Biomedical subjects

G B Baker

Publications and source records attributed to G B Baker.

At least 109 records · Page 6Linked to original sources

PubMed1993

Effects of two substituted hydrazine monoamine oxidase (MAO) inhibitors on neurotransmitter amines, gamma-aminobutyric acid, and alanine in rat brain.

Time- and dose-response analyses were undertaken to investigate the effects of the substituted hydrazine monoamine oxidase (MAO) inhibitors iproniazid and nialamide on the following: MAO-A and -B activity; levels of gamma-aminobutyric acid (GABA), alanine (ALA), and the neurotransmitter amines dopamine, noradrenaline, and 5-hydroxytryptamine (serotonin) and their acid metabolites; and the activity of GABA-transaminase and ALA-transaminase. The results showed that these drugs are relatively potent MAO inhibitors but, unlike the unsubstituted hydrazine MAO inhibitor phenelzine, they do not produce increased GABA and ALA levels in brain. These experiments suggest that a free hydrazine group is necessary for MAO inhibitors to also have marked effects on GABA and ALA.

Alanine↗

PubMed1993

Effects of age and of chronic antidepressant treatment on [3H]tryptamine and [3H]dihydroalprenolol binding to rat cortical membranes.

1. The effects of age and of chronic antidepressant treatment on [3H]tryptamine and [3H]dihydroalprenolol binding site density were measured in brain cortical membranes from male Sprague-Dawley rats. 2. The density but not the affinity of [3H]tryptamine binding sites was increased in 18-month-old rats relative to 3-month-old rats. Neither the density nor the affinity of [3H]dihydroalprenolol binding sites was affected by age. 3. Chronic administration (28 days s.c. via Alzet osmotic minipumps) of tricyclic antidepressant drugs (daily doses: imipramine.HCl, 30 mg kg-1; desipramine.HCl, 10 mg kg-1; clomipramine.HCl, 10 mg kg-1) resulted in decreases in [3H]dihydroalprenolol binding site density but no changes in [3H]tryptamine binding site density; no changes in affinity of either site were observed. 4. Chronic administration (s.c. via Alzet osmotic minipumps) of monoamine oxidase inhibitor antidepressant drugs (daily doses: tranylcypromine.HCl, 0.5 and 1.0 mg kg-1; phenelzine sulfate, 5 and 10 mg kg-1, each for 28 days; clorgyline.HCl, 1.0 mg kg-1; (-)-deprenyl.HCl, 1.0 mg kg-1, each for 14 days) resulted in decreases in [3H]tryptamine binding site density, without any effects on the affinity of this site. In addition, each of these monoamine oxidase inhibitors except (-)-deprenyl resulted in a decrease in [3H]dihydroalprenolol binding site density. No affinity changes were observed. 5. These data indicate that the [3H]tryptamine binding site exhibits physiological changes with aging and is differentially sensitive to the actions of tricyclic antidepressants and monoamine oxidase inhibitor antidepressants, respectively.

Age Factors↗

PubMed1993

Trace amines and Tourette's syndrome.

There has been considerable interest in recent years in possible neurochemical abnormalities in Tourette's Syndrome (TS). In studies combining neuropsychological and neurochemical measurements, we have investigated the possible roles of trace amines in this disorder. Urinary levels of free beta-phenylethylamine (PEA) and plasma levels of its precursor amino acid phenylalanine were decreased in TS patients when compared to values in normal children. These urinary PEA levels in TS patients were inversely related to several scores from the Tourette's Syndrome Global Scale (TSGS). Further investigation of the group of subjects with low urinary PEA indicated that they also had low levels of MHPG, normetanephrine, 5-HT and m- and p-tyramine. Patients with low PEA were also compared on an extensive battery of neuropsychological measures and observed to perform significantly worse than TS patients with normal urinary PEA levels. Biochemical measurements also suggest a possible abnormality in tryptamine turnover in TS since urinary levels of indole-3-acetic acid (IAA; the acid metabolite of tryptamine) are significantly lower in TS patients than in normal controls.

Biogenic Amines↗

PubMed1993

Urinary excretion of bioactive amines and their metabolites in psychiatric patients receiving phenelzine.

Phenelzine [2-phenylethylhydrazine] (PLZ), a potent inhibitor of monoamine oxidase (MAO)-A and -B, is used widely in psychiatry. We have studied the effects of PLZ administration on urinary excretion of several bioactive amines and their metabolites in psychiatric patients. Urine samples (24-hour) were collected prior to treatment and again at 2 and 4 weeks of treatment with PLZ (30-90 mg daily in divided doses). Amines and metabolites analyzed included 2-phenylethylamine (PEA), m- and p-tyramine (m- and p-TA), phenylacetic acid (PAA), m- and p-hydroxyphenylacetic acid (m- and p-OH-PAA), tryptamine (T), 5-hydroxytryptamine (5-HT), 5-hydroxyindoleacetic acid (5-HIAA), normetanephrine (NME), 3-methoxy-4-hydroxyphenylglycol (MHPG), 3-methoxytyramine (3-MT), and homovanillic acid (HVA). Levels of PEA, p-TA, 5-HT, and T were elevated during treatment with PLZ, but no significant changes in urinary excretion of the acid metabolites PAA, p-OH-PAA, and 5-HIAA were observed. Urinary levels of the noradrenaline metabolites NME and MHPG were increased and decreased, respectively; a similar pattern was observed with the dopamine metabolites 3-MT and HVA. There was an elevation in levels of m-TA and a decrease in its acid metabolite m-OH-PAA during the treatment with PLZ.

Adult↗

PubMed1993

Analysis of imipramine and three metabolites produced by isozyme CYP2D6 expressed in a human cell line.

1. A commercially-available human cytochrome P450 isozyme (CYP2D6) preparation was used in imipramine metabolism studies. This isozyme catalysed both aromatic C-oxidation and N-demethylation. 2-Hydroxyimipramine was the major metabolite; desipramine was isolated in a significant amount and 2-hydroxydesipramine was a trace metabolite. 2. To prevent decomposition of metabolites during the analytical procedure, the metabolism mixture was derivatized with acetic anhydride prior to extraction, and the derivatized metabolites were separated and quantified by g.l.c. with N/P detection. The analytical procedure had excellent sensitivity and was capable of routinely quantifying imipramine and its metabolites down to the 0.36 nmol level. 3. In excess of 90% of drug and metabolites was consistently recovered when metabolism was conducted over a 5-60-min duration. 4. The formation of the secondary metabolite, 2-hydroxydesimipramine, from imipramine proceeds by two pathways, via desipramine and via 2-hydroxyimipramine; the former is the preferred pathway. 5. CYP2D6 catalyses C-hydroxylation of imipramine to 2-hydroxyimipramine more efficiently than its N-demethylation to desipramine. Also, the C-hydroxylation of imipramine to 2-hydroxyimipramine proceeds more efficiently than the conversion of desipramine to 2-hydroxydesipramine.

Catalysis↗

PubMed1993

Metabolism of trimipramine in vitro by human CYP2D6 isozyme.

In vitro metabolism of the tricyclic antidepressant trimipramine using a commercial preparation of human CYP2D6 isozyme expressed in a human cell line is described. 2-Hydroxytrimipramine and a previously unreported metabolite, 2,10- or 2,11-dihydroxytrimipramine were isolated. Their structures were determined by gas chromatography/mass spectroscopy of underivatized and derivatized extracts. Acetylation of the new metabolite resulted in dehydration at C10 to give 10,11-dehydro-2-acetoxytrimipramine. No N-dealkylation of trimipramine was observed. Prior administration of quinidine produced a large reduction in the metabolic oxidation of trimipramine with CYP2D6 while prior administration of quinine had no effect. The use of this CYP2D6 isozyme preparation in vitro is of value in the identification of possible in vivo substrates for the human CYP2D6 isozyme.

Cell Line↗

PubMed1992

A gas chromatographic procedure for separation and quantitation of the enantiomers of the antidepressant tranylcypromine.

A novel assay procedure has been developed that allows for the separation and quantification of the enantiomers of the monoamine oxidase inhibitor tranylcypromine (TCP) in brain and liver of rats. The analytical method involves extraction of the drug from rat tissue with an organic solvent. TCP is then derivatized with S-(-)-N-(trifluoroacetyl)-prolyl chloride to allow gas chromatographic analysis of the resulting diastereoisomers. Conditions for analysis by a gas chromatograph equipped with a nitrogen-phosphorus detector and a capillary column are described. The method has been applied to the separation and quantification of the enantiomers of TCP in samples of brain and liver of rats that had been injected with this drug alone and after pretreatment with iprindole, a drug known to block aromatic ring hydroxylation.

Animals↗

PubMed1992

Simultaneous determination of fluoxetine and norfluoxetine enantiomers in biological samples by gas chromatography with electron-capture detection.

An electron-capture gas chromatographic procedure was developed for the simultaneous analysis of the enantiomers of fluoxetine and norfluoxetine. The assay involves basic extraction of these enantiomers from the biological samples, followed by their conversion to diastereoisomers using the chiral derivatizing reagent (S)-(-)-N-trifluoroacetylprolyl chloride. The method was utilized to detect and measure the quantity of these enantiomers in plasma and urine of patients and in liver and brain tissue of rats treated with (R,S)-fluoxetine.

Animals↗

PubMed1992

Effects of the antidepressant/antipanic drug phenelzine on GABA concentrations and GABA-transaminase activity in rat brain.

The effects of long-term (28-day) administration of several antidepressant/antipanic drugs [imipramine, desipramine, tranylcypromine and phenelzine (PLZ)] on gamma-aminobutyric acid-tranaminase (GABA-T) activity and GABA levels were investigated in rat frontal cortex. Of the drugs investigated, only PLZ inhibited GABA-T and elevated GABA levels. Additional short-term experiments were conducted with PLZ, and they demonstrated a dose-dependent inhibition of GABA-T in rat whole brain. Time-response studies on inhibition of GABA-T in whole brain demonstrated that at a dose of PLZ of 15 mg/kg i.p. inhibition of GABA-T remained relatively constant from 1 to 8 hr and that the enzyme was still inhibited by 23% at 24 hr after PLZ administration.

4-Aminobutyrate Transaminase↗

PubMed1992

4-Methoxytranylcypromine, a monoamine oxidase inhibitor: effects on biogenic amines in rat brain following chronic administration.

4-Methoxytranylcypromine (MeOTCP), a ring-substituted analogue of the monoamine oxidase (MAO)-inhibiting antidepressant tranylcypromine (TCP), was investigated in the rat after chronic (28-day) administration and the results compared with those observed with TCP using equimolar doses of both drugs. At the dose tested, MeOTCP produced a greater inhibition of type A MAO in brain, liver, and heart than did TCP. Both drugs caused a reduction in the specific binding to beta-adrenergic and tryptamine receptors in cortex from brain. MeOTCP produced a marked increase in 5-hydroxytryptamine levels in pons-medulla, hypothalamus, and hippocampus relative to values in vehicle-treated rats and also produced a significant increase in these levels over those observed in the TCP-treated rats.

Animals↗

PubMed1992

Electron-capture gas chromatographic procedure for simultaneous determination of amphetamine and N-methylamphetamine.

An electron-capture gas chromatographic procedure for the simultaneous determination of amphetamine and N-methylamphetamine in biological samples is described. The method employs extraction with the ion-pairing reagent bis(2-ethylhexyl)phosphoric acid, and back-extraction with 0.5 M hydrochloric acid. The hydrochloric acid phase is basified, and the amphetamines and the internal standard benzylamine are derivatized with pentafluorobenzenesulfonyl chloride prior to analysis on a gas chromatograph equipped with a capillary column. Levels of amphetamine and N-methylamphetamine have been determined in the urine and liver of rats treated chronically with (-)-deprenyl.

Amphetamine↗

PubMed1992

Chronic administration of the antidepressant-antipanic drug phenelzine and its N-acetylated analogue: effects on monoamine oxidase, biogenic amines, and alpha 2-adrenoreceptor function.

Phenelzine (PLZ), a nonselective monoamine oxidase inhibitor, is widely used in psychiatry for the treatment of panic disorder and depression. The effects of chronic (28-day) administration of PLZ (0.05 mmol/kg/day) and its N-acetylated analogue, 1-acetyl-2-(2-phenylethyl) hydrazine (N2-acetylphenelzine; N2AcPLZ; 0.10 mmol/kg/day), on alpha 2-adrenoreceptor function were investigated by use of a behavioral test on days 21 and 22. Rats treated with PLZ or N2AcPLZ displayed a significant attenuation of the suppressant effects of clonidine on spontaneous locomotor activity, compared with controls; these results suggest a reduced sensitivity of alpha 2-adrenoreceptors. By day 28, both PLZ and N2AcPLZ had produced greater than 85% inhibition of monoamine oxidases A and B in the brain, heart, and liver. Both drugs induced significant elevations of whole-brain levels of noradrenaline, 5-hydroxytryptamine, and dopamine, compared with those in controls. The levels of acid metabolites of dopamine and 5-hydroxytryptamine (homovanillic acid, 3,4-dihydroxyphenylacetic acid, and 5-hydroxyindole-3-acetic acid) were significantly reduced in both groups of drug-treated animals.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1992

Urinary indoleamines in Tourette syndrome patients with obsessive-compulsive characteristics.

Tourette syndrome patients with high levels of obsessive-compulsive symptoms were compared with patients without these symptoms on urinary measures of serotonin and its major metabolite, 5-hydroxyindoleacetic acid (5HIAA). Both groups were compared with normal controls, and it was hypothesized that patients with obsessive-compulsive symptoms would have lower levels of serotonin. Both groups of Tourette syndrome patients had lower levels than controls, but there was no difference between them. Obsessive symptoms were related to higher levels of 5HIAA and to a higher turnover of serotonin.

Adolescent↗

PubMed1992

Urinary amines in adults with Tourette's syndrome.

Urinary amines and their metabolites were examined in 32 adults who met DSM-III-R diagnostic criteria for Tourette's Syndrome. These patients were compared with a control group that was of similar age and sexual representation. Analyses revealed significantly lower levels of 3-methoxy-4-hydroxyphenylglycol and serotonin as well as the metabolites of several "trace" amines including indoleacetic acid and m- and p-hydroxyphenylacetic acid. These findings persisted when Tourette's Syndrome patients taking medications were eliminated from the analyses. These data are consistent with reports of neurotransmitter abnormalities in children with Tourette's Syndrome. The differences in several trace amine metabolites suggest that the pathophysiology in this disorder is complex and involves a number of neurotransmitter and neuromodulator systems.

Adolescent↗

PubMed1992

Insights into the mechanisms of action of the MAO inhibitors phenelzine and tranylcypromine: a review.

Although the non-selective monoamine oxidase inhibitors phenelzine and tranylcypromine have been used for many years, much still remains to be understood about their mechanisms of action. Other factors, in addition to the inhibition of monoamine oxidase and the subsequent elevation of brain levels of the catecholamines and 5-hydroxytryptamine, may contribute to the overall pharmacological profiles of these drugs. This review also considers the effects on brain levels of amino acids and trace amines, uptake and release of neurotransmitter amines at nerve terminals, receptors for amino acids and amines, and enzymes other than monoamine oxidase, including enzymes involved in metabolism of other drugs. The possible contributions of metabolism and stereochemistry to the actions of these monoamine oxidase inhibitors are discussed.

Amines↗

PubMed1991

The effects of serotonergic stimulation on hippocampal and neocortical slow waves and behavior.

The effect of central serotonergic stimulation on hippocampal and neocortical electrical activity and behavior was studied in freely moving rats by administering: (a) tranylcypromine followed by tryptophan, (b) fluoxetine followed by 5-hydroxytryptophan, or (c) p-chloroamphetamine alone. In all rats, scopolamine-resistant hippocampal rhythmical slow activity (RSA), thought to be dependent on brain serotonin, maintained its normal relation to behavior, occurring in close correlation with Type 1 behaviors (postural changes, turning of the head, walking). This RSA was generally absent during stereotyped behavior (head weaving, forepaw treading, hindlimb splaying and tremor). Scopolamine-resistant neocortical low-voltage fast activity (LVFA), also though to be dependent on brain serotonin, was present during Type 1 behaviors and also during stereotyped behavior. Most rats that developed a full stereotyped behavior syndrome had behavioral and electrocortical seizures which were associated with a reduction in the amplitude of hippocampal activity. These seizures were suppressed by methysergide or benserazide. Metergoline (and methysergide to a lesser extent) suppressed the stereotypic behaviors of the serotonin syndrome, resulting in a striking increase in the locomotion caused by central serotonergic stimulation. Such locomotion was accompanied by RSA and LVFA. It was concluded that increased serotonergic activity in the CNS causes an increase in motor activity and a correlated increase in scopolamine-resistant hippocampal RSA and scopolamine-resistant neocortical LVFA and suggested that metergoline blocks serotonin receptors mediating stereotyped behaviors, thereby permitting the expression of serotonin-mediated locomotion.

5-Hydroxytryptophan↗

PubMed1991

Phenylethylaminergic mechanisms in attention-deficit disorder.

Urinary excretion (24-hr) of beta-phenylethylamine (PEA), phenylacetic acid (PAA), phenylalanine (Phe), and p-tyrosine (Tyr), and plasma levels of PAA, Phe, and Tyr were examined in 18 normal children and 26 children diagnosed as having attention-deficit hyperactivity disorder (ADHD). The results indicated that urinary excretion (expressed per g of creatinine) of free and total PEA was significantly lower in the ADHD patients, and plasma levels of Phe and Tyr were also decreased in the ADHD subjects compared with the normal controls.

Attention Deficit Disorder with Hyperactivity↗

PubMed1991

Tissue levels and some pharmacological properties of an acetylated metabolite of phenelzine in the rat.

The metabolic generation of N2-acetylphenelzine by rats treated with phenelzine, and the activity of this metabolite as an inhibitor of monoamine oxidase enzymes in vivo were confirmed. The isomeric amide N1-acetylphenelzine was not a metabolic product of phenelzine and also did not inhibit monoamine oxidase enzymes. Levels of N2-acetylphenelzine in rat blood, after treatment with a dose (0.1 mmol.kg-1) of N2-acetylphenelzine sufficient to inhibit monoamine oxidase enzymes but not to increase brain levels of dopamine or noradrenaline, were higher than those generated metabolically from a higher dose (0.38 mmol.kg-1) of phenelzine which did increase brain levels of these biogenic amines. Metabolically derived N2-acetylphenelzine, therefore, probably does not contribute in any significant way to monoamine oxidase inhibition by phenelzine.

Acetylation↗