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Biomedical subjects

C J Fowler

Publications and source records attributed to C J Fowler.

At least 253 records · Page 14Linked to original sources
PubMed1984

Stereoselective inhibition of monoamine oxidase and semicarbazide-sensitive amine oxidase by 4-dimethylamino-2,alpha-dimethylphenethylamine (FLA 336).

The in vitro inhibition by amiflamine [FLA 336(+)] and related compounds of the activity of rat monoamine oxidase (MAO) -A and -B, rat semicarbazide sensitive amine oxidase (SSAO) and human platelet poor plasma benzylamine oxidase was studied. Amiflamine was an MAO-A selective inhibitor, but also inhibits SSAO with both a reversible (competitive, Ki = 200 mumol/l) and a small time-dependent component which was irreversible in nature. The optical isomer FLA 336(-) was ten times less potent towards MAO-A. However, this compound was much more potent an inhibitor of SSAO (competitive, Ki = 4.6 mumol/l). The amiflamine metabolites FLA 788(+) and FLA 668(+) inhibited SSAO, but only at concentrations considerably higher than required for MAO-A inhibition. Ex vivo experiments indicated that there was no significant irreversible inhibition of rat heart and lung SSAO after both single and repeated administration of amiflamine at doses up to 20 times higher than required for inhibition of MAO-A within central serotoninergic neurones.

Amine Oxidase (Copper-Containing)↗
PubMed1984

On the substrate specificities of the two forms of monoamine oxidase.

By use of the selective irreversible inhibitors clorgyline and selegiline [(-)-deprenyl], it is possible to determine the Km and Vmax values of the two forms of monoamine oxidase towards a variety of substrates. The validity of this procedure is demonstrated for the deamination of dopamine by rat liver monoamine oxidase -A and -B, and the specificities of the two forms are analysed in terms of their kinetic parameters towards different substrates.

Animals↗
PubMed1984

Clinico-anatomical correlations in uncomplicated stroke.

A method for making clinico-anatomical correlations by computer superimposition of brain maps derived from CT scan images, described in a companion paper, was tested in 19 patients with an uncomplicated left hemiparesis due to acute stroke. Eight patients with an isolated left hemiparesis had small lesions in the most rostral part of the right internal capsule. The composite lesion maps of 11 patients whose left hemiparesis was complicated only by spinothalamic sensory loss showed a larger area of damage more caudally in the posterior part of the posterior limb of the capsule, abutting the thalamus. The close correlation between the results obtained by this method and those obtained in previous clinico-pathological studies of patients with uncomplicated strokes, confirms the validity of this mapping technique.

Basal Ganglia↗
PubMed1984

A microcomputer assisted method for obtaining composite pictures of focal brain damage.

A method used to produce composite drawings of superimposed areas of brain infarction is described. The method uses a microcomputer interfaced to a digitising pad and linear plotter. Areas of brain damage are drawn on standardised maps, digitised, manipulated in computer memory, and summated using computer graphics facilities. The composites show the position of brain damage in groups of patients as a contour map of the extent of lesion overlap. The method can be used to study neurological and neuropsychological deficits using CT-scan, or other imaging techniques. Deep and superficial lesions may be displayed equally well.

Cerebral Infarction↗
PubMed1984

Individual motor unit analysis in the diagnosis of disorders of urethral sphincter innervation.

A technique is described for recording the electromyographic activity of striated muscle in the urethral sphincter. Using a concentric needle electrode and an oscilloscope with a delay line and trigger, individual motor units were isolated and measured. To validate the method as a means of detecting pathology, the results are presented of analysis of the motor units of a group of patients with disturbances of micturition, known to have either cauda equina lesions or pelvic nerve injury. These results are compared with those from a group of controls. In the control group 93% of the motor units were less than 6 ms in duration and 2.0 mv in amplitude. Of motor units recorded from patients with cauda equina or pelvic nerve injury 59% exceeded the control ranges for amplitude or duration. It is concluded that quantitative analysis of individual motor units may be a helpful technique in the investigation of patients with disorders of micturition.

Adult↗
PubMed1984

Intra- and extraneuronal monoamine oxidase.

By use of monoamine reuptake inhibitors, it is possible to study the intra- and extraneuronal components of monoamine deamination in brain. In both man and rat, the ratios of activities of MAO-A/MAO-B are higher intra- than extraneuronally . As a result of this difference in cellular localisation in the brain, loss of neurones produces a change in the ratios of activities of MAO-A/MAO-B. It is also possible selectively to inhibit the activity of MAO-A within a given neurone population. The alpha-methyl substituted monoamine amiflamine has been shown to inhibit MAO-A within serotoninergic neurones at lower doses than are required for inhibition in other neurones. The usefulness of this compound in the elucidation of the functions of intra- and extraneuronal MAO are discussed.

Animals↗
PubMed1983

Intestinal metabolism of tyramine by both forms of monoamine oxidase in the rat.

The two forms of monoamine oxidase (MAO) in rat intestine and brain homogenates were found to have different Km and Vmax values towards tyramine. The Km values for the A-form of the enzyme towards this substrate were around 120 microM in both cases, whereas the values for the B-form were about 240 microM. As a consequence, the ratio of activities (MAO-A: MAO-B) towards tyramine are dependent upon the substrate concentration. The MAO-A-selective inhibitors, toloxatone and cimoxatone, were found to be competitive inhibitors of the oxidation of tyramine by the A-form of this enzyme in the rat intestine, with Ki values of 3.4 microM and 3.7 nM respectively. The significance of these results in relation to the "cheese effect", a pressor response to tyramine after monoamine oxidase inhibition, are discussed.

Animals↗
PubMed1983

The enzyme-activated irreversible inhibition of type-B monoamine oxidase by 3-(4-[(3-chlorophenyl)methoxy]phenyl)-5-[(methylamino) methyl]-2-oxazolidinone methanesulphonate (compound MD 780236) and the enzyme-catalysed oxidation of this compound as competing reactions.

3-(4-[(3-Chlorophenyl)methoxy]phenyl)-5-[(methylamino)methyl]-2- oxazolidinone methanesulphonate (compound MD 780236) is a selective inhibitor of the B-form of monoamine oxidase. Inhibition involves an initial non-covalent interaction between enzyme and inhibitor followed by a time-dependent process resulting in irreversible inhibition. The initial, reversible, phase of inhibition was found to be competitive with respect to phenethylamine and 5-hydroxytryptamine, and a comparison of the Ki values indicated the affinity of the inhibitor for the B-form of the enzyme to be some 7-fold greater than its affinity for the A-form. This selectivity was considerably enhanced by preincubation of the enzyme and inhibitor. Time courses showed that complete inhibition was not achieved under conditions where the inhibitor concentration was over 100-fold greater than that of the enzyme. Assay of the activity of monoamine oxidase by determining the release of hydrogen peroxide fluorometrically showed compound MD 780236 to be a substrate for, as well as an inhibitor of, monoamine oxidase, and kinetic analysis revealed that the rate of product formation was some 530-fold greater than that of the process leading to irreversible inhibition of the B-form of the enzyme.

Animals↗
PubMed1983

The deamination of dopamine by human brain monoamine oxidase. Specificity for the two enzyme forms in seven brain regions.

The deamination of dopamine has been studied in seven regions of human brain. Both A and B forms of the enzyme were found to be active towards this substrate. The ratio of activities of MAO-A: MAO-B was found to vary considerably from brain region to brain region, from about 1:1 for the cerebral and cerebellar cortex to about 1:2 for the pons and medulla oblongata. Enzyme titration studies and comparisons of the substrate specificities of MAO-A and MAO-B across the brain indicated that dopamine was metabolised by the same MAO active centres as other monoamines. In the cerebral cortex, the Km values of MAO-A and -B towards dopamine were found to be 210 and 230 microM, respectively, indicating that the relative contributions of these two forms towards the oxidation of this substrate will not be significantly affected by changes in its concentration.

Brain↗
PubMed1983

The deamination of noradrenaline and 5-hydroxytryptamine by rat brain and heart monoamine oxidase and their inhibition by cimoxatone, toloxatone and MD 770222.

In both rat brain and heart, noradrenaline and 5-hydroxytryptamine are metabolised predominantly by monoamine oxidase-A. The Km values for 14C-noradrenaline in the rat brain and heart are 290 microM and 300 microM, respectively, whereas for 14C-5-hydroxytryptamine the values are 180 microM and 140 microM, respectively. In the rat brain, mixed substrate experiments suggested that 14C-noradrenaline and 14C-5-hydroxytryptamine are metabolised at the same active centre. Both substrates are inhibited with similar Ki values by the reversible inhibitors cimoxatone, toloxatone and MD 770222.

Animals↗
PubMed1983

The activity of monoamine oxidase -A and -B in brains from chronic alcoholics.

The activity of monoamine oxidase--A was found to be lower in homogenates of hypothalamus and caudate nucleus, but not in cortex of the gyrus cinguli and hippocampus, from chronic alcoholics with respect to homogenates from autopsy cases without histories of alcohol abuse. The activity of monoamine oxidase--B was also lower in the alcoholics, but this could be due to the selective effect of age upon this enzyme form, since the alcoholics were younger than controls. No difference was found for either monoamine oxidase -A or -B activities in brain homogenates from an alcohol preferring (AA) strain of rats, with respect to those from a water preferring (ANA) strain.

Aged↗
PubMed1983

Stereotaxic thalamotomy in 55 cases of dystonia.

The results of stereotaxic thalamotomy in 55 cases of dystonia are presented. The 16 cases with generalized dystonia were of varied pathogenesis, only 7 being typical of the idiopathic form of adolescent onset. Four of the 16 cases benefited considerably, but the others showed little or no lasting improvement. These results are in contrast to those obtained by Cooper (1976). Of the 27 cases with segmental or focal dystonia, 22 had spasmodic torticollis; 16 of these had bilateral thalamotomies, and 62 per cent were much improved. The incidence of operative complications, in particular dysarthria, was high following bilateral lesions. The incidence of hemiparesis, known to have persisted for more than a year, was 15 per cent. This complication was as frequent in those with unilateral as with bilateral thalamotomies. The incidence of dysarthria in those without preoperative bulbar dystonia was much higher in those who had bilateral lesions (56 per cent) as compared with those who had unilateral lesions (11 per cent). The group that has been identified as benefiting greatly from stereotaxic surgery comprises those with hemidystonia following unilateral brain damage. In these patients, symptomatic improvement in abnormal movement is striking and the incidence of operative side effects from unilateral lesions is low.

Dysarthria↗
PubMed1983

The metabolism of dopamine by both forms of monoamine oxidase in the rat brain and its inhibition by cimoxatone.

In the rat brain, dopamine is metabolised by both A and B forms of monoamine oxidase (MAO), although the A form of the enzyme is the major component. The Km of MAO-A toward dopamine (120 microM) is lower than the Km of MAO-B toward this substrate (340 microM). The activity of MAO-A was lower in old rats than in young rats, and the same degree of decrease was found for 5-hydroxytryptamine as for dopamine as substrates for this enzyme form. The activity of MAO-B was higher in the old rats, the degree of increase being the same for dopamine as for beta-phenethylamine as substrates for this enzyme form. The Ki values of the inhibition of MAO-A by cimoxatone and MD770222 (the principal plasma metabolite of cimoxatone) were independent of the substrate used to assay for activity, but were lower than the Ki values for the inhibition of MAO-B by these compounds.

Aging↗
PubMed1983

Cimoxatone is a reversible tight-binding inhibitor of the A form of rat brain monoamine oxidase.

Cimoxatone is a fully reversible inhibitor selective for the A form of monoamine oxidase. The inhibition is so potent against this enzyme form that it acts as a tight-binding inhibitor. Use of this inhibitor indicates that in rat brain homogenates the concentration of monoamine oxidase A is approximately 8-11 pmol . mg protein-1. Values similar to this were obtained by clorgyline titration, and both methods gave values similar to those found with a [3H]harmaline binding assay.

Animals↗
PubMed1983

Concentrations of 5-hydroxyindoleacetic acid and homovanillic acid in the cerebrospinal fluid of chronic therapy-resistant schizophrenics before and after hemodialysis therapy.

The concentrations of the monoamine metabolites 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA) have been determined by high-performance liquid chromatography in samples of lumbar cerebrospinal fluid from chronic therapy-resistant schizophrenics, both before and after either inactive or active hemodialysis for 10 weeks. A reasonable test-retest reliability was found for 5-HIAA during the inactive dialysis, but this was not found during active dialysis.

Adult↗
PubMed1983

The deamination of n-pentylamine by monoamine oxidase and a semicarbazide-sensitive amine oxidase of rat heart.

n-Pentylamine is deaminated by homogenates of rat heart. Clorgyline inhibition curves at 10 and 100 microM n-pentylamine indicated that this substrate was deaminated by MAO-A, -B and a clorgyline-resistant amine oxidase sensitive to inhibition by semicarbazide. These results have been compared with two other commonly used monoamine substrates, beta-phenethylamine and benzylamine.

Amine Oxidase (Copper-Containing)↗