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PubMed1979

An improved gas-liquid chromatographic procedure for the determination of amitriptyline and nortriptyline levels in plasma using nitrogen-sensitive detectors.

An improved gas-liquid chromatographic procedure for the plasma level determination of amitriptyline and nortriptyline using nitrogen-sensitive detectors is described. Derivatization of the secondary amines using trifluoroacetic anhydride greatly improves the response and reproducibility of the assay. Plasma samples containing as little as 5 ng/ml of amitriptyline and nortriptyline can be assayed precisely and reproducibly, using protriptyline as internal reference standard.

Amitriptyline↗

PubMed1985

Sensitive high performance liquid chromatographic analysis of ethmozin in plasma.

A sensitive high performance liquid chromatographic procedure for the quantitative determination of ethmozin is described. Following a one-step extraction of the drug and the internal standard, protriptyline, by diethylether at pH 9.0, the organic solvent is evaporated and the residue is reconstituted in the mobile phase and injected into the chromatograph. The separation is obtained using a CN-bonded column with a methanol-propanol-2-perchloric acid 1.16 M mobile phase. Ethmozin is detected at 268 nm. Under these conditions, the lower limit of detection is 11 nM, and the lower limit of quantification is 22 nM (10 ng/ml) for ethmozin. The procedure is linear between 0 and 8,620 nM.

Anti-Arrhythmia Agents↗

PubMed1987

Simultaneous quantitation of eight tricyclic antidepressants in serum by high-performance liquid chromatography.

An analytical procedure has been developed for the simultaneous separation and quantitation of amitriptyline (AMI), imipramine (IMI), doxepin (DOX), trimipramine (TRI), desipramine (DES), nortriptyline (NOR), desmethyldoxepin (DMD), and protriptyline (PRO) in serum using N-propionylprocainamide (NPPA) as an internal standard. Serum samples were extracted using Bond Elute C-18 columns. A 5-mu Supelcosil LC-PCN column separated the analytes, using a mobile phase consisting of 10 mmol/L sodium phosphate (pH 7.0):acetonitrile:methanol (28:58:14) by volume at ambient temperature. Column effluents were monitored at 254 and 280 nm. Typical recoveries ranged from 81.8% to 94.0% at 50 ng/ml and from 92.0% to 102.6% at 200 ng/ml. Within-run variations were less than or equal to 10.1% at 50 ng/ml and less than or equal to 4.5% at 200 ng/ml, whereas day-to-day variations were less than or equal to 7.4% at 50 ng/ml and less than 4.8% at 200 ng/ml for n = 10. Calibration curves showed linearity over the concentration range of 25-1,000 ng/ml. Superior resolution (Rs greater than or equal to 1.0) was obtained with this column, which completely separated the eight tricyclic antidepressants (TCAs) and the internal standard in 16 min. Sensitivity limit is 25 ng/ml for all TCAs studied. Phenothiazine tranquilizers interfere with the quantitation of TCAs.

Antidepressive Agents, Tricyclic↗

PubMed1988

Measurement of antidepressants using solid-phase extraction and wide-bore capillary gas chromatography with nitrogen-selective detection.

A comprehensive method is presented for the determination of nine antidepressant drugs and metabolites in serum: (1) amitriptyline, (2) nortriptyline, (3) imipramine, (4) desipramine, (5) maprotiline, (6) doxepin, (7) desmethyldoxepin, (8) protriptyline, and (9) trimipramine. Chlorimipramine is used as the internal standard. A simple solid-phase extraction procedure utilizing disposable reversed-phase C18 columns is described. Samples are analyzed by gas chromatography with nitrogen-selective detection using a wide-bore capillary column with a permanently bonded, non-polar stationary phase. The assay possesses linearity to 800 ng/mL for maprotiline and 500 ng/mL for the other antidepressants, sensitivity to at least 25 ng/mL, recovery ranging from 96 to 107%, and between-run precision reflected by CVs of 4.4 to 8.1%. Lack of interference is documented for over 27 commonly prescribed drugs. We conclude that the method reported here is ideally suited for monitoring therapeutic and toxic levels of antidepressant drugs.

Antidepressive Agents↗

PubMed1991

The assay of clozapine and N-desmethylclozapine in human plasma by high-performance liquid chromatography.

A high performance liquid chromatographic method for the simultaneous quantitation of clozapine--a member of the dibenzodiazepine class of antipsychotic drugs--and its reduced metabolite in human plasma has been developed. Clozapine and N-desmethylclozapine are concentrated from blood samples by liquid-liquid extraction, followed by reverse-phase liquid chromatography. Accuracy of the determination is ensured by application of an internal standard, protriptyline, which is closely related to clozapine. A detection limit of 15 ng/mL for clozapine and 30 ng/ml for N-desmethylclozapine was achieved.

Chromatography, High Pressure Liquid↗

PubMedDate not supplied

The effect of tricyclic antidepressant drugs on the isolated perfused guinea-pig heart.

1. The effects of tricyclic antidepressants were studied on the isolated perfused guinea-pig heart simultaneously recording myocardial contractile force and cardiac electrogram. 2. Tricyclic antidepressants in a concentration 4 X 10(-5) mol/1 decreased cardiac contractile force and increased cardiac conduction time. 3. Doxepin had significantly greater negative inotropic effect than nortriptyline, protriptyline, desipramine, amitriptyline and imipramine (P less than 0.01). 4. There was no significant difference in the increase in P-R interval (P less than 0.5) and QRS width (P greater than 0.95) between the tricyclic antidepressants. 5. The isolated perfused guinea-pig heart can be used as a toxicological model for testing and treating cardiac arrhythmias induced by tricyclic antidepressants.

Animals↗

PubMed1980

The importance of suspecting sleep apnoea as a common cause of excessive daytime sleepiness: further experience from the diagnosis and management of 19 patients.

Over an 18 month period, 19 patients were referred for assessment of excessive daytime sleepiness and/or loud snoring. Respiratory studies during sleep were performed in 14 of these patients with additional features such as disturbed sleep, observed apnoea during sleep, morning headache, mental and personality changes, hypertension and cardiac failure. Nocturnal respiratory studies undertaken for periods of 4-8 hours confirmed a diagnosis of the Sleep Apnoea Syndrome in eight patients. In these patients apnoeas, lasting from 30-144 seconds, occurred frequently during sleep (from 35-291 episodes per patient). In one severely affected patient, tracheostomy abolished all symptoms. The use of conservative therapy such as weight loss, protriptyline or a neck collar, highlighted the inadequacies of current medical treatment. Awareness of the symptom complex and potential complications of the Sleep Apnoea Syndrome is important because the diagnosis may easily be missed if the patient presents with one or two isolated complaints.

Adult↗

PubMed1972

A quantitative study of the anticholinergic action of several tricyclic antidepressants on the rat isolated fundal strip.

1. Investigations were carried out on the antagonism of the action of carbamylcholine chloride on the isolated fundus of the rat stomach by several tricyclic antidepressants.2. The anticholinergic potency of the compounds was in the order: GP 45437>amitriptyline>protriptyline>desmethylimipramine>opipramol. All of the antagonists were less effective than atropine.3. Statistical analysis was carried out to determine whether the theory of competitive antagonism would fit the data obtained.

Amitriptyline↗

PubMed1973

The effect of narcotic analgesics on the uptake of 5-hydroxytryptamine and (-)-metaraminol by blood platelets.

1. The effects of narcotic analgesic and related drugs were studied on the uptake of 5-hydroxytryptamine (5-HT) and (-)-metaraminol by blood platelets.2. The most potent drug in inhibiting the uptake of 5-HT (10 muM) by human platelets was methadone, followed by pentazocine>piminodine approximately pethidine approximately anileridine approximately cyclazocine approximately thebaine > dextropropoxyphene. Alphaprodine, papaverine, apomorphine, nalorphine, codeine, and morphine were almost without effect. Methadone was slightly less active than desipramine, and had 10% of the activity of imipramine under similar conditions. Naloxone did not antagonize the effect of methadone on 5-HT uptake.3. The most potent inhibitor of metaraminol (3 muM) uptake by human platelets was piminodine, followed by pentazocine>/=anileridine>cyclazocine=methadone > dextropropoxyphene approximately thebaine >/= papaverine approximately alphaprodine >pethidine>morphine. The activity of morphine was 1% of that of piminodine. Piminodine was more potent than desipramine and protriptyline under similar conditions. The order of potency of drugs studied in inhibiting the uptake of metaraminol by rabbit platelets was similar to that obtained with human platelets.4. The effects of the analgesics studied on inhibiting uptake of monoamines did not correlate with their pain-relieving properties.

Alphaprodine↗

PubMed1980

The relationship between nerve terminal adenosine triphosphatases and neurotransmitter release: as determined by the use of antidepressant and other CNS-active drugs.

1 The role of adenosine triphosphatases (ATPases) in neurotransmitter release was studied using nerve terminals (synaptosomes) prepared from rat cerebral cortex as a model. 2 Amitriptyline, nortriptyline, protriptyline, desipramine and imipramine were found to inhibit ATPases at concentrations of 10(-5) M and above. The drugs inhibited both the basal and electrically evoked release of acetylcholine (ACh) and noradrenaline (NA) at concentrations of 10(-4) M and above. 3 At low concentrations of antidepressants (10(-8) and 10(-7) M) release of NA was enhanced but there was no effect on ACh release. 4 Other drugs which inhibit Na+, K+-ATPase increase basal NA release as did drugs which inhibited vesicular MG2+-ATPase. 5 A model is proposed suggesting that transmitter release/re-uptake depends on (1) active Na+, K+-ATPase at the presynaptic membrane and (2) an active synaptic vesicular MG2+-ATPase.

Acetylcholine↗

PubMed1986

Activation and desensitization of presynaptic alpha 2-adrenoceptors after inhibition of neuronal uptake by antidepressant drugs in the rat vas deferens.

The isolated field-stimulated vas deferens of the rat (0.1 Hz, 3 ms, 30-40 V) was used to study the relationship between the in vivo inhibition of neuronal uptake of noradrenaline (NA) by cyclic antidepressant drugs and the subsequent activation/desensitization of presynaptic alpha 2-adrenoceptors. Receptor activation was indirectly measured by quantifying the ability of each drug to inhibit basal twitch responses after their acute administration. Receptor desensitization was also indirectly measured by quantifying the ability of the drugs to reduce the inhibitory effects of selective alpha 2-adrenoceptor agonists on the electrically-induced twitch responses after their long-term administration. The acute in vivo administration of desipramine and other antidepressants (0.5-10 mg kg-1; i.p.; 2 h) resulted in dose-dependent inhibitions of the basal twitch responses which were rapidly reversed to control values by idazoxan (10-5 M). In vitro, desipramine and other antidepressants also inhibited in a concentration-dependent manner (10(-9)-10(-5) M) the twitch responses. In rats pretreated 12 h earlier with reserpine (1 mg kg-1; i.p.) or oxypertine (4 mg kg-1; i.p.), desipramine (10 mg kg-1; 2 h) did not induce inhibition of the basal twitch responses or it induced a smaller effect, respectively. For the various antidepressants the degree of inhibition of the basal twitch responses (desipramine greater than protriptyline greater than nortriptyline greater than maprotiline = imipramine greater than amitriptyline greater than viloxazine greater than iprindole much greater than zimelidine) was highly correlated (r = 0.914) with the potency for blockade of [3H]-NA uptake into rat brain synaptosomes. Clonidine and xylazine inhibited in a concentration-dependent manner (10(-9)-10(-6) M) the twitch responses. The long-term (7-14 days) administration of antidepressants or cocaine (10 mg kg-1, i.p.) resulted in significant decreases in sensitivity to clonidine or xylazine. Short-term (3 days) treatment with desipramine did not reduce the sensitivity to clonidine. The results indicate that the acute in vivo inhibition of NA neuronal uptake by antidepressants leads to the activation (through endogenous NA) of presynaptic inhibitory alpha 2-adrenoceptors which results in inhibition of the twitch responses. In contrast, prolonged in vivo inhibition of NA reuptake is followed by a slow desensitization process of the same receptors which results in a reduction of sensitivity to clonidine.

Animals↗

PubMed1984

Seizures with antidepressants: an in vitro technique to assess relative risk.

The relative potential of various antidepressants to induce seizures while being used at therapeutic doses was studied by examining their action on spike activity in perfused guinea pig hippocampal slices. Within the range of concentration studied, imipramine, amitriptyline, nortriptyline, maprotiline, and desipramine tended to increase spike activity in a descending order of effect. Doxepin and nomifensine increased spike activity at lower concentrations, but reduced it at higher concentrations. Protriptyline and trimipramine reduced spike activity with increasing concentrations, whereas mianserin and viloxazine had little effect at any concentration. These findings are discussed in light of previous clinical and laboratory reports, and the clinical implications of these findings are presented. Finally, results with the antidepressants are compared with those previously observed with neuroleptics. On the basis of this comparison and a review of clinical reports, the assumption that neuroleptics have greater epileptogenic potential than antidepressants is questioned.

Animals↗

PubMed1983

Effects of zimeldine and other antidepressants on skilled performance: a comprehensive review.

Existing data suggest that amitriptyline, doxepin, mianserin, viloxazine and imipramine impair the performance of skilled psychomotor tasks. The degree of impairment, as well as the degree of interaction with alcohol, is closely related to the sedative potency of the drug. the adverse effects on psychomotor skills are, however, mainly limited to the first 10 days of treatment. In contrast, nortriptyline, clomipramine, desipramine, protriptyline, nomifensine and zimeldine have much less marked effects on skilled performance. Despite its being a relatively new antidepressant, the effects of zimeldine on psychomotor skills have already been extensively investigated. It has been shown to be without stimulant or sedative effects, and there does not appear to be any additive effect between zimeldine and ethanol. The lack of detrimental effects on skills related to such tasks as driving, makes zimeldine suitable for use in out-patient populations.

Antidepressive Agents↗

PubMed1981

A gas chromatographic method for the determination of antidepressant drugs in human serum.

A universal gas chromatographic method for the determination of the most commonly used antidepressant drugs in 1 ml of serum is described. Prior to extraction the samples were washed with hexane at acid pH. After the hexane wash the drugs were extracted into hexane at pH approximately 10, and subsequently reextracted from the hexane into a 1% solution of formic acid in methanol. The methanolic phase was evaporated, the residue dissolved in isopropanol and analysed by gas chromatography with nitrogen detection on a 3% OV-225 column. Recoveries for amitriptyline, nortriptyline, clomipramine, desmethylclomipramine, doxepin, desmethyldoxepin, imipramine, desipramine, maprotiline, protriptyline, trimipramine and desmethyl-trimipramine were found to be 80% or higher. Limits of detection were found to be 5-10 ng/ml for teritary amines and 10-20 ng/ml for secondary amines. Interferences from some common basic drugs were investigated as well as interferences between different antidepressant drugs. Gas chromatographic data are given for 28 drugs and metabolites.

Antidepressive Agents, Tricyclic↗

PubMed1998

Serotonin transporter function in vivo: assessment by chronoamperometry.

Local application of selective serotonin reuptake inhibitors, fluvoxamine and citalopram, prolonged the clearance of exogenously administered serotonin (5-HT) in both the dentate gyrus and CA3 region of the dorsal hippocampus, as measured using in vivo chronoamperometry. These effects were abolished in rats pretreated with 5,7-dihydroxytryptamine. The NE uptake inhibitors, desipramine and protriptyline, did not alter the 5-HT signal in the CA3 region, but prolonged the clearance of 5-HT in the dentate gyrus; this effect was absent in rats pretreated with 6-hydroxydopamine. From these data, it is inferred that both the SERT and NET contribute to the active clearance of exogenously applied 5-HT in the dentate gyrus. In another experiment, cyanopindolol, an antagonist of the serotonin terminal autoreceptor, also prolonged the clearance of 5-HT from the CA3 region. These and other data have generated a working hypothesis that activation of the terminal serotonin autoreceptor enhances the kinetics of 5-HT uptake through an effect on the serotonin transporter.

Animals↗

PubMed1978

Aggregation of antidepressant drugs in aqueous solution.

Light scattering, conductivity and pH methods have been used to examine the aggregation in aqueous solution of a series of antidepressant drugs. The drugs investigated included the hydrochlorides of amitriptyline, butriptyline, protriptyline, nortriptyline, imipramine, desipramine, clomipramine, dothiepin, dibenzepin, opipramol, iprindole, doxepin, mianserin and maprotiline. No significant association of dibenzepin, mianserin or maprotiline hydrochlorides could be detected up to their respective solubility limits. A micellar pattern of association was established for all other compounds. Critical micelle concentrations and micellar properties are reported.

Antidepressive Agents↗

PubMed1985

Photon correlation spectroscopy of surface active cationic drugs.

Photon correlation spectroscopy (PCS) has been used to examine the aggregation in aqueous NaCl solution of a series of antidepressant and antihistamine drugs (hydrochlorides of imipramine, clomipramine, amitriptyline, butriptyline, protriptyline, doxepin, dothiepin, iprindole, diphenhydramine, bromodiphenhydramine, orphenadrine) propranolol hydrochloride and propantheline bromide. Critical micelle concentrations were measured by surface tension and PCS. Micellar sizes were investigated as functions of drug structure and drug and NaCl concentration. Generally, antidepressants formed the largest micelles. We propose that the antidepressants aggregate in a similar fashion to the phenothiazines by stacking with size increasing by addition of single monomers to stacks and by addition of more stacks to the aggregate.

Adrenergic beta-Antagonists↗

PubMed2002

Effects of antidepressants in rats trained to discriminate centrally administered isoproterenol.

Previous work has shown that the discriminative stimulus effects of centrally administered isoproterenol are mediated primarily via beta1-adrenergic receptors. In the present study, this model was used to investigate the ability of antidepressant drugs displaying various pharmacological profiles to stimulate beta1-adrenergic receptors in vivo; this was assessed by determining whether they substituted for the discriminative stimulus effects of isoproterenol. Rats were trained to discriminate centrally administered isoproterenol (10 microg i.c.v.) from artificial cerebral spinal fluid using a water-reinforced, two-lever operant task (fixed ratio 10 schedule). After acquisition of the discrimination, drugs were tested for substitution (i.p.). The tricyclic antidepressants protriptyline and desipramine, the norepinephrine uptake inhibitor nisoxetine, the monoamine oxidase inhibitor phenelzine, and the atypical antidepressants bupropion, mirtazapine, and venlafaxine all produced greater than 90% isoproterenol-appropriate responding. The serotonin uptake inhibitor fluoxetine, the atypical antidepressants buspirone and trazodone, and the novel, putative antidepressants N(G)-nitro-L-arginine and N-acetyl-L-tryptophan 3,5-bis benzyl ester failed to substitute for isoproterenol at the dose ranges tested. Antagonism studies carried out with betaxolol for those drugs that fully generalized to isoproterenol's cue verified mediation by beta1-adrenergic receptors. The present results indicate that drugs with noradrenergic activity generalize to isoproterenol's discriminative stimulus. Although this suggests a role for central beta1-adrenergic receptors in the mechanism of action of certain antidepressant drugs, it does not seem that stimulation of these receptors is an effect shared by antidepressants from all pharmacological classes.

Animals↗