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Biomedical subjects

P H Yu

Publications and source records attributed to P H Yu.

At least 109 records · Page 6Linked to original sources
PubMed1993

The effect of L-deprenyl on behavior, cognitive function, and biogenic amines in the dog.

Behavioral and pharmacological effects of oral administration of L-deprenyl in the dog are described. Spontaneous behavior is unaffected at doses below 3 mg/kg while at higher doses there was stereotypical responding. There was evidence of improved cognitive function in animals chronically treated with a 1 mg/kg dose but the effectiveness varied considerably between subjects. Chronic administration produced a dose dependent inhibition in brain, kidney and liver monoamine oxidase B, and had no effect on monoamine oxidase A. There were also dose dependent increases in brain phenylethylamine and in plasma levels of amphetamine. Dog platelets did not have significant levels of MAO-B. Brain dopamine and serotonin metabolism were unaffected by L-deprenyl at doses up to 1 mg/kg. It appears that for the dog, deamination of catecholamines is controlled by MAO-A. Nevertheless, it is suggested that L-deprenyl serves as a dopaminergic agonist, and there is also evidence that it affects adrenergic transmission. These catecholaminergic actions may account for the effects of L-deprenyl on behavior and cognitive function.

Administration, Oral↗
PubMed1993

Chronic effects of monoamine oxidase-B inhibitors on the behaviour of aged mice.

In order to measure the chronic effects of monoamine oxidase-B (MAO-B) inhibitors on the physical and cognitive condition of 60 aged male mice, 1-deprenyl or N-methyl-N-(2-pentyl)-propargylamine (M-2-PP) were administered in drinking water (10 micrograms/ml/day) for 37 weeks. The spontaneous open-field locomotion, balancing ability and weight gain of the mice were assessed continuously. At the end of the study the spatial learning ability of all surviving mice was assessed in a Morris water maze. Both drug groups exhibited a reduction in spontaneous locomotion at the same rate as the control group, while there were no changes in balancing ability. The mice receiving 1-deprenyl, however, performed the water maze task less well than the control group. The mice receiving 1-deprenyl also gained weight at a significantly reduced rate compared to both the M-2-PP and water treated groups. A brain MAO assay indicated that MAO-B was completely inhibited by both drugs while MAO-A remained unchanged. The implications of these data on longevity studies using 1-deprenyl and other MAO-B inhibitors are discussed.

Aging↗
PubMed1993

A longitudinal study of the relationships between psychometric test scores, offence history and the plasma concentrations of phenylacetic and 5-hydroxyindoleacetic acids in seven inmates of a prison for the psychiatrically disturbed.

1. The plasma concentrations of phenylacetic (PAA) and 5-hydroxyindoleacetic (5HIAA) acids in seven inmates incarcerated in the Regional Psychiatric Centre (Prairies), Correctional Service of Canada, were assessed each weekday for four weeks (i.e., 20 samples each). Psychometric assessments for hostility, anger, depression and anxiety were also performed daily. Mean differences between subjects in psychometric and biochemical measures were subjected to tests of statistical significance. 2. The subject who was clearly most aggressive by offence history/institutional behavior scored significantly highest on scales of anger and hostility and significantly lowest with respect to PAA concentration. It was concluded that PAA may be a trait marker for aggression. 3. Plasma 5HIAA concentrations were invariant between subjects. 4. The psychometric measures were intercorrelated, thus confounding the variables of interest. They also varied little, proving insensitive to subtle mood changes.

Adult↗
PubMed1993

Oxidative deamination of methylamine by semicarbazide-sensitive amine oxidase leads to cytotoxic damage in endothelial cells. Possible consequences for diabetes.

Methylamine was observed to be deaminated by several semicarbazide-sensitive amine oxidases, which were prepared from blood and vascular tissues of various species, including humans. Although methylamine itself is relatively nontoxic toward endothelial cells obtained from both human umbilical vein and calf pulmonary artery, it becomes very toxic in the presence of SSAO. SSAO inhibitors (i.e., MDL-72974A) effectively protected the cells from methylamine-SSAO-induced damage. The cytotoxicity seems, therefore, to be a consequence of the deamination of methylamine. Our findings suggest that formaldehyde, the deaminated product of methylamine, may be responsible for these toxic effects. Human serum, which also contains SSAO, was also capable of deaminating methylamine and causing cytotoxicity to cultured endothelial cells. Both methylamine and SSAO circulate in human blood, and their concentrations in the blood of normal healthy subjects are quite close to those required to induce cytotoxicity in tissue-cultured cells. Both SSAO activity and methylamine levels have been reported to be increased in the blood of diabetic individuals. Blood SSAO activity also has been reported to be elevated in the blood of STZ-induced diabetic rats. It is possible, therefore, that an abnormal metabolism of methylamine may be involved in endothelial injury, and that it may subsequently induce atherosclerotic plaque formation and thus be involved in the cardiovascular disorders seen in diabetes.

Amine Oxidase (Copper-Containing)↗
PubMed1993

Rescue of axotomized immature rat facial motoneurons by R(-)-deprenyl: stereospecificity and independence from monoamine oxidase inhibition.

The role of monoamine oxidase B (MAO-B) in R(-)-deprenyl-mediated rescue of rat facial motoneurons axotomized at postnatal day 14 (P14) was investigated using the (+)- and (-)-enantiomers of deprenyl [S(+)-deprenyl and R(-)-deprenyl]. Previously, doses of R(-)-deprenyl sufficient to inhibit MAO-B were shown to increase the survival of motoneurons following an apparent loss of target-derived trophic support caused by axotomy in P14 rats. In the present experiments, motoneuronal survival was measured 21 d after unilateral facial nerve transection at P14. The animals were treated with saline or doses of R(-)- or S(+)-deprenyl ranging from 0.001 to 10 mg/kg every 2 days (/2d). Frontal serial 10 microns sections were taken through the length of the facial nuclei ipsilaterally and contralaterally to the facial nerve transections. Every third section was immunoreacted for an antibody against ChAT to identify the motoneuron somata, while every adjacent third section was Nissl stained to assess motoneuronal survival. A second series of P14 rats was treated with similar doses of the two deprenyl enantiomers or saline and the brainstems removed for measurement of MAO-A and MAO-B activity at 4 hr after the treatments. Averages of 24% of the facial motoneurons survived axotomy with either saline treatment or 0.001 mg/kg/2d doses of R(-)-deprenyl. Doses of R(-)-deprenyl of 0.005, 0.01, and 10.0 mg/kg/2d increased the surviving facial motoneuron to 38%, 51%, and 48%, respectively, indicating an ED50 of about 0.005 mg/kg/2d. Doses of S(+)-deprenyl as high as 10 mg/kg/2d did not increase motoneuronal survival, revealing a stereospecificity for the increased survival of at least 2000-fold. The ED50 for MAO-B inhibition in the P14 brainstem was approximately 0.1 mg/kg for the (-)-enantiomer and 2.0 mg/kg for the (+)-enantiomer, revealing a 20-fold higher sensitivity of the enzyme toward the (-)-enantiomer in the P14 rat brainstem. A dose of 10 mg/kg of S(+)-deprenyl inhibited about 65% of brainstem MAO-B activity without increasing motoneuronal survival, whereas 0.005 and 0.01 mg/kg of R(-)-deprenyl increased motoneuronal survival without significant inhibition of brainstem MAO-B activity.(ABSTRACT TRUNCATED AT 400 WORDS)

Aging↗
PubMed1992

Aliphatic propargylamines: potent, selective, irreversible monoamine oxidase B inhibitors.

A series of aliphatic propargylamine derivatives has been synthesized. Some of them possess highly potent, irreversible, selective, inhibitory activity toward monoamine oxidase B (MAO-B). The potency of the inhibitors is related to chain length and substitution of a hydrogen on the terminal carbon of the aliphatic chain. MAO inhibitory activity as assessed in vitro increased as the aliphatic carbon chain length increased. Substitution of a hydrogen by hydroxyl, carboxyl, or carbethoxyl groups at the aliphatic chain terminal or replacement of the methyl group on the nitrogen atom by an ethyl group considerably reduced the inhibitory activity. Stereospecific effects were observed with the R-(-)-enantiomer being 20-fold more active than the S-(+)-enantiomer. Inhibitors with relatively short carbon chain lengths (i.e. four to six carbons) were found to be more potent than those with longer chains in inhibiting brain MAO-B activity in vivo especially after oral administration. Chronic administration of low doses of the aliphatic propargylamines caused a slight cumulative inhibition of MAO-A activity in the mouse brain. These MAO-B inhibitors appear to be nontoxic, and they do not possess an amphetamine-like moiety in their structure as is the case for deprenyl. We expect that these aliphatic propargylamines may be useful in the treatment in certain neuropsychiatric disorders.

Animals↗
PubMed1992

Inhibition of a type B monoamine oxidase inhibitor, (E)-2-(4-fluorophenethyl)-3-fluoroallylamine (MDL-72974A), on semicarbazide-sensitive amine oxidases isolated from vascular tissues and sera of different species.

(E)-2-(4-Fluorophenethyl)-3-fluoroallylamine hydrochloride (MDL-72974A) has been discovered recently to be a very potent and highly selective type B monoamine oxidase inhibitor. We have found that this inhibitor is also capable of inhibiting semicarbazide-sensitive amine oxidases (SSAOs) obtained from vascular tissues and sera of different species. The inhibition of SSAO by MDL-72974A was irreversible and time dependent. It was competitive without preincubation of the enzyme with the inhibitor and demonstrated a mixed-type of inhibition when the enzyme was preincubated with the inhibitor. The IC50 values were estimated to be 2 x 10(-9) M, 5 x 10(-9) M, 8 x 10(-8) M and 2 x 10(-8) M for SSAO from dog aorta, rat aorta, bovine aorta and human umbilical artery, respectively. SSAO obtained from bovine serum was relatively insensitive to MDL-72974A (IC50 = 3 x 10(-7) M. Following intraperitoneal administration of MDL-72974A, rat brain MAO-B was inhibited with the ED50 value being about 0.2 mg/kg. Rat aorta SSAO was also inhibited and to a similar extent by the same dose. MDL-72974A is the most potent SSAO inhibitor that has been described thus far.

Allyl Compounds↗
PubMed1992

Semicarbazide-sensitive amine oxidase from the smooth muscles of dog aorta and trachea: activation by the MAO-A inhibitor clorgyline.

Semicarbazide-sensitive amine oxidase (SSAO) has been identified in the dog trachea and aorta smooth muscles. The dog SSAO is blocked by hydrazine inhibitors. SSAOs from several different vascular smooth muscle sources, such as the rat and bovine aorta, and human umbilical artery, as well as the bovine plasma, are insensitive to the MAO-A inhibitor clorgyline; the dog SSAO on the other hand is significantly activated by clorgyline. Two methods, i.e. radioenzymatic and fluorometric methods, have been applied to substantiate this clorgyline-induced activation. The activation was detected with respect to the deamination of different substrates, such as benzylamine, beta-phenylethylamine and longer carbon chain aliphatic amines, but not with respect to methylamine. The clorgyline effect is reversible, non-competitive and time-independent; it depends on electrostatic and hydrophobic interactions between clorgyline and hydrophobic regions of the dog SSAO enzyme.

Amine Oxidase (Copper-Containing)↗
PubMed1991

Longitudinal effect of amitriptyline and fluoxetine treatment on plasma phenylacetic acid concentrations in depression.

Unconjugated (U-PAA), conjugated (C-PAA), and total phenylacetic acid (T-PAA) concentrations in blood plasma and monoamine oxidase (MAO) activity in platelets towards phenylethylamine (PE) were determined in 40 drug-free, depressed patients (23 melancholic, 17 nonmelancholic) from five psychiatric treatment centers, and in 34 normal healthy volunteers. No significant differences were found between controls and all depressed patients or between melancholic and nonmelancholic depressed patients. Treatment of the depressed patients with amitriptyline or fluoxetine over a 6-week period resulted in clinical improvement and in a significant increase in plasma PAA concentrations. A decline in the Beck and Hamilton rating scores during treatment correlated significantly with increases in the concentrations of unconjugated, conjugated, and total phenylacetic acid but not with MAO activity, which did not change during treatment. At each of the three assessment times, however, plasma PAA concentrations and psychiatric rating scores were not significantly correlated. Except for higher end-of-study T-PAA concentrations in the amitriptyline-treated subjects, no significant differences were found between the effects of the two drugs with regard to plasma phenylacetic acid levels, MAO activity, or rating scores.

Adult↗
PubMed1991

High-performance liquid chromatographic procedure for the simultaneous determination of aromatic L-amino acid decarboxylase activity towards 3,4-dihydroxyphenylalanine and 5-hydroxytryptophan.

A high-performance liquid chromatographic method with electrochemical detection has been developed and applied in the simultaneous determination of aromatic L-amino acid decarboxylase activity with respect to L-3,4-dihydroxyphenylalanine and 5-hydroxytryptophan as substrates. Both substrates are included in the incubation mixture, and the decarboxylated products, dopamine and serotonin, respectively, are detected. In contrast to several earlier claims, we found that the ratio of the decarboxylase activity to L-3,4-dihydroxyphenylalanine and 5-hydroxytryptophan is quite constant across several different rat tissues, supporting the notion that there is only one major single enzyme rather than two. We also observed that an erroneous ratio with respect to the L-3,4-dihydroxyphenylalanine/5-hydroxytryptophan decarboxylation activities, is obtained if these activities are assessed under non-linear kinetic conditions.

5-Hydroxytryptophan↗
PubMed1991

Simultaneous delivery of valproic acid and glycine to the brain. Deamination of 2-propylpentylglycinamide by monoamine oxidase B.

2-Propylpentylglycinamide (2-PPG), a branched aliphatic amine derivative, was found to be readily deaminated by rat liver monoamine oxidase B in vitro and in vivo. The deamination leads to production of 2-propyl-1-pentaldehyde, which can be subsequently converted to valproic acid (VPA), and glycinamide, which is then subsequently converted to glycine. Absorption and biotransformation of a single ip dose of 2-PPG into blood as well as transfer of the drug and its metabolite into the brain were rapid processes. Although VPA (an anticonvulsant) and glycine (an inhibitory neurotransmitter) can be detected in the brain following administration of 2-PPG, its anticonvulsant action cannot be determined. 2-PPG at relatively low doses exhibited distinct tremor effects. Furthermore, 2-PPG appeared to potentiate the convulsant effect induced by pentylenetetrazol.

Animals↗
PubMed1991

2-propyl-1-aminopentane, its deamination by monoamine oxidase and semicarbazide-sensitive amine oxidase, conversion to valproic acid and behavioral effects.

2-Propyl-1-aminopentane (2-PAPN), a branched aliphatic amine, was found to be readily deaminated by monoamine oxidase B in the liver of the rat and semicarbazide-sensitive amine oxidase in the aorta of the rat. The deaminated product, 2-propyl-1-pentaldehyde, could be subsequently converted to valproic acid in the presence of aldehyde dehydrogenase and beta-NAD cofactor in vitro as well as in vivo. Valproic acid was identified after derivatization with 4-bromomethyl-6,7-dimethoxycoumarin, followed by HPLC-fluorometric assessment. Absorption and biotransformation of a single intraperitoneal dose of 2-PAPN resulted in the rapid appearance of the drug and its metabolite in the blood and in the brain. The formation of valproic acid from 2-PAPN in vivo, however, was insufficient to facilitate anticonvulsant action. In fact, 2-PAPN itself, at relatively small doses, exhibited distinct tremor effects. Such tremor effects could be prevented by valproic acid. However, 2-PAPN was also found to potentiate the convulsant effect induced by mercaptopropionic acid (MPA) and, in addition, the 2-PAPN-induced tremor could be potentiated by MPA in mice.

Amines↗
PubMed1991

Longitudinal study of inmates of a prison for the psychiatrically disturbed: plasma concentrations of biogenic amine metabolites and amino acids.

Plasma concentrations of eight large and neutral amino acids and 10 acidic metabolites of biogenic amines in seven inmates incarcerated in the Regional Psychiatric Centre (Praries), Correctional Service of Canada, were assessed each week day for 4 weeks (i.e., 20 samples each). Measures of central tendency and dispersion of the variables were calculated. The measures are distinctively different in their variability and their normality of distribution. The large and neutral amino acid (LNAA) measures are somewhat less variable, but also less likely to be normally distributed than most acid metabolites. Acid metabolites tend to show consistent interindividual differences that persist over time, with the notable exception of 5-hydroxyindoleacetic acid. LNAA measures tend to show differences across time but not between individuals. The distributional properties of LNAA measures are largely accounted for by the observation of a downward convergence of values of these variables over the 4 weeks of the study.

Adult↗
PubMed1991

Effect of dietary phenylalanine on the plasma concentrations of phenylalanine, phenylethylamine and phenylacetic acid in healthy volunteers.

1. Phenylethylamine has been proposed as a neuromodulator in several psychiatric and other brain disorders, and its concentration and that of its major metabolite, phenylacetic acid, in plasma may prove useful as state or trait markers in diagnosis, treatment or in the elucidation of biochemical mechanisms of these disorders. 2. The effect of dietary phenylalanine intake and changes in dietary phenylalanine intake on the plasma concentrations and changes in plasma concentrations, respectively, of phenylalanine, phenylethylamine and unconjugated and conjugated phenylacetic acid have been investigated. 3. Dietary phenylalanine affects the concentration of plasma phenylalanine on the following day, but has no effect on phenylethylamine or phenylacetic acid concentrations. Thus single measurements per subject of phenylethylamine or phenylacetic acid do not need to take dietary factors into account. 4. Changes in dietary phenylalanine (whether in absolute amount or in the proportion of phenylalanine in the diet) are significantly correlated with changes in unconjugated phenylacetic acid. Therefore, in longitudinal studies, dietary factors should be taken into account.

Adult↗
PubMed1991

Deuterium-labelled p-tyramine challenge test and phenolsulfotransferase activity in depressed patients--failure to replicate decreased p-tyramine conjugation in depression.

1. Depressed and normal subjects were challenged with deuterium-labelled p-tyramine and urine was collected for 3 h. 2. Urinary excretion of conjugated p-tyramine was not significantly different between normal, melancholic and non-melancholic depressed subjects. 3. Platelet phenolsulfotransferase activity to p-tyramine (p less than 0.05) and to phenol (p less than 0.005) were significantly lower in the depressed patients.

Amitriptyline↗
PubMed1991

Studies on the properties of some peripheral MAO inhibitors.

1. Studies were carried out on three monoamine oxidase (MAO) inhibitors, two of which, debrisoquine and para- hydroxyphenelzine, are purported to be peripheral inhibitors and one, phenelzine, is a peripherally acting inhibitor, which has been included for comparitive purposes. 2. All three showed varying degrees of specificity towards MAO type A. 3. The action of debrisoquine was very rapid as was that of para- hydroxyphenelzine. 4. The inhibition caused by debrisoquine was competitive and reversible, while that caused by both phenelzine and para- hydroxyphenelzine was irreversible. 5. The inhibition caused by debrisoquine appeared to be unaffected by the pH of the medium.

Animals↗
PubMed1991

Deamination of 2-propyl-1-aminopentane and 2-[(2-propyl)pentylamino] acetamide by amine oxidases: formation of valproic acid.

1. 2-Propyl-1-aminopentane and 2-[(2-propyl)pentylamino]acetamide are deaminated by rat liver monoamine oxidase (MAO) and aorta semicarbazide-sensitive amine oxidase (SSAO). 2. The deaminated product, 2-propylpentaldehyde, is further converted to valproic acid in vitro as well as in vivo. 3. The anticonvulsant action of these two compounds could not be substantiated, because both drugs at relatively low doses caused distinct tremor in mice and rats. 4. Both compounds also potentiate the convulsant effect induced by mercaptopropionic acid.

Amine Oxidase (Copper-Containing)↗