Determination of amoxapine and metabolites in plasma by liquid chromatography with electrochemical detection.
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Amoxapine↗
Biomedical subjects
T B Cooper
Publications and source records attributed to T B Cooper.
Percutaneous transluminal coronary angioplasty after intracoronary streptokinase in evolving acute myocardial infarction.
To achieve optimal myocardial revascularization and prevent rethrombosis of the infarct-related coronary artery, percutaneous transluminal coronary angioplasty (PTCA) was attempted in 18 patients with evolving acute myocardial infarction (9 anterior and 9 inferior) after administration of intracoronary streptokinase. PTCA was attempted 338 +/- 151 minutes after the onset of symptoms. After thrombolytic therapy, 11 patients had a severe residual stenosis and 7 a persistent total occlusion of the infarct-related coronary artery. PTCA was successful in 13 of 18 patients: in 9 of 11 with coronary stenoses and in 4 of 7 with total coronary occlusions. PTCA reduced the severity of the coronary lesion from 91 +/- 2% to 27 +/- 7% (p less than 0.001), and the transstenotic pressure gradient from 38 +/- 5 to 6 +/- 2 mm Hg (p less than 0.01). One patient in cardiogenic shock died during urgent coronary surgery after unsuccessful PTCA. After PTCA, all patients received heparin and antiplatelet agents. One patient had reinfarction with reocclusion of the infarct-related artery 5 days after PTCA. The other 12 patients had an uneventful hospital course, and cardiac catheterization before hospital discharge (8 to 17 days) revealed reocclusion of the infarct-related coronary artery in 3 and persistent patency in 9. Persistent patency of the infarct-related artery was associated with preservation of left ventricular end-diastolic volume (initial 86 +/- 6 ml/m2, follow-up 91 +/- 6 ml/m2), and improvement in left ventricular ejection fraction in some patients.
Adult↗
Attenuation by electroshock treatment of the haloperidol-induced rise in the binding of 3H-imipramine to rat brain membranes.
Studies were conducted in rats to investigate whether chronic haloperidol treatment, electroshock treatment (EST), or a combination of both affects the high-affinity binding of 3H-imipramine to cerebral membranes. Chronic haloperidol (2 mg/kg SC daily for 28 days) resulted in a significant decrease in the density of binding sites in animals killed 1 h after the last treatment, but binding was markedly enhanced after a "washout" period of 5 days. In animals subjected to EST (20-30 mA, 1.5 s, 60 Hz; three times a week for 4 weeks) and killed 1 h after the last treatment, there were no apparent changes, but when animals were allowed a recovery period of 5 days there appeared to be a slight increase in binding. The marked increase in binding seen after haloperidol withdrawal was no longer apparent in animals treated with both haloperidol and EST, indicating that EST acts to attenuate the increase in binding seen after withdrawal of chronic haloperidol. It is suggested that chronic haloperidol may influence presynaptic recognition sites that regulate serotonin uptake and that EST may interact with haloperidol to "stabilize" these presynaptic sites.
Animals↗
Tricyclic antidepressant and metabolite levels in chronic renal failure.
Serial blood samples were drawn from 12 patients undergoing hemodialysis who were receiving tricyclic antidepressants (TCAs). Samples were drawn before, during, and after a dialysis session (two to 17 sessions per subject). Samples were analyzed by HPLC before and after hydrolysis with beta-glucuronidase/sulfatase to determine the conjugated and nonconjugated metabolites. Analysis of these data in comparison with those of controls with depression and normal renal function showed that: (1) at steady state, tertiary and secondary amine TCA levels did not differ; (2) levels of the hydroxylated metabolites had greater variability and were somewhat higher at steady state; (3) levels of the conjugated hydroxylated compounds were markedly elevated, reaching 500% to 1500% normal; (4) the time to reach a steady-state level appeared to be slightly increased; and (5) elimination t1/2 s of unconjugated and conjugated drug forms were longer in our patients with normal renal function than those reported in the literature. Levels of the tertiary, secondary, and hydroxylated metabolites were not changed by dialysis, whereas there were substantial decrements in glucuronidated metabolite levels. These findings demonstrate increased concentrations of conjugated drug forms and suggest an abnormal distribution or delayed elimination of unconjugated and conjugated metabolites. These observations may shed some light on the apparent hypersensitivity of these patients to TCA side effects, particularly because glucuronides may exert peripheral pharmacologic effects.
Adult↗
Amitriptyline and hydroxylated metabolite plasma levels in depressed outpatients.
As part of a double-blind clinical trial comparing phenelzine and amitriptyline in outpatients with predominantly major depressive disorder, plasma tricyclic antidepressant drug concentrations were measured in 83 amitriptyline-treated patients. In 29 of these patients, hydroxymetabolites were also assayed. Patients were treated for 6 weeks at a fixed dose of 150 mg/day of amitriptyline after the first 5 days. Therapeutic outcome was assessed with a structured depression interview schedule, the Symptom Checklist-90, a side effects checklist, and a global improvement scale. Steady state plasma levels of 10-hydroxynortriptyline were in the same range as amitriptyline or nortriptyline concentrations. Clinical response did not relate significantly to plasma levels of either the parent drug, its metabolites, or the sum of all four pharmacologically active substances. Minimum threshold tricyclic antidepressant levels for therapeutic effect were not found. Assay of its active hydroxymetabolites does not appear to improve the clinical utility of routine amitriptyline level monitoring in patients with major depression in an outpatient setting.
Adult↗
Neuroleptic drug monitoring and radioreceptor assays.
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Antipsychotic Agents↗
Dose and plasma levels of nortriptyline and chlorpromazine in delusionally depressed adolescents and of nortriptyline in nondelusionally depressed adolescents.
Eight adolescents with major depressive disorder were treated with nortriptyline and six adolescents with delusional depression were treated with combined nortriptyline and chlorpromazine. Dose and plasma levels of nortriptyline for the two groups were compared. The delusional group receiving combined drug treatment needed significantly less nortriptyline than did the nondelusional group receiving only nortriptyline to obtain similar mean steady state plasma levels of the drug. The mean plasma chlorpromazine levels were quite low.
Adolescent↗
Serial ECG measurements at controlled plasma levels of nortriptyline in depressed children.
The authors investigated ECG measurements in 21 children with major depressive disorder treated with nortriptyline at plasma levels of 50-100 ng/ml. P-R and QRS intervals and heart rate measured at baseline and once a week during treatment remained within guidelines.
Age Factors↗
Child and adolescent nortriptyline single dose kinetics predict steady state plasma levels and suggested dose: preliminary data.
The use of nortriptyline single dose kinetics to predict steady state plasma levels and suggested dose was investigated in 33 pediatric subjects who were diagnosed as having major depressive disorder. The data were analyzed separately for the 11 subjects 5 to 9 years old who received a single dose of 25 mg and a fixed daily dose of 20 mg of nortriptyline, and for the 22 subjects 10 to 16 years old who received a single dose of 50 mg and a fixed daily dose of 50 mg of nortriptyline (N = 17) or a fixed daily dose of 20 mg (N = 5) because of a very slow rate of metabolism of the drug. Correlations within the group of 5 to 9 years olds between the steady state plasma levels and the five sampling points after the single dose were all highly significant. Correlations between the steady state plasma levels within the group of 10 to 16 year olds and the five sampling points after the single dose and a fixed daily dose of 50 mg (N = 17) were also highly significant. Similar correlations for the total group of 10 to 16 year olds (N = 22) were performed (prorating the steady state plasma levels of the slow metabolizers), and these too were highly significant. Suggested dose schedules for each age group were developed from the regression equations of nortriptyline steady state plasma levels versus 24-hour nortriptyline plasma levels after the single dose. The regression equation for the group of 5 to 9 year olds was highly significant.(ABSTRACT TRUNCATED AT 250 WORDS)
Adolescent↗
Serial monitoring and achievement of steady state nortriptyline plasma levels in depressed children and adolescents: preliminary data.
Children and adolescents 6 to 16 years old (N = 25), who were diagnosed as having major depressive disorder, received a fixed daily dose of nortriptyline during an 8-week period. Nortriptyline plasma levels were drawn and assayed weekly. Data were analyzed for the total sample (N = 25) and separately for the subgroup of 6 to 9 year olds (N = 9) and for the subsample of 10 to 16 year olds (N = 16). There were no significant differences between the day 7 (week 1) plasma levels and the means of weeks 2 to 8 or between the means of weeks 1 to 4 and 5 to 8 within the total sample or within either subgroup. These findings suggest that nortriptyline steady state plasma levels within the pediatric age range are achieved by day 7 (week 1) and that nortriptyline (during the pediatric years) does not induce its own metabolism during an 8-week period. The achievement of steady state by day 7 is similar to that found in adults. The mean coefficients of variation were calculated for the total sample and for each subsample and were 13.7 +/- 4.0% (range, 8 to 20%) for the 6 to 9 year olds; 13.8 +/- 3.2% (range, 10 to 21%) for the 10 to 16 year olds; and 13.8 +/- 3.4% (range, 8 to 21%) for the total sample. These coefficients of variation are similar to the 10 to 20% range reported in adult subjects.(ABSTRACT TRUNCATED AT 250 WORDS)
Adolescent↗
Metabolism and pharmacokinetics of phenelzine: lack of evidence for acetylation pathway in humans.
Earlier studies have suggested that patients with slow acetylation phenotype were more likely to respond to phenelzine treatment and more likely to experience side effects. The metabolism of phenelzine has not been extensively investigated in humans because of limitations in analytical methodology. A labeled form of phenelzine is required for metabolite identification because these same compounds can arise from endogenous substances e.g., phenylacetic acid. The use of a stable isotope-labeled compound has the advantage that in vivo studies can be performed without radiation exposure. Site-specific, stable isotope-labeled phenelzine analogs were synthesized and used in metabolic and pharmacokinetic studies in humans. The authors were unable to detect N-acetylphenelzine in any urine or plasma samples. The major metabolites phenylacetic acid and parahydroxyphenylacetic acid constitute up to 79% of the administered dose excreted via the urine in the first 96 hours. These studies indicate that N-acetylation of phenelzine is not a significant metabolic pathway in humans, which helps explain recent clinical studies that failed to find an association between acetylation phenotype and clinical effects of phenelzine.
Acetylation↗
The tyramine challenge test as a marker for melancholia.
A previous study reported that unipolar depressives excrete significantly lower amounts of urinary tyramine-O-sulfate following oral administration of a tyramine hydrochloride load than do normal control subjects. This study replicates and extends those findings by showing that within the heterogeneous group of unipolar depressives, patients with melancholia and bipolar patients with a history of melancholia manifest a tyramine excretion deficit. A small subgroup of medication-free patients in remission from episodes of melancholia had abnormally low tyramine sulfate excretion levels while they were euthymic, supporting the suggestion that reduced tyramine sulfate excretion following oral tyramine loading is a trait marker for depression. Further study of the role of trace amines in affective illness is warranted. Clinical application is not warranted until further evaluation of the sensitivity, specificity, and reproducibility of this oral tyramine challenge test.
Adult↗
Determination of bupropion and its major basic metabolites in plasma by liquid chromatography with dual-wavelength ultraviolet detection.
A method for the determination of bupropion and its three major basic metabolites in plasma is described. Following an extraction from alkaline plasma into 1.5% v/v isoamyl alcohol in n-heptane, a portion of the acid-backwashed extract was injected onto a column packed with trimethylsilyl reverse-phase material and eluted with a phosphate buffer-acetonitrile (80:20) mobile phase containing an ion-pairing reagent and triethylamine. The compounds were detected with a dual-wavelength UV detector (214 and 254 nm) to optimize sensitivity and facilitate simultaneous detection. The method provides an absolute recovery of approximately 85% for bupropion and approximately 98% for the metabolites. Day-to-day reproducibility did not exceed 4.0% for all compounds. The detection limits were approximately 5 ng/mL for bupropion and 100 ng/mL for the major metabolites. The limit of 100 ng/mL for metabolite quantitation is imposed by the internal standard concentration selected for steady-state studies. In single-dose pharmacokinetic studies, 10% of the steady-state concentration of internal standard was used; this permitted a 10-ng/mL lower limit of detection. Steady-state plasma levels of bupropion and the metabolites from eight different patients are presented.
Bupropion↗
Determination of trimipramine and metabolites in plasma by liquid chromatography with electrochemical detection.
A procedure for the determination of trimipramine, the demethyl, 2-hydroxy, and 2-hydroxy demethyl metabolites in plasma by liquid chromatography with electrochemical detection is described. A 1-mL plasma sample is made alkaline with a carbonate buffer (pH 9.8) and extracted with 20% ethyl acetate in n-heptane. After back-extraction into an acid phosphate buffer, an aliquot is injected onto a reverse-phase trimethylsilyl-packed column and eluted with a phosphate buffer-acetonitrile mobile phase (65:35) containing n-butylamine. The peaks were detected at +1.1 V versus the silver-silver chloride reference electrode. The method provides absolute recoveries of 60-91% and a day-to-day precision of less than 9% for all compounds. The minimum quantifiable level for all compounds was 3 ng/mL. Steady-state plasma concentration data for 29 depressed patients receiving either 75 mg or 150 mg/d is reported.
Chromatography, High Pressure Liquid↗
Elevated plasma tricyclic levels with therapeutic doses of imipramine.
Nine (15%) of 59 patients treated with imipramine at doses of 150 to 300 mg/day had steady-state plasma levels greater than 500 ng/ml. Low capacity for hydroxylation was found in all six patients for whom hydroxy metabolites were measured. Maximum tricyclic levels in the nine study patients were comparable to levels found in tricyclic antidepressant overdoses (651-2439 ng/ml). No study patient experienced any adverse effects: QRS durations were all less than 100 msec, and a mildly dry mouth was the most commonly reported side effect (five of nine patients). Depressive symptoms recurred in three patients when their imipramine dose was decreased.
Adult↗
Antidepressant drugs with varying pharmacological profiles alter rat pineal beta adrenergic-mediated function.
The effects of acute and chronic administrations of two antidepressant drugs with differing pharmacological profiles on pineal beta adrenergic receptor-mediated functions were examined in the rat. Animals were treated with control powdered food or with either imipramine or iprindole-containing diets (0.067%, w/w) for various time intervals. Animals were sacrificed during different phases of the light/dark cycle and pineal [3H]dihydroalprenolol (DHA) binding, N-acetyltransferase (NAT) activity, N-acetylserotonin (NAS) and melatonin levels were measured. Plasma drugs and metabolite concentrations were also assessed. A 3-day treatment with imipramine resulted in an unchanged pineal [3H] DHA binding and an increase in pineal serotonin (5-HT), NAS and melatonin. A comparable treatment with iprindole did not alter any pineal measures. Three weeks of imipramine treatment resulted in therapeutic plasma drug and metabolite concentrations and elicited a reduction (31%) in the density of pineal [3H] DHA binding. This treatment, in addition, suppressed the dark-induced activation of the intracellular enzyme NAT (38%) and the concentrations of NAS (25%) and melatonin (23%) without altering pineal 5-HT rhythm. No apparent shift was observed in the NAT, NAS and melatonin rhythms. Chronic treatment with the atypical antidepressant iprindole for 3 weeks resulted in-plasma iprindole concentrations of 76 ng/ml and a significant reduction (24%) in pineal 5-HT levels 5 hr into the dark phase of the light/dark cycle. Pineal NAT activity and NAS and melatonin content were not significantly reduced by this treatment. However, 4 weeks of iprindole ingestion produced plasma drug concentrations of 141 ng/ml and significantly reduced pineal [3H] DHA binding density (18%) without changing binding affinity.(ABSTRACT TRUNCATED AT 250 WORDS)
Acetyltransferases↗
Nortriptyline pharmacokinetic parameters in depressed children and adolescents: preliminary data.
The pharmacokinetic parameters of nortriptyline in the pediatric age group following oral administration of a single dose of 25 or 50 mg were investigated from nortriptyline plasma level assays at 12, 18, 24, 36, and 48 hours postdose. Data were analyzed separately for the nine prepubertal and 11 postpubertal subjects, all of whom were diagnosed major depressive disorder. These data were compared with studies in the literature of nortriptyline pharmacokinetics from adult and geriatric normal and depressed populations. Similar to adults, the elimination of nortriptyline in children and adolescents is apparently first order kinetics with a logarithmically linear rate of disappearance. The prepubertals had a shorter mean half-life (17.6 +/- 3.7 hours) than some adult groups and twice a day dosage would, therefore, be more appropriate for many children. Although the mean half-life (27.1 +/- 17.1 hours) for the adolescent group suggested that once a day dosage would be sufficient, some adolescents would need twice a day dosage for optimum plasma level control because there was a wide range (14.1 to 76.2 hours). The almost twofold variation in half-life in prepubertals and fivefold variation in postpubertals were similar to differences in adult groups and emphasize the value of plasma level monitoring in the clinical use of nortriptyline.
Adolescent↗
Serum dopamine-beta-hydroxylase activity in depression and anxiety.
Three studies were done to determine whether serum dopamine-beta-hydroxylase (DBH) activity is affected by the symptoms of depression or anxiety. In the population-screening study, serum DBH activity was measured in a heterogeneous sample of 548 medical, surgical, and psychiatric outpatients. No association was found between serum DBH activity and scores on either the Zung Self-rating Depression Scale or the Taylor Manifest Anxiety Scale. In the longitudinal depression study, enzyme activity was measured in 14 patients with major depressive illness treated with imipramine. Serum DBH activity remained unchanged throughout treatment whether or not the patient recovered from the depressive illness. Furthermore, there was no association between enzyme activity and steady state antidepressant plasma levels. In the longitudinal anxiety study, evaluation of 45 anxious outpatients in a placebo-controlled double-blind evaluation of two benzodiazepines (diazepam and alprazolam) indicated that serum DBH activity failed to reflect either state changes in anxiety or pharmacological variables. These results are reviewed with respect to current knowledge regarding neuronal release and extraneuronal disposal of circulating DBH.
Adult↗