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Measurement of clozapine and norclozapine in plasma/serum by high performance liquid chromatography with ultraviolet detection.

A simple method for the measurement of clozapine and its N-desmethyl metabolite in human plasma or serum by high performance liquid chromatography is described. An internal standard (aqueous nortriptyline, 4 mg/L) (50 microL) and Tris buffer (2 mol/L, pH 10.6) (100 microL) are added to plasma/serum (200 microL) and the analytes and internal standard extracted into methyl tert-butyl ether (200 microL). The extracts are analysed on a 150 mm column containing Spherisorb S5SCX using methanol containing ammonium perchlorate (35 mmol/L, pH 6.7) as eluent at a flow rate of 1.5 mL/min. Detection is by ultraviolet absorption (215 nm). The limit of detection is better than 0.05 mg/L for both analytes and the intra-assay precision (CV) for clozapine and norclozapine was 5.3 and 7.3% at 0.5 mg/L and 2.6 and 2.8% at 1.5 mg/L, respectively. The method can be applied to the measurement of these compounds in plasma after acute overdosage, for the assessment of compliance in patients apparently refractory to therapy and to identify interactions between clozapine and other neuroleptic and antidepressant drugs which may effect toxicity.

Adult↗

PubMed1976

Amitriptyline plasma levels and therapeutic response.

Eighteen depressed outpatients were treated for 6 wk with amitriptyline. Clinical improvement was monitored using the Hamilton Depression Rating Scale administered by two psychiatrists blind to the tricyclic used for treatment, dosage, and plasma levels. Amitriptyline and its desmethyl metabolite, notriptyline, were assayed twice weekly by gas chromatography-mass fragmentography. For the 17 patients having total tricyclic plasma levels between 0 and 250 ng/ml, there was a negative correlation between the Hamilton score and the mean total tricyclic level (p less than 0.01) and amitriptyline level (p less than 0.005). The mean nortriptyline level did not significantly correlate with the Hamilton score. The 10 patients having mean total tricyclic levels above 95 ng/ml had lower median Hamilton scores at week 3 (p less than 0.025) and at week 6 (p less than 0.0025) than those whose tricyclics were lower. The percentage of recovered patients increases significantly as the plasma levels rise to 250 ng/ml, the maximum plasma level considered in this study.

Adolescent↗

PubMed1998

Enhanced separation of antidepressant drugs using a polymerized nonionic surfactant as a transient capillary coating.

The separation of seven structurally similar antidepressant drugs (amitriptyline, nortriptyline, imipramine, desipramine, protriptyline, doxepin, and nordoxepin) was achieved in under 15 min using a novel nonionic micelle polymer, poly(n-undecyl-alpha-D-glucopyranoside) (PUG) by use of capillary zone electrophoresis (CZE). Systematic studies with varying polymer concentration, pH, and percent organic modifier were conducted in order to find the optimum conditions for baseline separation of the seven tricyclic antidepressants. In addition, equations for capacity factor were used to estimate the extent of what was initially thought to be micelle analyte interaction. A series of calculations show that a modified CZE system (PUG-CZE) was the actual mode of separation. Thus, our study concluded that PUG functioned in a non-electrokinetic chromatography mode.

Antidepressive Agents↗

PubMed2005

Somatic symptoms of depression in elderly patients with medical comorbidities.

OBJECTIVE: Somatic symptoms of depression such as fatigue create a diagnostic dilemma when assessing an older patient with medical comorbidities, since chronic medical illnesses may produce similar symptoms. Alternatively, somatic symptoms attributed to medical illness may actually be caused by depression. These analyses were designed to determine if somatic symptoms in older patients are more strongly associated with chronic physical problems or with depression. DESIGN: Reanalysis of data from an observational study of depression in primary care and a randomized trial of paroxetine and nortriptyline for the treatment of major depression. Patients were evaluated with a structured diagnostic interview and a battery of psychiatric, physical, and psychosocial measures. PARTICIPANTS: Two hundred and forty eight primary care and psychiatric patients aged >or= 60 years. METHODS: Associations among depression, somatization, and chronic physical problems were examined using correlations and regression modeling. RESULTS: Two somatization measures, the Asberg Side Effects Rating Scale and the Utvalg for Kliniske Undersogelser (UKU), were significantly associated with psychological symptoms of depression (r = 0.73 and r = 0.76, p < 0.0001) but not with medical comorbidities (r = 0.02, p = 0.16 and r = 0.10, p = 0.78). In multiple regression models, psychological symptoms of depression remained significant predictors of somatization (p < 0.0001) after controlling for age, gender, and medical comorbidities. CONCLUSIONS: In older patients with medical disorders and multiple somatic complaints, clinicians should consider the possibility of depression. Rating scales emphasizing somatic symptoms associated with depression may provide a more accurate measure of depression severity than those excluding such symptoms.

Aged↗

PubMed2004

Serotonin and noradrenaline reuptake inhibitors in animal models of pain.

Animal models of chronic pain serve as an experimental basis for testing new therapeutic interventions and for mechanistic investigations. In an animal model of chronic pain, based on the injection of formalin into the paw of a rodent, inhibitors of noradrenaline reuptake such as nisoxetine, nortriptyline and maprotiline and dual inhibitors of the noradrenaline and serotonin reuptake such as imipramine and milnacipran produce potent anti-nociceptive effects, whereas selective serotonin reuptake inhibitors, such as fluvoxamine, are much less potent. In another model, neuropathic pain resulting from the chronic constriction injury of the sciatic nerve was prevented by the dual uptake inhibitor, venlafaxine. The experimental model involving ligation of the 5th spinal nerve induces behavioural signs in rats and mice that are similar to the symptoms of human neuropathic pain. In this model amitriptyline, a non-selective serotonin and noradrenaline reuptake blocker, the preferential noradrenaline reuptake inhibitor, desipramine and the selective serotonin and noradrenaline reuptake inhibitors, milnacipran and duloxetine, produce a decrease in pain sensitivity whereas the selective serotonin reuptake inhibitor, fluoxetine, is ineffective. Antidepressants acting on the noradrenergic or both the noradrenergic and serotonergic systems thus appear to be more effective than those working on the serotonin system alone.

Adrenergic Uptake Inhibitors↗

PubMed1989

Nonlinear kinetics of trimipramine in depressed patients.

An increase of the dose of trimipramine (TM) results in a markedly disproportionate increase of the steady-state plasma concentration of the major active metabolite desmethyltrimipramine (DMT). Ten patients receiving 75 mg/day of TM had a mean steady-state plasma concentration of 53.8 ng/ml TM and 26.3 ng/ml DMT. Ten others receiving 150 ng/ml TM had a mean concentration of 122.5 ng/ml TM and 133.8 ng/ml DMT. This is most likely due to the saturation within therapeutic dosage range of the subspecies of cytochrome P-450 responsible for hydroxylation of DMT. Available data on metabolism of tricyclic antidepressants shows that the hydroxylation of desmethylimipramine (desipramine) but not that of desmethylamitriptyline (nortriptyline) reaches saturation within therapeutic dosage range. Clinicians should take into consideration the possibility of dose-dependent kinetics when adjusting the dose of tricyclic antidepressants. This finding highlights the value of monitoring of blood levels of antidepressants.

Adult↗

PubMed1998

Multiple-dose pharmacokinetics and pharmacodynamics of OROS and immediate-release amitriptyline hydrochloride formulations.

The pharmacokinetics and pharmacodynamics of amitriptyline hydrochloride after oral administration of an OROS osmotic system, which provides controlled drug delivery, and an immediate-release (IR) tablet, were evaluated in 24 healthy volunteers after repeated administration for 14 days. Each morning, subjects received either 75 mg of the OROS (amitriptyline HCl) controlled-release formulation or the 75 mg IR amitriptyline tablet for 14 days on two separate occasions with a washout period of 21 days according to a randomly assigned sequence. Serial blood samples were collected for a period of 58 hours after the day 14 dose, then these samples were analyzed by the gas chromatography method for amitriptyline and nortriptyline. Subjective ratings of dry mouth and drowsiness were collected at specific times throughout each treatment period. Administration of the OROS formulation resulted in much more consistent plasma concentrations of the drug and metabolite compared with the IR formulation at steady state. The mean maximum concentration (Cmax) of amitriptyline was significantly lower after administration of OROS than the IR formulation. Mean values for area under the concentration--time curve (AUC0-24) for the OROS and IR formulations were 1,265 and 1,393 ng. hr/mL, respectively. The drug-to-metabolite ratio was found to be similar for both treatments, suggesting that there was no difference in metabolism between treatments. Incidence and severity of the anticholinergic effects were similar for the two treatments. A clockwise hysteresis between baseline-corrected drowsiness and drug concentration suggests development of tolerance of the anticholinergic effects after both treatments. Using a hypothetical anatagonist metabolite model to explain tolerance development, the shape of the hysteresis curves of the two treatments could be explained by differences in dosing frequency.

Adult↗

PubMed1998

Five distinct human cytochromes mediate amitriptyline N-demethylation in vitro: dominance of CYP 2C19 and 3A4.

The human cytochromes P450 (CYPs) mediating amitriptyline N-demethylation have been identified using a combination of enzyme kinetic and chemical inhibition studies. Amitriptyline was N-demethylated to nortriptyline by microsomes from cDNA transfected human lymphoblastoid cells expressing human CYPs 1A2, 2C9, 2C19, 2D6, and 3A4. CYP 2E1 showed no detectable activity. While CYP 2C19 and CYP 2D6 showed high affinity, CYP 3A4 showed low affinity; CYP 2C9 and 1A2 showed intermediate affinities. Based on these kinetic parameters and estimated relative abundance of the different CYPs in human liver, CYP 2C19 was identified as the major amitriptyline N-demethylase at low (therapeutically relevant) amitriptyline concentrations, whereas CYP 3A4 may be more important at higher amitriptyline concentrations. Chemical inhibition studies with ketoconazole and omeprazole indicate that CYP 3A4 is the major amitriptyline N-demethylase at 100 mumol/L amitriptyline, while CYP 2C19 is equally important at a substrate concentration of 5 mumol/L. The CYP 1A2 inhibitor alpha-naphthoflavone and the CYP 2C9 inhibitor sulfaphenazole produced much less inhibition of amitriptyline N-demethylation at both substrate concentrations. Quinidine produced no detectable inhibition. The kinetics of amitriptyline N-demethylation by human liver microsomes were consistent with a two enzyme model, with the high affinity component exhibiting Michaelis Menten kinetics and the low affinity component exhibiting Hill enzyme kinetics. No difference was apparent in the kinetics of amitriptyline N-demethylation in two liver samples with low levels of CYP 2C19 activity compared with two other samples with relatively normal 2C19 activity. This may reflect the importance of higher substrate concentration values in estimation of kinetic parameters in vitro.

Amitriptyline↗

PubMed1978

Analysis of tricyclic antidepressants in human plasma by GLC--chemical-ionization mass spectrometry with selected ion monitoring.

A method is described for the analysis of amitriptyline, doxepin, imipramine, nortriptyline, desmethyldoxepin, desipramine, and protriptyline in human plasma utlizing GLC-chemical-ionization mass spectrometry with selected ion monitoring. The assay is highly specific and is quantitative to at least 1 ng/ml with a standard error typically less than 5%. Representative concentrations of the parent compounds and their monodemethylated metabolites, as meeasured in plasma samples from patients under treatment with tertiary amine tricyclic antidepressants, are given.

Antidepressive Agents, Tricyclic↗

PubMed1978

Quantitative GLC determination of cis- and trans-isomers of doxepin and desmethyldoxepin.

A GLC method for the simultaneous quantitative determination of the cis- and trans-isomers of doxepin and desmethyldoxepin in human plasma was developed. The method involves the use of a capillary column for efficient separation of the four compounds and the internal standards, amitriptyline and nortriptyline. A high sensitivity is obtained with a nitrogen detector, enabling quantitation of the compounds in plasma of humans treated chronically with doxepin. Confirmation of the identity of the cis- and trans-isomers of doxepin and desmethyldoxepin in biological samples was carried out by selected ion monitoring.

Adult↗

PubMed1982

GLC method for iminodibenzyl and desipramine impurities in imipramine hydrochloride and its formulated products.

A GLC method is described for the determination of iminodibenzyl and desipramine impurities in imipramine hydrochloride and its formulated products. These impurities were extracted from an alkaline solution with a mixture of 30% methylene chloride in hexane for chromatography on a 3% OV-17 GLC column. Iminodibenzyl was determined using anthracene as an internal standard and desipramine was determined (after derivatization) using nortriptyline as an internal standard. Based on spiked excipient mixtures typically used to compound imipramine tablets, recoveries were 93-109% for iminodibenzyl and 93-107% for desipramine at 0.2-0.4% of the labeled claim of imipramine. Minimum detection levels were approximately 0.02% for each impurity, and procedural standards gave coefficients of variation of less than 1% for each impurity. The method was linear in the 0.05-0.5 microgram range and typically gave correlation coefficients greater than or equal to 0.999.

Amines↗

PubMed1982

High-pressure liquid chromatographic determination of amitriptyline and its major metabolites in human whole blood.

A sensitive, specific, high-pressure liquid chromatographic method using an internal standard was developed for the determination of amitriptyline and its major metabolites in whole blood. Analysis was carried out on a microparticulate silica column with a mobile phase consisting of acetonitrile-methanol-aqueous ammonium hydroxide (93:7:0.4). Linear calibration curves ranging to 250 ng/ml were obtained for all compounds using UV absorbance detection at 220 nm. The lower limit of detection was 2 ng/ml for amitriptyline and 10-hydroxyamitriptyline, and 6 and 16 ng/ml for nortriptyline and its 10-hydroxylated metabolite, respectively. Human whole blood samples collected after single intravenous and single oral doses can be analyzed using this procedure.

Amitriptyline↗

PubMed2005

On-line pretreatment using methylcellulose-immobilized cation-exchange restricted access media for direct liquid chromatography/mass spectrometric determination of basic drugs in plasma.

A novel methylcellulose-immobilized restricted access media column with strong cation-exchange groups on an internal surface (MC-SCX) was evaluated for the direct injection analysis of basic polar drugs in plasma by column-switching liquid chromatography/mass spectrometry (LC/MS). Analytical conditions, including an automated pretreatment step and MS detection, were optimized for a series of basic drugs (doxepin, desipramine, imipramine, nortriptyline, amitriptyline, clomipramine). On-line pretreatment with the MC-SCX column followed by fast gradient analysis using a C18 column resulted in a total analysis cycle time of 7 min for each spiked plasma sample. More than 150 plasma samples spiked with target compounds were measured without compromising MS detection (relative standard deviations less than 11% for all compounds, and regression coefficients greater than 0.99).

Animals↗

PubMed1996

Tricyclic antidepressants inhibit human natural killer cells.

The commonly used antidepressants imipramine, amitriptyline, and nortriptyline were found to significantly inhibit human natural killer (NK) cell-mediated cytolysis in vitro and suppress the stimulation of NK cells by IFN-gamma. This is a previously unrecognized biologic property of these drugs with psychotropic activity. Tricyclic antidepressants did not decrease effector-target cell conjugation formation, nor did they induce target cell resistance to NK lysis, indicating that the drugs might interfere with the killing mechanism of the effector cells. Kinetic data reveal that the drug interference is related to an early postbinding event in the activation of NK cells. Results also showed that the inhibitory effect of tricyclic antidepressants on human NK cell activity occurred in parallel to an increase in intracellular cyclic GMP concentration. However, the attenuation in the cyclic GMP formation by methylene blue, a selective inhibitor of soluble guanylate cyclase, was not accompanied by a corresponding increase in NK cell cytolytic activity. It is suggested that the stimulation of cyclic GMP was not directly involved in the inhibitory effect of antidepressants on NK cells and perhaps was a secondary phenomenon. This immune cell modulatory property of tricyclic antidepressants seems to indirectly provide evidence for the concept that human brain neurons and NK cells might share regulatory system(s).

8-Bromo Cyclic Adenosine Monophosphate↗

PubMed1990

New pharmacologic approaches to obsessive compulsive disorder.

Although obsessive compulsive disorder (OCD) traditionally has been considered a treatment-refractory syndrome, rigorous treatment studies over the past decade have demonstrated that most OCD patients respond to specific behavioral or pharmacologic therapies. In terms of the pharmacologic treatment of OCD, a relatively small group of antidepressant drugs (clomipramine, fluvoxamine, and fluoxetine) have been demonstrated to be antiobsessional. Several related antidepressants (desipramine, nortriptyline) appear to be ineffective for OCD. Clinical response requires prolonged treatment (greater than 6 weeks) with antiobsessional drugs and efficacy is not limited to depressed OCD patients. The few drugs that have been demonstrated to be antiobsessional share a high potency for the blockade of serotonin reuptake, suggesting a serotonergic mechanism for antiobsessional drug action. This suggestion has been further strengthened by studies demonstrating a high correlation between clinical response and changes in serotonergic markers with clomipramine treatment. Moreover, a serotonin antagonist, metergoline, appears to partly reverse the improvement observed following chronic clomipramine treatment. Overall, only about 50% of OCD patients appear to respond in any given pharmacologic treatment trial. Adjunctive treatments, such as lithium or L-tryptophan, have been reported to help in some cases. In addition, the use of neuroleptics either alone or in combination with antiobsessional drugs may be useful for OCD patients with psychotic features or tics. Pharmacologic treatments should be considered only one element of the therapeutic approach to be integrated with behavioral techniques as well as psychosocial interventions for the relief of this very intriguing syndrome.

Behavior Therapy↗

PubMed1989

Influence of cooling on the responsiveness of rat isolated anococcygeus muscle to noradrenaline.

The isolated anococcygeus muscle of the rat was used to study the effect of temperature on noradrenaline-induced contraction. The preparation was suspended in an organ bath containing Krebs bicarbonate solution for isometric tension recording. A decrease of the bath temperature from 37 degrees C to 20 degrees C (cooling) produced an increase in tissue sensitivity to noradrenaline, as reflected in a 5.37-fold leftward shift in the concentration-response curve, and increased the maximum contractile response to this agonist (14.3%). Cooling had no effect on tissue sensitivity to a selective alpha 1-adrenoceptor agonist, methoxamine, but increased (12.4%) the maximum contraction to a similar extent to that to noradrenaline. 6-Hydroxydopamine pretreatment or nortriptyline (1 mumol/l) induced a leftward shift of the noradrenaline concentration-response curve at 37 degrees C, and profoundly inhibited the potentiating effect of cooling on tissue sensitivity to the catecholamine; the effect of cooling on the maximum response was unaffected. The affinity of noradrenaline or methoxamine for alpha 1-adrenoceptors at 37 degrees C, determined from its dissociation constant (KA), was not significantly different from that at 20 degrees C. KA values were determined by use of irreversible antagonism with phenoxybenzamine. On the other hand, diltiazem at concentration of 3 mumol/l, which almost completely abolished the calcium ion-induced contraction of the potassium ion-depolarized muscle, caused only slight inhibition in the concentration-response curve for noradrenaline. The contractile responses to Ca2+ of the K+-depolarized muscle and of the tissue incubated in Ca2+ -free (EGTA 0.1 mmol/l) Krebs solution containing diltiazem and noradrenaline were both depressed by cooling.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic alpha-Agonists↗

PubMed1988

Selectivity in the binding of psychotropic drugs to the variants of alpha-1 acid glycoprotein.

The S- and F-forms of alpha-1 acid glycoprotein (AAG) variants have been isolated by isoelectric focusing with immobilines from commercially available AAG. In equilibrium dialysis experiments using a multicompartmental system, a higher affinity for various basic drugs has been found with S- in comparison with F-AAG: Amitriptyline, nortriptyline, imipramine, desipramine, trimipramine, methadone, thioridazine, clomipramine, desmethylclomipramine, and maprotiline. The selectivity (binding to S- vs. F-AAG) is the most pronounced for methadone and the lowest for thioridazine, while it is absent for the acidic drug mephenytoin.

Amitriptyline↗

PubMed1988

Platelet membrane fluidity and treatment response in cognitively-impaired, depressed elderly: initial results.

A prospective study of response to treatment with nortriptyline was carried out in a group of 14 inpatients with mixed symptoms of depression and dementia. Platelet membrane fluidity, as reflected by the fluorescence anisotropy of DPH labeled membranes, was determined for all 14 drug-free subjects prior to treatment by staff who were blind to clinical and demographic data. Patients who exhibited worsening of their cognitive impairment exhibited "increased" platelet membrane fluidity, an abnormally found in approximately 50% of patients with Alzheimer's disease.

Aged↗