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Biomedical subjects

G B Baker

Publications and source records attributed to G B Baker.

At least 127 records · Page 7Linked to original sources
PubMed1991

N2-acetylphenelzine: effects on rat brain GABA, alanine and biogenic amines.

The neurochemical properties of N2-acetylphenelzine were compared with those of phenelzine in a rat model. N2-Acetylphenelzine is a relatively potent inhibitor of monoamine oxidase-A and -B and causes increases in whole-brain levels of noradrenaline and 5-hydroxytryptamine, and decreases in homovanillic acid, 5-hydroxyindole-3-acetic acid, and 3,4-dihydroxyphenylacetic acetic after acute i.p. administration of the drug. Phenelzine is a more potent monoamine oxidase inhibitor than is N2-acetylphenelzine. The most marked difference in the profile was that N2-acetylphenelzine had no effect on whole brain levels of the amino acid neurotransmitters alanine and gamma-aminobutyric acid, whereas phenelzine caused dramatic increases. Acetylation of phenelzine at the N2 position presumably interferes with the inhibition of the transaminase enzymes for gamma-aminobutyric acid and alanine.

Alanine↗
PubMed1991

Analysis of p-chloroamphetamine and a side-chain monofluorinated analogue in rat brain.

p-Chloro-alpha-fluoromethylphenylethylamine (fluoro-p-chloroamphetamine) (FpCA) has been shown in acute studies to be a less potent depletor of the neurotransmitter amine 5-hydroxytryptamine (5-HT) in brain than is p-chloroamphetamine (pCA). Gas chromatographic assay procedures for FpCA and PCA have been developed in our laboratories and applied to preliminary measurements in brain tissue from rats injected intraperitoneally with pCA or FpCA. Groups of male Sprague-Dawley rats were injected with pCA (0.03 mmol/kg) or FpCA (0.05 or 0.1 mmol/kg) and killed 1, 2, or 4 hr later. The brains were analyzed for the halogenated amphetamines by gas chromatography with electron-capture detection (GC-ECD) following derivatization with pentafluorobenzenesulfonyl chloride (for pCA) or trichloroacetic anhydride (for FpCA). At the 0.05-mmol/kg dose, FpCA attained lower brain concentrations at 1, 2, and 4 hr after injection than did pCA at a considerably lower dose (0.03 mmol/kg). Even at the higher dose of FpCA used (0.10 mmol/kg), where concentrations of FpCA were higher than those of pCA initially, concentrations of FpCA had dropped below those of pCA by 4-hr. These preliminary results indicate that FpCA attains lower brain concentrations and is eliminated from the brain more rapidly than is the parent drug, pCA. However, differences in potency between FpCA and pCA on 5-HT depletion cannot be explained fully on the basis of obtained brain levels of the drug as even at time intervals where FpCA levels were higher than or equal to those of pCA, there was less depletion of 5-HT by the former drug.

Animals↗
PubMed1991

Effects of the antidepressant phenelzine on brain levels of gamma-aminobutyric acid (GABA).

Time- and dose-response studies were carried out on the effects of the monoamine oxidase-inhibiting antidepressant and antipanic drug phenelzine on GABA levels in rat whole brain. At a dose of 15 mg/kg i.p., phenelzine significantly elevated GABA levels at all time intervals studied (1, 2, 4, 8, 16, and 24 h). A further investigation indicated that this was a dose-dependent effect. The possible importance of GABA in the etiology and pharmacotherapy of depression and panic disorder is discussed.

Animals↗
PubMed1991

Metabolism of antidepressants: urinary metabolites of trimipramine in the rat.

1. Studies on the metabolism of the tricyclic antidepressant trimipramine (TMP) in the rat are described. 2. Twenty metabolites of TMP were isolated from rat urine after enzymatic hydrolysis and their structures were determined by a gas chromatographic-mass spectrometric (GC-MS) method. 3. Twelve TMP metabolites were the result of alicyclic (C10 or C11) oxidation in addition to the other metabolic pathways.

Animals↗
PubMed1991

Tourette syndrome and neuropsychological performance.

This study examined performance on a battery of neuropsychological tests in a sample of 28 patients with Tourette's syndrome (TS). Test scores were converted to age-corrected T-scores to control for the effect of age on test performance. The frequency of abnormal test performances was variable, but more frequent on motor and sensory tasks. Symptom severity as measured by the Tourette Syndrome Global Scale was inversely related to neuropsychological performance. In general, neuropsychological performance was mildly below average. The pattern of performance was similar to previous studies of TS patients.

Adolescent↗
PubMed1991

Depression and memory in major depressive disorder.

The relationship between memory function and depression was examined in 23 patients who met DSM-III criteria for major depression. All patients were unmedicated at the time of examination, which included the Wechsler Memory Scale, Minnesota Multiphasic Personality Inventory-Depression Scale (MMPI-D), and Hamilton Depression Rating Scale (HDRS). Consistent with previous studies, there was no relationship between the MMPI-D and any of the Wechsler Memory Scale measures. In contrast, poor memory was related to elevated scores on the HDRS. These data indicate that depression does influence memory performance. The most important implication of this study is the need for the use of appropriate measurement instruments in studies of neuropsychological correlates of neuropsychiatric disorders.

Adolescent↗
PubMed1991

Neuropsychological performance and urinary phenylethylamine in Tourette's syndrome.

Patients with Tourette's syndrome (TS) were grouped on the basis of levels of urinary phenylethylamine (PEA). These groups of TS patients were compared on an extensive battery of neuropsychological measures converted to age-corrected T scores based on published normative data. Patients with PEA levels below that of normal controls performed significantly worse than TS patients with normal PEA levels. The data were interpreted to suggest that abnormalities in PEA may contribute to neuropsychological deficits. Furthermore, these data may provide further support for an etiological subgroup of TS patients characterized by an abnormality in PEA metabolism. These data are discussed in regard to directions for further investigation.

Adolescent↗
PubMed1991

Structural characterization of the urinary metabolites of iprindole in rat.

1. The in vivo metabolism of iprindole in rat is described. Each rat received a single dose of iprindole (10 mg/kg) and urine was collected for 48 h. 2. Fourteen metabolites of iprindole were isolated from rat urine after enzymic hydrolysis and their structures were determined by a computerized g.l.c.-mass spectrometric technique, before and after appropriate chemical derivatization. 3. Three concurrent metabolic pathways have been identified for iprindole in rat; aromatic ring hydroxylation is a minor pathway. 4. This is the first reported comprehensive study on the in vivo metabolism of iprindole in rat.

Animals↗
PubMed1991

Effect of iprindole on the metabolism of trimipramine in the rat.

Major metabolites of trimipramine in young male Sprague-Dawley rats are the result of alicyclic and aromatic ring oxidation. The four major urinary metabolites have been identified as 10-oxotrimipramine, 2-hydroxytrimipramine, 2-hydroxynortrimipramine, and 2-hydroxy-10-oxotrimipramine. When iprindole was administered to rats prior to trimipramine, the effect on trimipramine metabolism was profound. The formation of both 10-oxo metabolites was virtually completely inhibited; the production of 2-hydroxytrimipramine was significantly reduced while the metabolic formation of 2-hydroxynortrimipramine was increased. It is apparent from these preliminary results that metabolic alicyclic and aromatic hydroxylations are catalyzed by different cytochrome P450 isozymes and more than one P450 isozyme is involved in the aromatic ring oxidation of trimipramine and nortrimipramine.

Animals↗
PubMed1991

Aromatic ring oxidation of N-n-butylamphetamine is enhanced in the rat by prior treatment with quinidine.

Prior administration of quinidine is known to reduce aromatic oxidation of amphetamine and its analog methoxyphenamine by inhibiting the cytochrome P450IID6 results in isozyme. In contrast, it is now shown that prior administration of quinidine results in a significant increase in the aromatic oxidation of N-n-butylamphetamine in rat, suggesting that the P450IID6 isozyme is not involved in this metabolic reaction.

Animals↗
PubMed1991

Interactions of iprindole with fenfluramine metabolism in rat brain and liver.

An assay procedure utilizing electron-capture gas chromatography was developed for simultaneous analysis of fenfluramine and norfenfluramine. This method was applied to brain and liver samples from rats which had been injected with fenfluramine with or without pretreatment with iprindole. The tissues from rats treated with fenfluramine showed extensive formation of norfenfluramine, consistent with findings reported previously in the literature. Pretreatment with iprindole led to an increase in brain and liver levels of fenfluramine, and, unexpectedly, to a marked decrease in levels of norfenfluramine in these tissues. These findings suggest that iprindole blocks N-deethylation and that it may be a useful tool with which to study the effects of fenfluramine in the absence of norfenfluramine. The results also emphasize the importance of considering drug-drug interactions in future research on fenfluramine.

Animals↗
PubMed1990

The metabolism of trimipramine in the rat.

Studies on the metabolism of the tricyclic antidepressant trimipramine, 5-(3-dimethylamino-2-methylpropyl)-10,11-dihydro-5H-dibenz[b,f]azepine, in the rat are described. Many metabolites of trimipramine (TMP) were isolated from rat urine after enzymatic hydrolysis and their structures were identified by a gas chromatographic/mass spectrometric method, before and after appropriate chemical derivatization. Besides unchanged TMP, 20 metabolites were characterized (underivatized, and after acetylation), of which 12 had undergone alicyclic (C10 or C11) oxidation. This is a hitherto unreported metabolic pathway for TMP in the rat.

Animals↗
PubMed1990

Ring-substituted analogues of tranylcypromine as monoamine oxidase inhibitors.

4-Fluorotranylcypromine and 4-methoxytranylcypromine, in which the 4-position of the phenyl ring is protected from metabolic ring hydroxylation, were tested for their ability to inhibit, relative to tranylcypromine, monoamine oxidase (MAO) -A and -B in rat brain after administration of low doses (1.2 and 3.7 mumol/kg) of the drugs. One hour after intraperitoneal injection of the lower dose, tranylcypromine was weaker than 4-fluorotranylcypromine and 4-methoxytranylcypromine at inhibiting MAO-A. After long-term (28 day) administration of a dose of 3.7 mumol/kg/day (administered via osmotic minipumps), 4-fluorotranylcypromine had a slightly stronger inhibitory effect on MAO-B than did the other two drugs. At the same time and dose both 4-substituted analogues were slightly more potent inhibitors of MAO-A than was tranylcypromine. After 28 days of administration at a daily dose of 1.2 mumol/kg/day, both analogues produced greater inhibition of MAO-A and -B than did tranylcypromine. 4-Methoxytranylcypromine and 4-fluorotranylcypromine were similar in their extent of inhibition of MAO-B but the former was more potent than the latter at inhibition MAO-A.

Animals↗
PubMed1990

Recent studies on the MAO inhibitor phenelzine and its possible metabolites.

Although N2-acetylphenelzine (N2AcPLZ) appears to be only a minor metabolite of phenelzine (PLZ), other investigations have demonstrated that it may be worthy of study as an antidepressant in its own right. In the present report, the possibility of ring hydroxylation as a metabolic route for PLZ was investigated in the rat. Indirect evidence for such a route was obtained using iprindole, a drug known to block ring hydroxylation. Treatment of rats with iprindole followed by PLZ was demonstrated to result in increased brain levels of PLZ and beta-phenylethylamine (control rats were treated with vehicle and then PLZ). The possibility that hydroxylation in the para-position might be a metabolic route for PLZ has led to interest in the possible use of analogues in which this position is blocked with a substituent. In preliminary acute studies at a dose of 0.1 mmol/kg p-chloro-PLZ was found to have a similar effect to PLZ on the inhibition of MAO and to lead to an elevation of catecholamines and 5-hydroxytryptamine (5-HT) in rat whole brain.

Animals↗
PubMed1990

Urinary excretion of metabolites of norepinephrine in Tourette's syndrome.

Urinary excretion of the norepinephrine metabolites 3-methoxy-4-hydroxyphenylethylene glycol (MHPG) and normetanephrine (NMR) was measured in Tourette's Syndrome (TS) patients and in control subjects matched for age and education. The 24-h excretion (expressed per gram of creatinine) of total MHPG and of free and total (free + conjugated) NME was significantly lower in TS patients than in the normal subjects.

Child↗
PubMed1990

Effects of p-chlorophenylalanine and scopolamine on retention of habits in rats.

Rats were trained on a conventional maze test or on a swim-to-platform test. Retention of swim-to-platform performance 7 days later was severely impaired by posttraining treatment with a combination of p-chlorophenylalanine (PCPA) and scopolamine although neither drug alone had any effect. Retention of the maze habit was moderately impaired by scopolamine alone and severely impaired by a combination of scopolamine and PCPA, but was unaffected by PCPA alone. Polygraphic recordings confirmed previous reports that a combination of PCPA and scopolamine can abolish neocortical low voltage fast activity and hippocampal rhythmical slow activity. Combined blockade of central cholinergic and serotonergic neurotransmission in rats may provide a useful animal model of Alzheimer's disease.

Animals↗
PubMed1990

A rapid procedure for the analysis of phenylalanine in brain tissue utilizing electron-capture gas chromatography.

A rapid procedure has been developed for the analysis of phenylalanine in brain tissue. Perchloric acid extracts of brain tissue were made basic, and benzoyl chloride was added to derivatize the amine function. The aqueous layer was retained and made slightly acidic. To derivatize the carboxylic acid group, a solution of pentafluorobenzyl alcohol was added in the presence of the coupling agent dicyclohexylcarbodiimide and chloroform. After shaking for 15 min, the organic phase was retained and taken to dryness. The residue was taken up in toluene, washed, and an aliquot used for analysis on a gas chromatograph equipped with an automatic injector, a capillary column and an electron-capture detector. The procedure has been utilized for analysis of phenylalanine in brains of rats treated with vehicle or phenylalanine.

Animals↗