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PubMed1971

5-hydroxytryptamine metabolism in sheep.

1. 5-Hydroxytryptamine (5-HT) (10 mg) administered intravenously to sheep was mostly excreted in the urine as 5-HT-O-glucuronide (705+/-162 mug, mean from six wethers+/-S.E.M.) and 5-hydroxyindolylacetic acid (5-HIAA) (6,850+/-1,538 mug). Oral administration of 5-HT (100 mg) led to the excretion of 590+/-212 mug 5-HT-O-glucuronide (mean from five wethers+/-S.E.M.) and 7,394+/-2,093 mug 5-HIAA in the urine.2. After administration of DL-5-hydroxytryptophan (DL-5-HTP) (20 mg i.v. or 200 mg orally) sheep excreted about 5 mg 5-HT in the urine together with 5-HT-O-glucuronide and 5-HIAA. The excretion of 5-HT suggests that some DL-5-HTP perfused the liver and the lungs before being decarboxylated.3. Twenty-four hour specimens of control urine contained 335+/-45 mug 5-HT, 909+/-90 mug 5-HT-O-glucuronide and 3,352+/-362 mug 5-HIAA (seven sheep in each instance). Thus endogenous 5-HT seemed to be conjugated with glucuronic acid to a greater extent than administered 5-HT.4. Although urinary 5-HIAA was reduced after a single dose of isocarboxazid (20 mg/kg daily) the 5-HT-O-glucuronide content of the specimens was not increased until two or three doses of the drug had been given.5. Carbon tetrachloride (4 ml orally) reduced the urinary excretion of 5-HT-O-glucuronide. Although the conjugation of 5-HT with glucuronic acid was inhibited after administration of carbon tetrachloride the excretion of 5-HT and 5-HIAA was not increased. This observation suggests that carbon tetrachloride impaired the formation or clearance of endogenous 5-HT in sheep.

5-Hydroxytryptophan↗
PubMed1995

The effects of phenelzine and other monoamine oxidase inhibitor antidepressants on brain and liver I2 imidazoline-preferring receptors.

1. The binding of [3H]-idazoxan in the presence of 10(-6) M (-)-adrenaline was used to quantitate I2 imidazoline-preferring receptors in the rat brain and liver after chronic treatment with various irreversible and reversible monoamine oxidase (MAO) inhibitors. 2. Chronic treatment (7-14 days) with the irreversible MAO inhibitors, phenelzine (1-20 mg kg-1, i.p.), isocarboxazid (10 mg kg-1, i.p.), clorgyline (3 mg kg-1, i.p.) and tranylcypromine (10 mg kg-1, i.p.) markedly decreased (21-71%) the density of I2 imidazoline-preferring receptors in the rat brain and liver. In contrast, chronic treatment (7 days) with the reversible MAO-A inhibitors, moclobemide (1 and 10 mg kg-1, i.p.) or chlordimeform (10 mg kg-1, i.p.) or with the reversible MAO-B inhibitor Ro 16-6491 (1 and 10 mg kg-1, i.p.) did not alter the density of I2 imidazoline-preferring receptors in the rat brain and liver; except for the higher dose of Ro 16-6491 which only decreased the density of these putative receptors in the liver (38%). 3. In vitro, phenelzine, clorgyline, 3-phenylpropargylamine, tranylcypromine and chlordimeform displaced the binding of [3H]-idazoxan to brain and liver I2 imidazoline-preferring receptors from two distinct binding sites. Phenelzine, 3-phenylpropargylamine and tranylcypromine displayed moderate affinity (KiH = 0.3-6 microM) for brain and liver I2 imidazoline-preferring receptors; whereas chlordimeform displayed high affinity (KiH = 6 nM) for these receptors in the two tissues studied, Clorgyline displayed very high affinity for rat brain (KiH = 40 pM) but not for rat liver I2 imidazoline-preferring receptors (KiH = 169 nM). 4. Preincubation of cortical or liver membranes with phenelzine (10-4 M for 30 min) did not alter the total density of I2 imidazoline-preferring receptors, indicating that this irreversible MAO inhibitor does not irreversibly bind to I2 imidazoline-preferring receptors. In contrast, preincubation with 10-6 Mclorgyline reduced by 40% the Bmax of [3H]-idazoxan to brain and liver I2 imidazoline-preferring receptors.5. Chronic treatment (7 days) with the inducers of cytochrome P-450 enzymes phenobarbitone (40 or 80 mg kg-1, i.p.), 3-methylcholanthrene (20 mg kg-1, i.p.) or 2-methylimidazole (40 mg kg-1, i.p.) did not alter the binding parameters of [3H]-idazoxan to brain and liver 12 imidazoline-preferring receptors.The compound SKF 525A, a potent inhibitor of cytochrome P-450 enzymes which forms a tight but reversible complex with the haemoprotein, completely displaced with moderate affinity (KiH = 2-10 microM)the specific binding of [3H]-idazoxan to brain and liver 12 imidazoline-preferring receptors. Preincubation of total liver homogenates with 3 x 10-4 M phenelzine in the presence of 10-3 M NADH, a treatment that irreversibly inactivates the haeme group of cytochrome P-450, did not reduce the density of liver I2 imidazoline-preferring receptors. These results discounted a possible interaction of [3H]-idazoxan with the haeme group of cytochrome P-450 enzymes.6. Together the results indicate that the down-regulation of I2 imidazoline-preferring receptors is associated with an irreversible inactivation of MAO (at least in the brain) that is not related either to the affinity of the MAO inhibitors for I2 imidazoline-preferring receptors or to an irreversible binding to these putative receptors. These findings indicate a novel effect of irreversible MAO inhibitors in the brain and suggest a new target for these compounds that could be of relevance in the treatment of depression, a disease in which an increased density of brain I2 imidazoline-preferring receptors has been reported.

Adrenergic alpha-Antagonists↗
PubMed1984

The Newcastle Endogenous Depression Diagnostic Index: validity and reliability.

The newcastle Endogenous Depression Diagnostic Index of Carney et al. was studied for reliability and validity. Good inter-rater reliability was obtained for diagnostic category and for item scores in 36 patients. The scale showed construct validity with reference to the Hamilton and Montgomery-Asberg rating scales. Concurrent validity was shown relative to other diagnostic scales of endogenous depression. Predictive validity was demonstrated in that endogenous and nonendogenous depressive responded differently to isocarboxazid. The continued use of 5 as the point of separation between endogenous and nonendogenous depression is questionable.

Depressive Disorder↗
PubMed1968

Growth hormone secretion during sleep.

Plasma growth hormone (GH), insulin, cortisol, and glucose were measured during sleep on 38 nights in eight young adults. Blood was drawn from an indwelling catheter at 30-min intervals; EEG and electrooculogram were recorded throughout the night. In seven subjects, a plasma GH peak (13-72 mmug/ml) lasting 1.5-3.5 hr appeared with the onset of deep sleep. Smaller GH peaks (6-14 mmug/ml) occasionally appeared during subsequent deep sleep phases. Peak GH secretion was delayed if the onset of sleep was delayed. Subjects who were awakened for 2-3 hr and allowed to return to sleep exhibited another peak of GH secretion (14-46 mmug/ml). Peak GH secretion was not correlated with changes in plasma glucose, insulin, and cortisol. The effects of 6-CNS-active drugs on sleep-related GH secretion were investigated. Imipramine (50 mg) completely abolished GH peaks in two of four subjects, whereas chlorpromazine (30 mg), phenobarbital (97 mg), diphenylhydantoin (90 mg), chlordiazepoxide (20 mg), and isocarboxazid (30 mg) did not inhibit GH peaks. Altered hypothalamic activity associated with initiation of sleep results in a major peak of growth hormone secretion unrelated to hypoglycemia or changes in cortisol and insulin secretion.

Adult↗
PubMed1986

Comparative effects of seven antidepressant regimes on appetite, weight and carbohydrate preference.

Appetite, weight, and preference for carbohydrate-containing food were followed in patients treated in double-blind trials of seven antidepressant regimes. Trimipramine and isocarboxazid combined had a significant effect in increasing appetite, carbohydrate preference, and weight; in patients who had lost appetite at presentation and were on this treatment, improvement in Hamilton score was linked to increase in weight--a finding not true of the other treatments.

Antidepressive Agents↗
PubMed1995

Serotonin syndrome.

We describe a patient treated with trazodone, isocarboxazid, and methylphenidate hydrochloride who developed confusion, agitation, poor concentration, rigidity, myoclonus, involuntary movements, orthostatic hypotension, and hyperreflexia. CK was normal, and the syndrome resolved spontaneously over 12 hours. The serotonin syndrome occurs following the use of serotomimetic agents (serotonin reuptake inhibitors, tricyclic and tetracyclic antidepressants, tryptophan, 3,4-methylenedioxy-methamphetamine, dextromethorphan, meperidine, S-adenosylmethionine) alone or in combination with monoamine oxidase inhibitors. It is characterized by various combinations of myoclonus, rigidity, hyperreflexia, shivering, confusion, agitation, restlessness, coma, autonomic instability, low-grade fever, nausea, diarrhea, diaphoresis, flushing, and rarely, rhabdomyolysis and death.

Depressive Disorder↗
PubMed1987

Effects of RS-2232, a potential antidepressant, on the levels of monoamines, precursor amino acids and their related metabolites in mouse brain.

The effects of RS-2232, a new antidepressant, on the levels of monoamines, precursor amino acids and their related metabolites in mouse brain were investigated and compared with some clinically effective antidepressants. RS-2232 (3, 10 and 30 mg/kg, p.o.) increased the levels of norepinephrine (NE), dopamine (DA) and 5-hydroxytryptamine (5-HT) dose-dependently, 60 min after administration. Tyrosine (TYR) levels were not changed, but tryptophan (TRP) was significantly increased by 20% at 30 mg/kg of the compound. On the other hand, DA metabolites such as 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were significantly reduced at all doses. 5-Hydroxyindoleacetic acid (5-HIAA), a 5-HT metabolite, was decreased by 32% at 10 mg/kg. These changes caused by RS-2232 administration were similar to those of the classical inhibitor of monoamine oxidase (MAO), isocarboxazid (ISO), but rather different from those of imipramine (IMP) and mianserin (MIA). RS-2232 and ISO antagonized against reserpine (2 mg/kg, s.c.)-induced changes in the contents of monoamines and their metabolites. Furthermore, time-course experiments clearly showed that increase in the levels of monoamines by 10 mg/kg of RS-2232 was restored to the control levels within a few hours. These results suggest that RS-2232 has reversible MAO inhibiting properties in vivo in mouse brain.

Amino Acids↗
PubMed1993

Differences in the induction of carboxylesterase isozymes in rat liver microsomes by perfluorinated fatty acids.

1. Differences in the ability of metabolically-inert peroxisome proliferators (perfluoro-n-decanoic acid (PFDA, C10), perfluoro-n-octanoic acid (PFOA, C8), perfluorooctane sulphonic acid (PFOS, C8) and 1-H,1-H-pentadecafluoro-n-octanol (PFOL, C8)) to induce three forms of hepatic microsomal carboxylesterase, namely RL1, RL2 and RH1, in the male rat were studied by measuring changes in hydrolytic activities towards p-nitrophenyl acetate (PNPA), isocarboxazid (ISOC) and butanilicaine (BUTA), which are thought to be specific substrates for RL1, RL2 and RH1, respectively, and by evaluating changes in the contents of the three isozymes by radial immunodiffusion assay with specific antibodies. 2. The administration of PFDA rather specifically decreases PNPA hydrolase activity and RL1 content. On the other hand, PFOA, PFOS and PFOL markedly increase all three hydrolase activities and the content of all three isozymes (except RH1 in the case of PFOA, where the increase was not statistically significant). 3. The correlations between hydrolase activities and isozyme contents supported specificity of the three substrates, with the exception that the content of the predominant isozyme, RL2, showed a higher correlation with BUTA hydrolase activity than with ISOC hydrolase activity. 4. In conclusion, we have demonstrated that metabolically-inert perfluorinated fatty acids induce hepatic microsomal carboxylesterase isozymes, as determined by radial immunodiffusion analysis using specific antibodies. This is the first report that perfluorinated fatty acid affect carboxylesterase isozymes in rat liver microsomes, and is indicative of the importance of peroxisome proliferators in hepatic metabolism of xenobiotics. Further work is needed to determine the regulatory mechanisms involved.

Acetanilides↗
PubMed1975

[Effects of beta-phenylethylamine derivatives on the central nervous system. (5) Changes in the volume of spontaneous movement in mice with intracerebral administration of tyramine].

Influence of tyramine (Ty) on behavioural changes in mice was studied and the following results obtained: 1) 30 min after Ty (160 mug, i.c.), brain noradrenaline and serotonin levels decreased while dopamine levels increased. 2) When Ty was injected i.c. into isocarboxazide (Iso) pretreated mice, spontaneous motor activity (SMA) measured by photo-cell counters method increased markedly but SMA by wheel cage method decreased. 3) When Ty was injected i.c. into Iso and p-chlorophenylalanine (p-CPA) (400 mg/kg, i.p., daily X 2) pretended mice, SMA measured by photo-cell counters method increased. While, SMA increased from 30 to 90 min after Ty, SMA measured by wheel cage method decreased till 30 min after Ty. 4) When Ty was injected i.c. into Iso and alpha-methyl-p-tyrosine (alpha-MPT) (125 mg/kg, i.p., daily X 2), SMA measured by photo-cell counters method decreased markedly when compared with Iso+saline treated group. When SMA was measured by wheel cage method, a difference between alpha-MPT+Iso-Ty treated group and Iso-saline group was not obtained. 5) When Ty was injected i.c. into p-CPA+alpha-MPT+Iso pretreated mice, SMA measured by photo-cell counters method did not show any increase compared with control group. 6) SMA produced by Iso-Ty in mice pretreated with haloperidol was significantly inhibited. A 50% dose of inhibition was seen with 0.3 mg/kg. From our results, it appears that an increase of SMA induced by Iso+Ty as revealed by the photo-cell counters method may be related to brain catecholamines and serotonin while a decrease of SMA in wheel cage method may be related to brain serotonin.

Animals↗
PubMed1989

[Hyperpyrexia following poisoning with a monoamine oxidase inhibitor].

A 35-year old woman took 1 gram of isocarboxazide (Marplan) with suicidal intent. She was admitted to hospital approximately six hours later with nystagmus, generalized hypertonia and jaw trismus. Four hours after admission, she became comatose with poor ventilation, increasing rigidity of all muscles and temperature rising to 41.1 degrees C. She was intubated and ventilated. Dantrolen was used for muscular relaxation but because of minor unfavourable experience with dantrolen pancuron was employed instead. After this, the temperature fell and the patient became relaxed. After two days, she was extubated and transferred to psychiatric care in a normal physical state. It is concluded that a non-depolarizing neuromuscular blocking drug should be used in patients with hyperpyrexia caused by MAOI overdose, because of the generally more favourable experience with these drugs and because of the potential hepatoxicity of dantrolen.

Adult↗
PubMed1977

[Central effects of beta-phenylethylamines. (8). Increase in spontaneous motor activities of mice caused by intracerebrally administered metaramino].

Metaraminol (MA) (40, 80 and 160 microng) was injected i.c. into mice and spontaneous motor activity (SMA) measured by photo-cell counters method was found to increase 30 min after the injection. Ninety min after, the SMA was restored to the saline treated control. MA (80 microng i.c.) was also injected into isocarboxazide (Iso) pretreated mice and the SMA markdly increased as compared with the Iso+saline treated group or tween+MA treated group. When MA was injected i.c. into alpha-methyl-p-tyrosine (alpha-MT) pretreated mice, the SMA significantly increased as compared with that of the alpha-MT+saline treated group, but there was a decrease as compared with that of the tween+saline or tween+MA treated group. In alpha-MT treated mice. L-Dopa restored the hyper-motor activity of animals treated with MA. Diethyldithiocarbamate (700mg/kg i.p.) had no influence, whereas haloperidol markedly blocked the hyper-motor activity induced by MA. The hyper-motor activity induced by MA in mice raised the question of a possible role of noradrenaline and dopamine in the mediation of this action.

Animals↗
PubMed1993

Effectiveness of piracetam in cortical myoclonus.

Twenty-one patients with disabling spontaneous, reflex, or action myoclonus due to various causes, who had shown apparent clinical improvement on introduction of piracetam, entered a placebo-controlled double-blind crossover trial of piracetam (2.4-16.8 g daily). All but one patient had electrophysiological evidence of cortical myoclonus. Patients were randomly allocated to a 14-day course of piracetam followed by identical placebo, or placebo followed by piracetam. Nineteen patients received piracetam/placebo in addition to their routine antimyoclonic treatment (carbamazepine, clonazepam, phenytoin, primidone, sodium valproate, or tryptophan plus isocarboxazid, alone or in combination) and two received piracetam/placebo as monotherapy. All patients were rated at the end of each treatment phase using stimulus sensitivity, motor, writing, functional disability, global assessment, and visual analogue scales. Ten of the 21 patients had to be rescued from the placebo phase of the trial because of a severe and intolerable exacerbation of their myoclonus. No patients required rescue from the piracetam phase of the double-blind trial. When the 21 patients were considered together, there was a significant improvement in motor, writing, functional disability, global assessment, and visual analogue scores during treatment with piracetam compared with placebo. The total rating score also improved significantly with piracetam, by a median of 22%. Piracetam, usually in combination with other antimyoclonic drugs, is a useful treatment for myoclonus of cortical origin.

Adult↗
PubMed2000

R-(-)-Deprenyl inhibits monocytic THP-1 cell neurotoxicity independently of monoamine oxidase inhibition.

R-(-)-Deprenyl (deprenyl, selegiline), a monoamine oxidase B (MAO-B) inhibitor, delays progression of Parkinson's disease. This action could be mediated by inhibition of MAO-B but there may also be unrelated mechanisms. Direct neuroprotective and antiapoptotic actions of deprenyl have previously been observed in vitro. Here we describe an antineurotoxic action of deprenyl which is independent of direct neuronal effects. We employed a previously described assay in which human neuroblastoma SH-SY5Y cells are exposed to cell-free supernatants of stimulated human monocytic THP-1 cells. Deprenyl reduced the secretion of neurotoxic products by such stimulated cells in a concentration-dependent manner, while the MAO inhibitors iproniazid, isocarboxazid, nialamide, tranylcypromine, phenelzine, and clorgyline were without effect. No antineurotoxic action was observed when deprenyl was added directly to SH-SY5Y cells. Messenger RNAs for MAO-A and MAO-B were not detected in THP-1 cells by reverse transcriptase-polymerase chain reaction analysis of total RNA extracts. Such mRNAs were easily detected in extracts of SH-SY5Y cells under comparable conditions. MAO enzymatic activity was also undetectable in THP-1 cell lysates, while it was readily observed in SH-SY5Y cells. It was concluded that the effect of deprenyl on THP-1 cells was not mediated by MAO and that deprenyl itself was not protecting neurons. These data suggest that deprenyl may have utility in neurodegenerative diseases due to its antineurotoxic actions.

Alzheimer Disease↗
PubMed1982

Behavioural teratology: post-natal consequences of drug exposure in utero.

The effects of pre-natal exposure to drugs that subsequently affect the post-natal behaviour without apparently causing noticeable brain damage forms the subject of behavioural teratology. This review summarizes the experimental studies of several investigators who showed that pre-natal administration of such psychotropic drugs as meprobamate, isocarboxazid and reserpine reduced the maze-learning ability of the mature offspring. A more detailed survey of the effects of D-amphetamine and diazepam is then given. Both drugs were not foetotoxic and only caused appreciable changes in locomotor activity of the offspring at least 14 days after birth. With the amphetamine treated rats, these changes were biphasic (elevated at 15 days and reduced at 21 days) whereas the diazepam treated animals showed a reduction in locomotor activity for at least 21 days after birth. The results of our own studies, and those of others, do not enable a correlation to be made between the effects of the various drugs on the development of specific central neurotransmitters and the behavioural deficits noticed. The review concludes with an outline proposal for screening drugs for their potential as behavioural teratogens. The possible mechanisms whereby behavioural teratogens may cause subtle changes in the maturation of the brain are also outlined.

Amphetamines↗
PubMed1977

Effect of benzodiazepines on central serotonergic neuron systems.

Intracerebral (i.c.) injection of serotonin (5-HT) into mice induced head twitches in a dose-dependent manner at 10 min after injection. The head twitches induced by 5-HT (i.c.) were potentiated by the pretreatment of isocarboxazid (3 mg/kg i.p.), and inhibited by cyproheptadine (0.3 mg/kg i.p.), a 5-HT antagonist. Benzodiazepines such as fludiazepam and diazepam potentiated the head twitches induced by 5-HT (i.c.) in a dose-dependent manner. Mescaline (50 mg/kg i.p.) also induced head twitches in mice at 15 and 30 min after injection. Benzodiazepines potentiated the head twitches induced by mescaline in a dose-dependent manner. Cyproheptadine blocked the potentiating effect of benzodiazepines on the head twitches induced by both 5-HT (i.c.) and mescaline. By repeated administration of fludiazepam or diazepam for 5 days, the potentiating effect of both drugs on the head twitches induced by mescaline was unchanged and their anticonvulsant effects were not modified. In contrast, the potency of both drugs on muscle relaxation was significantly decreased by repeated administration. Benzodiazepines failed to change the uptake of 5-HT into the synaptosomal fractions from the rat brain. These results suggest that the pharmacological action of benzodiazepines is derived at least in part from their activating effect on 5-HT receptors.

Animals↗
PubMed1984

Assessment of the anticholinergic effects of antidepressants in a single-dose cross-over study of salivation and plasma levels.

In order to evaluate the anticholinergic effect of antidepressant drugs, 11 healthy volunteers were given single oral doses of reference drug, test drugs or placebo on a double-blind basis at weekly intervals. The doses corresponded to average daily patient medications. Spontaneous whole mouth and parotid salivation, and plasma levels of drug and possible metabolites were measured 2, 6 and 10 h after drug administration. Moderate, statistically significant inhibition of salivation was found when nortriptyline, imipramine-N-oxide and mianserin were given. Less pronounced, but still statistically significant inhibition occurred after ingestion of nomifensine and zimelidine. The zimelidine effect was exclusively due to the metabolite norzimelidine, and the inhibition after imipramine-N-oxide was mainly due to the metabolite imipramine, but imipramine-N-oxide itself also had slight activity. Isocarboxazide and lithium had no effect on salivation. From these results and reported values of pharmacokinetic variables, the average level of anticholinergic activity during long-term treatment may be predicted: for mianserin and (nor-)zimelidine moderate inhibition of salivation, although less pronounced than with nortriptyline; for nomifensine no clinically significant effect; and for imipramine-N-oxide a negligible contribution from the unmetabolized drug.

Adult↗
PubMed1987

Effect of decarboxylase inhibitors on brain p-tyrosine levels.

A number of inhibitors of L-aromatic amino acid decarboxylase (AAD) and monoamine oxidase (MAO) were tested to determine whether they also inhibited tyrosine aminotransferase (TAT). The AAD inhibitors carbidopa, NSD-1015, NSD-1034 and Ro4-5127 inhibited liver TAT. Carbidopa inhibited brain AAD and liver TAT equally well. In contrast, other AAD inhibitors (Ro4-4602 and alpha-monofluoromethyldopa) did not inhibit TAT. Phenelzine, an MAO inhibitor, inhibited liver TAT, but other MAO inhibitors (tranylcypromine and isocarboxazid) did not. Systemic administration of those drugs that were found to be inhibitors of TAT in vitro caused significant increases in rat brain p-tyrosine levels.

Animals↗