination of sub ng quantities of CPZ per ml cerebrospinal fluid. The method has been applied to the analysis of drug concentrations in plasma and cerebrospinal fluid (CSF) of chlorpromazine-treated patients. The amount of CPZ in CSF was about 3% of the plasma level. The CPZ levels in plasma and CSF were significantly correlated.

Chlorpromazine

Individual differences in basal cisternal cerebrospinal fluid 5-HIAA and HVA in monkeys. The effects of gender, age, physical characteristics, and matrilineal influences.

We examined the effects of gender, age, weight, length, body shape (ectomorphy), and matrilineal influences on cisternal cerebrospinal fluid 5-hydroxyindoleacetic acid (CSF 5-HIAA) and homovanillic acid (HVA) in 78 socially living adult and adolescent vervet monkeys. CSF 5-HIAA and the 5-HIAA:HVA ratio were higher (by 27% and 18%, respectively) in females. In both sexes, CSF 5-HIAA and the 5-HIAA:HVA ratio increased with age. Neither weight nor length were independently related to CSF 5-HIAA or HVA; however, shape correlated with CSF 5-HIAA and HVA in males (higher in thin, long subjects). Male offspring had CSF 5-HIAA concentrations and 5-HIAA:HVA ratios that were significantly closer to their mothers than did age-matched, maternally unrelated males. Repeated measures of CSF 5-HIAA and HVA in another 22 males living in unvarying settings showed that individual differences in these measures persisted over time. The data underscore the impact of gender, age, and matrilineal relationships on individual differences in CSF monoamine metabolites and highlight the importance of controlling for age and gender in neuropharmacological investigations of clinical populations.

Aging

Effect of ECT and imipramine treatment on the concentration of 5-hydroxyindoleacetic acid (5HIAA) and homovanillic acid (HVA) in the cerebrospinal fluid of depressed patients.

The influence of probenecid administration on 5HIAA and HVA concentrations in the CSF of depressed patients, was studied before and after treatment with imipramine or ECT. The average increase of the two metabolites in the CSF after probenecid was similar in the untreated depressed patients and in the same patients improved after both imipramine or ECT treatment. The treatment determined a significant increase in the CSF concentration of the acid metabolites also before the probenecid administration.

Adult

Uptake of 5(125I) iodo-2-deoxyuridine (IDU) in plasma and cerebrospinal fluid in a case of herpes encephalitis with a comparative study on the uptake in plasma, cerebrospinal fluid and brain tissue in dogs.

A case of herpes encephalitis diagnosed by brain biopsy and treated with 5-iodo-2-deoxyuridine (IDU) is presented. The infection occurred in a previously well 19-year-old female patient. Plasma and cerebrospinal fluid (CSF) uptake of the substance was determined using 125I labelled IDU. Top CSF levels of IUD and metabolites of less than 4 microgram/ml, about 1/10 of the corresponding plasma level, were obtained after 6 hours of continuous infusion. The result is discussed and compared with a similar study made on 5 healthy beagle dogs where in addition the levels obtained in various parts of the brain were determined. In the animal experiment a mean value of 2.5 microgram/ml of IDU and metabolites was obtained in the CSF after 8 hours, less than 1/20 of the plasma level. The levels in brain tissue were only slightly higher than in the CSF. The causes of therapeutic failures with IDU treatment are discussed.

Adult

Reduction of MOPEG levels in cerebrospinal fluid of psychotic women after electroconvulsive treatment.

The effect of ECT on concentrations of monoamine metabolites in lumbar CSF of psychotic women with a schizophrenic symptomatology was examined. After a series of ECT there was a significant reduction of the concentration of the major noradrenaline metabolite, MOPEG. Levels of HVA, 5-HIAA, prolactin, or total protein in CSF were not significantly influenced by treatment. The results indicate a specific alteration of central noradrenaline metabolism in relation to ECT.

Biogenic Amines

Monoamine metabolites in cerebrospinal fluid during treatment with clonidine or alprenolol.

Lumbar cerebrospinal fluid (CSF) concentrations of the major metabolites of noradrenaline (4-hydroxy-3-methoxyphenyl glycol, HMPG), serotonin (5-hydroxyindoleacetic acid) and dopamine (homovanillic acid) were measured before and during the administration of clonidine or alprenolol to hypertensive patients. The noradrenaline receptor stimulant clonidine significantly decreased the CSF level of HMPG, but there was no consistent change in the concentration of serotonin or dopamine metabolites. Patients on alprenolol showed no change in the levels of these metabolites in CSF.

Adult