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Biomedical subjects

T B Cooper

Publications and source records attributed to T B Cooper.

At least 217 records · Page 12Linked to original sources
PubMed1984

Imipramine and its metabolites: relationship to cerebral catecholamines in rats in vivo.

The relationship between blood and brain levels of imipramine (IMI) and its demethylated and hydroxylated metabolites was studied in rats after chronic administration of IMI. It was found that the combined concentration of IMI and its metabolites was about 10-fold higher in brain than in plasma and this ratio was independent of the dose or the time of sacrifice. However, the brain-to-plasma ratio for the individual compounds varied with the time of sacrifice after the last IMI dose. The metabolite, didesmethylimipramine, was found in significant quantities in plasma and brain tissue with a distribution similar to that of desmethylimipramine. The hydroxylated metabolites constituted less than 6% of the combined concentration of IMI and its metabolites in plasma. Small amounts of 2-OH-desmethylimipramine were found in brain but 2-OH-IMI was rarely detected in cerebral tissue. With the exception of the hypothalamus, there were no significant differences in the distribution of IMI or its metabolites among various brain regions. The relationship between the concentrations of IMI or its active metabolites in plasma or brain and the extracellular availability of cerebral norepinephrine was also studied and found to be nonlinear: the concentration of norepinephrine in the cerebroventricular fluid approached a maximal value when the combined concentration of IMI and its metabolites was 10 micrograms/g in the brain or 1.5 micrograms/ml in plasma. Cerebroventricular application of IMI or each of its metabolites resulted in an increased concentration of both norepinephrine and dopamine in the cerebroventricular fluid whereas the concentrations of catecholamine metabolites remained unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1983

The use of imipramine in depressed patients with congestive heart failure.

Previous studies of left ventricular performance (LVP) in depressed patients receiving tricyclic antidepressants have been performed on patients without severe heart disease. This study reports the effect of imipramine hydrochloride on LVP, assessed by radionuclide angiography, in a group of depressed patients with notable preexisting left ventricular dysfunction. Ejection fraction was measured at rest by first-pass radionuclide angiography before and after treatment with imipramine. Ejection fraction was unchanged during treatment, but seven of 15 patients experienced orthostatic hypotension of such severity that administration of the drug had to be discontinued. Plasma concentrations of the drug were essentially twice those usually seen. It is important to appreciate that although imipramine does not further impair resting LVP, this does not mean it is without risk. The physician must watch carefully for orthostatic hypotension when using imipramine in depressed patients with impaired LVP.

Aged↗
PubMed1983

Effects of chronic antidepressant treatment on serotonin receptor activity in mice.

The effect of acute and chronic treatments with conventional and atypical antidepressant drugs on serotonin receptor activity was assessed by the responsiveness of mice to the serotonin receptor agonist 5-methoxy-N,N-dimethyltryptamine. Acute treatment with 10 mg/kg of amitriptyline, imipramine, trazodone, mianserin or viloxazine reduced the head twitch response measured 1 h following a challenged dose of the serotonin agonist. Acute iprindole and desmethylimipramine, however, had no effect on the serotonergic response. Chronic treatment with the clinically effective antidepressants amitriptyline, imipramine, desmethylimipramine, iprindole, and trazodone produced an enhanced responsiveness to 5-MeODMT. The enhanced responsiveness was first observed 24 h after cessation of treatment with most drugs. The effect lasted for at least 48 h. Chronic treatment with the neuroleptic haloperidol did not result in altered responsivity to the serotonin agonist. Brain accumulation of imipramine and amitriptyline and their deaminated metabolites were measured. Brain drug and metabolite levels peaked 1 h following both acute and chronic treatments. Brain accumulations of amitriptyline and its metabolite were much greater than those of imipramine and its metabolite. This pharmacokinetic data is consistent with an early (1 h) antagonism of the 5-MeODMT response and the emergence of hightened responsiveness to 5-MeODMT after chronic treatment, when brain drug levels are reduced. These findings are also consistent with the greater inhibitory effect found after treatment with amitriptyline than with imipramine. It is concluded that enhanced serotonin neurotransmission which develops during chronic treatment with antidepressant drugs may be related to the clinical action of these drugs.

Amitriptyline↗
PubMed1983

Relationship between plasma desipramine levels and clinical outcome for RDC major depressive inpatients.

Depressed patients (N = 31), who met Research Diagnostic Criteria for major affective disorder-depressed, were severely ill and maintained drug-free for a 1-week period on inpatient status. They received a fixed dose (150 mg/day) of desipramine for a 4-week period with drug plasma level determination and clinical ratings performed at fixed time intervals throughout the study. Despite these rigid criteria for entrance and clinical outcome measures, no obvious relationship between plasma desipramine level and clinical outcome was found. The clinical implications of this finding are discussed.

Adult↗
PubMed1983

Plasma levels of catecholamines and dihydroxyphenylglycol during antidepressant drug treatment.

Plasma norepinephrine, epinephrine, and 3,4-dihydroxyphenylglycol levels were measured in depressed outpatients treated in a double-blind controlled clinical trial with 150 mg/day of amitriptyline or 60 mg/day of phenelzine for 6 weeks. Both antidepressant drug treatments were associated with a significant decline in plasma dihydroxyphenylglycol concentrations, which was more pronounced with phenelzine. Plasma norepinephrine levels also declined during phenelzine but not amitriptyline treatment, and the posttreatment values correlated with clinical improvement with the monoamine oxidase inhibiting drug. Reductions in norepinephrine and dihydroxyphenylglycol correlated highly with the degree of platelet monoamine oxidase inhibition. Mechanisms of these antidepressant drug effects on amine metabolism and their implications are discussed.

Adult↗
PubMed1983

Pharmacokinetics of chlorimipramine and its demethylated metabolite in blood and brain regions of rats treated acutely and chronically with chlorimipramine.

The pharmacokinetic profiles for chlorimipramine (CIM) and its demethylated metabolite desmethylchlorimipramine (DCIM) in blood and in specific brain regions were obtained in rats after acute or chronic treatment with 15 mg/kg of the tricyclic antidepressant CIM. In blood, chronic drug treatment resulted in 1) a decrease in the time to maximal concentration of DCIM; 2) increases in maximal concentrations of CIM and of DCIM; and 3) a decrease in T1/2 of elimination of both CIM and DCIM. These changes induced a small reduction in the area under the CIM curve and a 4-fold increase in the area under the DCIM curve. In brain, both CIM and DCIM were unevenly distributed after both treatment schedules. Maximal accumulations of CIM and DCIM elimination were greatly enhanced in all brain areas by the chronic treatment. In brain, the area under the CIM concentration-time curve was only slightly affected by the chronic treatment, chronic drug treatment induced a 4-fold increase in the DCIM area. The subcellular distribution of CIM and DCIM in brain was similar in the acutely and chronically treated animals. The highest specific activity was found in the soluble fraction. These results demonstrate 1) regional brain differences in CIM and DCIM distribution and accumulation; 2) differences in pharmacokinetics between acute and chronic tricyclic antidepressant drug treatment regimens; and 3) differences between blood and brain drug and metabolite pharmacokinetics were observed which suggest that generalizations based on blood parameters should be made with great caution.

Animals↗
PubMed1982

Will amitriptyline prevent the "cheese" reaction of monoamine-oxidase inhibitors?

Administration of amitriptyline greatly diminished the pressor response to intravenous tyramine in patients receiving monoamine-oxidase inhibitors (MAOIs). Dothiepin and trimipramine, however, produced little change in sensitivity to tyramine. It is suggested that a combination of amitriptyline and an MAOI, started together in a modest dose that is then increased, may protect patients against the potential dangers of eating tyramine-containing foods. However, because MAOIs allow a high proportion of ingested tyramine to be absorbed into the systemic circulation, patients treated with MAOIs, even in combination with amitriptyline, should not be encouraged to eat foods containing tyramine.

Adult↗
PubMed1982

Simultaneous determination of amitriptyline, nortriptyline and their respective isomeric 10-hydroxy metabolites in plasma by liquid chromatography.

An ion-pair reversed-phase liquid chromatographic method for the determination of the tricyclic antidepressant amitriptyline, the demethylated metabolite nortriptyline, and their respective cis- and trans-hydroxylated metabolites in plasma is presented. After extraction from 1 ml of plasma, the reconstituted residue was chromatographed on a trimethylsilyl packed column using a mobile phase of acetonitrile and acetate buffer with sodium heptane-sulfonate and triethylamine. Recovery of the drugs and its metabolites from plasma ranged from 56 to 99%. The method is suitable for determining plasma concentrations as low as 5 ng/ml (C.V. less than 9%) for all six compounds. Plasma concentrations of amitriptyline and its metabolites from eleven different patients are presented.

Amitriptyline↗
PubMed1982

Determination of mianserin and metabolites in plasma by liquid chromatography with electrochemical detection.

A procedure for the determination of mianserin, desmethylmianserin, and 8-hydroxymianserin in plasma at therapeutic concentrations by liquid chromatography with electrochemical detection is described. Following a multiple-step extraction from alkaline plasma into methyl-tert-butyl ether, the reconstituted extract was injected onto a reversed-phase trimethylsilyl-packed column and eluted with an acetate-acetonitrile mobile phase containing an ion-paired reagent. The method provides an absolute recovery of 71-76% and a day-to-day precision of 5.4-9.1% for each compound at 25 ng/ml. The minimum quantifiable level for all three compounds was 5 ng/ml (RSD greater than 11%), and the detector response was linear up to 500 ng/ml. Fixed-dose steady-state plasma level data for 34 patients are reported.

Biotransformation↗
PubMed1982

Naloxone, tardive dyskinesia, and endogenous beta-endorphin.

The subjects were 13 psychiatric inpatients with tardive dyskinesia. Each subject participated in two sessions. Either naloxone (10 mg) or placebo was administered intravenously during each session. In a subset of subjects (n = 7), blood samples for beta-endorphin were drawn before and at 30 and 60 minutes after the injection. The Abnormal Involuntary Movement Scale was administered before and at 10, 20, 40, 60, 120, and 360 minutes after the injection. Double-blind procedures were maintained throughout the experiment. Neither naloxone nor placebo had any appreciable effect on the involuntary movements. Naloxone elicited a significant increase in the plasma beta-endorphin.

Adult↗
PubMed1982

Lithium dosing guide.

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Dose-Response Relationship, Drug↗