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Biomedical subjects

M B Youdim

Publications and source records attributed to M B Youdim.

At least 253 records · Page 14Linked to original sources
PubMed1981

Effect of prolactin and prostaglandins on the stimulation of prolactin binding sites in the male rat liver.

Induction of prolactin hepatic receptors in the male rat by exogenous prolactin and the possible involvement of prostaglandins in this process were studied. When ovine prolactin 500 microgram/kg was administered sc in saline containing 10% PVP (polyvinylpyrrolidone), twice daily for 6.5 days and the rats killed 48 h after the last injection, the specific binding of 125I-labelled ovine prolactin to prolactin hepatic receptors was raised 26-fold, while administration of prolactin in saline only caused a 7-fold increase. A well correlated log dose-response relationship was demonstrated between 12.5 and 500 microgram of prolactin in saline-PVP, with lowest dose causing an 18-fold increase in binding. A shorter 4.5 day treatment of prolactin in saline-PVP caused only a small 3-fold increase in prolactin binding. Scatchard analysis showed that these increases resulted from increases in receptor concentration. The effect of prolactin on the induction of the hepatic receptors could not be mimicked by PGE1, PGE2 or PGF2 alpha, nor could PGF2 alpha synergize with a short treatment with prolactin. Further, indomethacin caused no significant effect on this action of prolactin. It seems that prolactin does not induce its own receptors in the rat liver by stimulation of prostaglandins in this tissue.

Animals↗
PubMed1981

Effects of TRH and PS-24 on colonic temperature and motor activity of rats: possible role of dopamine.

TRH and PS-24 (a TRH peptidase resistant analogue) induce different effects on body temperature and motor activity in rats kept at 4 degrees C. PS-24 induced hypothermia, but TRH did not. PS-24 induced hypermotility, while TRH induced slight hypomotility. The thermal effect of TRH in hypophysectomized rats was similar to its effect in control intact rats, but PS-24 induced marked hypothermia in hypophysectomized rats. While TRH partially blocked d-amphetamine-induced hypothermia, PS-24 induced marked hypothermia in hypophysectomized rats. While TRH partially blocked d-amphetamine-induced hypothermia were blocked in olfactory tubercle-lesioned rats. The data indicate that the thermal effects of PS-24 are mediated by the dopaminergic neurons in the nucleus accumbens and are reversible by pretreatment with haloperidol in hypophysectomized rats. In addition, no correlation between the effects of the treatments on thermoregulation and motor activity was found.

Animals↗
PubMed1981

Human platelet function as a model for investigating the clinical efficacy of chlorpromazine.

1 Enhancement of platelet aggregation response (PAR) to 5-hydroxytryptamine (5-HT) in some schizophrenic patients receiving chlorpromazine (CPZ) may provide a biological index for the efficacy of this drug. 2 In a double-blind study 33 schizophrenic patients hospitalized following their first psychotic breakdown were followed up clinically with concurrent assessment of their PAR to 5-HT. The patients followed a standardized treatment schedule with (CPZ) as the sole antipsychotic medication. 3 Twelve patients (Group A) developed an enhanced biphasic 5-HT PAR, within 2-3 weeks and improved clinically by the sixth week. In most cases, the appearance of the enhanced biphasic PAR preceded clinical improvement. Twenty-one patients (Group B) did not have enhanced biphasic PAR to 5-HT by the sixteenth week of treatment. However, twelve subjects from this group showed clinical response to CPZ by the end of this period, while the remaining patients did not improve. 4 The enhanced PAR to 5-HT in Group A discriminated best between good and bad outcome cases when Feighner's research diagnostic criteria were used. We could not confirm the previous reports of platelet aggregation response to dopamine in pre- or post-chlorpromazine treatment.

Adult↗
PubMed1981

Ontogenesis of uptake and deamination of 5-hydroxytryptamine, dopamine and beta-phenylethylamine in isolated perfused lung and lung homogenates from rats.

1. Uptake of 5-hydroxytryptamine (5-HT) and beta-phenylethylamine (PEA) was studied in perfused lung from male rats between 10 and 70 days old. 2. Monoamine oxidase (MAO) activity towards 5-HT, PEA and dopamine was studied in homogenate preparations of lung from rats aged between 5 and 80 days. 3. Uptake of 5-HT (10 microM) decreased throughout the age range studied but uptake of PEA (50 microM) increased for the first 30 days and beyond this age it decreased. Metabolites formed for both amines reflected the changes in uptake. 4. MAO activity deaminating 5-HT is well developed by day 10 and reaches its maximum by day 40. For dopamine and PEA, MAO activity remained low until day 20, and the developed rapidly, reaching a maximum by day 40 for dopamine; activity towards PEA did not reach a maximum by day 80. 5. These results show that uptake and MAO activity changes with age and thus the lung responds like other tissues. 6. These results also demonstrate the independent development of uptake and MAO activity towards 5-HT, PEA and dopamine.

Age Factors↗
PubMed1981

Effect of hyperoxia on uptake and metabolism of 5-hydroxytryptamine and beta-phenylethylamine in rat lung: a sex difference.

1 The uptake of 5-hydroxytryptamine (5-HT) and beta-phenylethylamine (PEA) and their deamination by monoamine oxidase (MAO) were studied in perfused lung from male and female rats exposed to 100% O(2) at 1 ATA for up to 60 h.2 The uptake and metabolism of 5-HT in lungs from both male and female rats was not changed by exposure to O(2).3 The uptake and metabolism of PEA by lungs from male rats was unchanged. Uptake of PEA by lungs from female rats was inhibited 20% and 62% after 37 h and 50 h exposure respectively.4 MAO activity, both in vitro and in perfused lung, was increased towards PEA after 35 h of hyperoxia.5 Metabolism of PEA in perfused lung, measured over 30 min, was inhibited 52% after 50 h of O(2) hyperoxia.6 These results show that exposure to high concentrations of O(2) damages lung, resulting in inhibition of uptake of PEA and consequently in inhibition of metabolism of PEA.7 These results also indicate that, in lung from female rats, MAO-type B is more susceptible to changes in O(2) tension than MAO type A.

Animals↗
PubMed1981

Selective acetylenic 'suicide' and reversible inhibitors of monoamine oxidase types A and B.

1 A number of aromatic-N-propargyl (acetylenic) compounds and indoleamines were tested for their inhibitory action on monoamine oxidase (MAO) type A and type B using the substrates 5-hydroxytryptamine (5-HT), beta-phenylethylamine (PEA) and dopamine. 2 Structure activity studies with aromatic-N-propragyl (acetylenic) derivatives have shown that MAO inhibitory potency is least dependent on the aromatic portion of the compounds. N-methylated propargyl derivatives are the most active and replacement of the methyl group with a higher alkyl or aromatic group results in significant reduction of activity. The triple bond in the N-propargyl portion is absolutely essential for activity and must be beta-to the nitrogen. It is the acetylenic group that gives these compounds their irreversible MAO inhibitory property. 3 The present study has indicated that since the acetylenic compounds resemble the enzyme substrates the distance between the aromatic ring and the N-propargyl terminal is crucial in designating the type A or type B MAO inhibitory property. For MAO type A inhibition, a distance equivalent to at least three carbon units is required, while for the inhibition of the B type enzyme this distance can be 1 or 2 carbon units. 4 The compounds AGN-1133 and AGN-1135 show most promise in Parkinson's disease or as anti-depressants because of their irreversible selective type B MAO inhibition in vitro and in vivo. 5 A number of indoleamine derivatives were found to be reversible selective type A inhibitors.

Acetylene↗
PubMed1981

Tyramine antagonistic properties of AGN 1135, an irreversible inhibitor of monoamine oxidase type B.

1 The effects of the irreversible monoamine oxidase (MAO) inhibitors, AGN 1133, AGN 1135 and (-)-deprenyl, on tyramine and noradrenaline responses and uptake of [3H]-metaraminol were investigated in the isolated vas deferens of the rat. Uptake of [3H]-metaraminol and [3H]-octopamine was compared in mouse vas deferens. The modification of tyramine and noradrenaline-induced pressor responses by AGN 1133 and AGN 1135 was examined in anaesthetized rats and cats. 2 AGN 1133 (7.5 x 10(-6)M) greatly potentiated responses to tyramine in the rat isolated vas deferens. Both AGN 1135 and (-)-deprenyl inhibited tyramine responses selectively at concentrations above 10(-5)M (which caused almost complete inhibition of MAO types A and B) but tyramine responses were potentiated on washing out the inhibitors. 3 AGN 1135 (10(-4)M) and (-)-deprenyl (10-5)M) inhibited [3H]-metaraminol uptake by about 20% in rat and mouse vas deferens; neither inhibitor affected [3H]-octopamine uptake in mouse vas deferens. Desmethylimipramine (10(-6)M) inhibited amine uptake by more than 70%. 4 AGN 1133 (1.5 mg/kg) potentiated pressor responses to tyramine in rats and cats whereas AGN 1135 (1.5 mg/kg) did not. 5 AGN 1135 possesses tyramine antagonistic activity which is qualitatively similar to that of (-)-deprenyl but which cannot satisfactorily be explained by inhibition of neuronal or granula amine uptake.

Animals↗
PubMed1980

Inactivation of monoamines by the lung.

Inactivation of monoamines was the first pharmacokinetic property of lung to be identified. For some amines inactivation in perfused lung but not in liver is limited by uptake. Inactivation of beta-phenylethylamine in lung is limited not by uptake but by the activity of intracellular monoamine oxidase. The uptake of this amine is like that of basic drugs such as amphetamine and propranolol. Changes in the external environment of the lung (exposure in vivo to gaseous anaesthetics or to high concentrations of oxygen, greater than 95%) change amine inactivation processes in lung. The oestrous cycle and administration of ovarian steroids also affect the inactivation of 5-hydroxytryptamine and phenylethylamine. Monoamine oxidase activity in lung homogenates is highest at met- and lowest at pro-oestrus for both substrates. However, in perfused lung, inactivation is better correlated with variations in uptake. Therefore the main effect of the oestrous cycle is on uptake rather than on enzymic activity. Uptake processes are thus crucial determinants of monoamine activation in lung and the pharmacokinetic properties of lung are capable of responding to changes in its internal or external environment.

Amines↗
PubMed1980

Monoamine oxidase inhibitors as anti-depressant drugs and as adjunct to L-dopa therapy of Parkinson's disease.

Monoamine oxidase inhibitors have been used in psychiatric disorders for many years. However, due to the toxic side effects of the drugs they are often replaced by the tri- and tetracyclic antidepressants. Selective monoamine oxidase inhibitors like deprenyl, however, have been tried with success as adjuvant therapy in Parkinson's disease and depression because of their ability to inhibit dopamine oxidation. Perhaps their greatest advantage is their lack of pressor response.

Antidepressive Agents↗
PubMed1980

Antidepressant potentiation of 5-hydroxytryptophan by L-deprenil in affective illness.

In an open trial study, L-Deprenil, an irreversible selective MAO-B inhibitor without 'chesse effect' was given to 14 patients with unipolar and bipolar depression receiving L-5-Hydroxytryptophan (L-5-HTP) and benzerazide. Ten out of 14 patients showed a good response to the combination of drugs and a correlation was found between the degree of platelet MAO inhibition and clinical response. In a double-blind controlled study, 18 affectively ill patients were randomly allocated to L-Deprenil plus L-5-HTP and benzerazide, 21 patients were treated with L-5-HTP and benzerazide and 19 patients with placebo only. Patients treated with the combination of L-Deprenil and L-5-HTP showed a significantly greater clinical improvement than placebo patients but this was not the case for patients treated with 5-HTP alone. A positive relationship was demonstrated between mood improvement and degree of platelet MAO inhibition in patients treated with L-Deprenil.

5-Hydroxytryptophan↗
PubMed1980

Biochemical characterization of the active site of brain monoamine oxidase.

Until recently little was known concerning the chemical details of the mechanism of interaction of flavin-linked mitochondrial membrane bound monoamine oxidase (MAO) with its substrates and inhibitors. Substrates which have enzymes as their targets have been valuable in elucidating active site residues and structural features. Acetylenic amines as exemplified by clorgyline, deprenyl and pargyline are called 'suicide inhibitors' because an irreversible inhibitor is formed by the action of MAO from a relatively innocuous compound which acts as a substrate. These inhibitors can selectively inactivate MAO 'type A' and/or 'type B'. MAO isolated in homogeneous form from liver or kidney contains 1 mole of covalently bound coenzyme, cysteinyl-flavin, per mole enzyme. The flavin is bound to a pentapeptide via the thio-ether of cysteine at the 8 alpha-position of the isoalloxazine. A comparison of the inhibitory effects of clorgyline, deprenyl and pargyline on liver enzyme preparations from bovine or rat have confirmed our expectation that these irreversible inactivators form the same type of adduct with the cysteinyl-flavin active site of MAO 'type A' and 'type B', and that binding is stoichiometric at the N-5 of the covalently bound flavin in a flavocyanine linkage. Substrates protect from inhibition. In contrast to the reported observation of Tipton (39), pig brain mitochondrial MAO purified by two alternative methods contains cysteinyl-flavin in substantial amounts. The turnover number of enzyme from brain per mole of cysterinyl-flavin in apparently homogeneous samples is nearly the same as that of highly purified kidney and liver enzyme. Thus it is apparent that brain MAO also contains cysteinyl-flavin at the active center and therefore it is expected that acetylenic as well as hydrazine inhibitors form the same linkage with the flavin moiety as that formed with enzyme from peripheral tissues. A specific inhibitor for the deamination and potentiation of dopamine formed in the brain of Parkinsonian patients after treatment with L-Dopa has been regarded desirable. Deprenyl, a selective MAO 'type B inhibitor without the 'cheese effect', is the most potent inactivator of human brain MAO, and clinical results show that the drug is very useful in the treatment of Parkinson's disease and depression.

Antidepressive Agents↗
PubMed1980

Serotonin receptor site in human platelets from control and chlorpromazine treated subjects.

Human platelets are activated by epinephrine (E), norepinephrine (NE), ADP, and serotonin (5-HT) by a process that can be measured as cellular aggregation and at the completion of which 5-HT is released from storage vesicles. Among the three neurotransmitters, only the 5-HT response at its maximum concentration is transient (reversible), and in a given platelet preparation can be produced only once. This effect is highly specific. Structural analogues of 5-HT, such as tryptolines (TLNs) or 5-methoxy-N,N dimethyltryptamine (5-MNDTA), with agonist properties in animal behavioral models, cannot induce a 5-HT-like response in the platelet system; however, they competitively inhibit the platelet aggregation response (PAR) to 5-HT if preincubated with the platelets. Inhibition constants of TLNs for 5-HT and E are of an order of magnitude higher than the KM values for aggregation. A transient '5-HT-like' PAR can be produced by compounds structurally unrelated to 5-HT, such as the following: a preparation of adenylylimidodiphosphate (AIP) can cause a transient PAR similar to the 5-HT response with a KM of 0.2-0.5 mM. Experimental evidence suggests that this ATP analogue is also an inhibitor of the second phase of aggregation (17) and release of dense vesicle content, thereby exhibiting only a monophasic and transient PAR. A '5-HT-like' PAR can also be produced by a combination of E and ATP at concentrations at which neither by itself causes aggregation. These transient PARs may serve as tools to investigate the underlying mechanism of the self-restricted yet exhaustible ability of platelets to respond to the aggregation inducer. Drug-free schizophrenic patients having their first psychotic episode have a transient 5-HT PAR indistinguishable from that of control subjects. However, after 2-3 weeks on chlorpromazine (CPZ) as the sole neuroleptic, the patients defined as schizophrenic could be divided into 2 sub-groups: a) those who developed an enhanced and irreversible PAR to 5-HT and were reported as good clinical responders; and b) those whose transient 5-HT PAR remained unchanged for 10-12 weeks and were reported as slow, poor or non-responders. The study of the mechanism of the enhanced 5-HT PAR in CPZ-treated patients may contribute to the understanding of certain aspects of the mode of action of CPZ.

Adenosine Triphosphate↗
PubMed1979

Developmental changes in the activity of catechol-O-methyl transferase in rat and rabbit fetuses.

Variations in the activity of catechol-O-methyltransferase (COMT) in peripheral organs in the brain of rat and rabbit fetus during development have been studied. The pattern of changes in COMT activity in rat fetus differed to a great extent according to the respective organs studied. In kidney and liver sharp declines occurred between days 18 and 20 and days 16 and 18 of fetal life respectively, followed by progressive increases up to onset of birth. Brain COMT of rat fetus declined progressively from day 16 of fetal life up to 0 hours after birth, while COMPT activity in adrenal and heart showed its maximum value at the 20th day of fetal life and at 0 hours after birth respectively. In the contrary, the developmental changes in activity of rabbit fetus were very similar in all the organs except in the adrenals, since it decreased between day 24 to 8 hours after birth in heart, liver, brain and kidney. In the adrenals an important increase could be seen between the 24th and 28th days of fetal life. Rat COMT activity during 4 and 8 hours of postnatal life in heart, liver and kidney declined from 0-hour value but it increased in the brain and adrenals. COMT in rabbit increased after birth in all the organs studied. The results suggest that metabolic degradation of catecholamines by 3-O-methylation in rat and rabbit fetus may have different developmental patterns to some extent according to the physiological status of the organ concerned. These species related differences for monoamine inactivation during fetal development may suggest a physiological role for COMT as a marker of the maturation of the autonomic nervous system.

Adrenal Glands↗
PubMed1979

Tranylcypromine ('Parnate') overdose: measurement of tranylcypromine concentrations and MAO inhibitory activity and identification of amphetamines in plasma.

A case of tranylcypromine overdose is reported. Tranylcypromine, amphetamine methamphetamine and phenylethylamine were detected in the plasma by gas chromatography and their identity confirmed by mass spectrometry. The data suggested that the amphetamines were metabolic products of tranylcypromine. Platelet monoamine oxidase activity was more than 95% inhibited during the 72 h after the overdose despite complete clinical recovery by that time. The possible role of amphetamines and phenylethylamine in causing the clinical manifestations of tranylcypromine overdose is discussed.

Amphetamine↗