Bioavailability and kinetics of maprotiline.

Six male subjects received simultaneously single 50-mg oral doses of a maprotiline hydrochloride tablet and a trideuterated maprotiline hydrochloride aqueous solution. No side effects or other problems were encountered. The blood levels of unlabeled and isotope-labeled maprotiline for each subject were essentially superimposable. Peak levels, averaging about 50 ng/ml, were attained between 8 and 24 hr after drug. The biologic t1/2 (beta-phase) averaged 58 hr for the unlabeled and 60.5 hr for the labeled drug. The total areas under the curves (extended to time infinity) averaged 3,862 and 3,944 ng . hr/ml for maprotiline and trideuterated maprotiline, respectively (differences between the two are not significant). At the 95% degree of confidence the Westlake confidence limits show less than 10% differences between the formulations with respect to area under the curve data (calculated both to 168 hr and extended to time infinity), peak blood levels, and biologic t1/2s. There were no differences between formulations with respect to times of peak concentrations. Estimates were made for apparent volumes of distribution (about 1,000 l), apparent blood clearance (about 14 l/hr), lag times (about 1.42 hr for tablets and 1.31 hr for solution), and absorption rate constants (about 0.34 hr-1 for the tablets and 0.42 hr-1 for the solution).

Amitriptyline versus maprotiline in postherpetic neuralgia: a randomized, double-blind, crossover trial.

Amitriptyline (AT) relieves some patients with postherpetic neuralgia (PHN). Many patients suffer side effects and better therapies are necessary. The aim of this study was to evaluate the efficacy of maprotiline (MT) (noradrenergic) compared to AT (mixed noradrenergic and serotonergic) in this disorder. Thirty-five patients entered a randomized, double-blind, crossover trial of these two agents. We found that MT relieved PHN in many patients but was not as effective as AT. Side effects were troublesome with both agents. Relief of steady pain, brief pain and pain on tactile stimulation occurred. Four groups of responses were identified. Some patients reported relief with both agents, some with neither agent and others with only one of the drugs. Most patients were not depressed and analgesia was observed to occur without change in depression ratings in most patients who responded. This result provides evidence that in some patients AT may act via a selective noradrenergic mechanism in relieving PHN and that individuals may differ in the balance and type of neurotransmitters inhibiting pain. Selective noradrenergic agents may be effective if AT fails.

Atrial flutter and maprotiline: case report.

Atrial flutter developed in an 80-year-old woman after 10 days of treatment with maprotiline at therapeutic concentrations. This cardiac irregularity is extremely rare with the conventional antidepressants. Evidence is reviewed to suggest that the likely mechanism was reuptake blockade of noradrenergic amines stimulating reentrant excitation within the atria.

Plasma levels of tricyclic antidepressants and clinical efficacy: review of the literature -- part II.

The authors have critically reviewed the literature regarding the relationship between plasma levels of tricyclic antidepressant and their clinical efficacy. When available, drug-drug interactions, pharmacokinetics, and other factors influencing plasma levels of tricyclic antidepressants are discussed. Although many studies are confounded by significant methodological and statistical problems, it appears to these reviews that the available evidence suggests a curvilinear relationship between nortriptyline plasma levels and antidepressant efficacy in tricyclic responsive endogenously depressed inpatients, with maximal therapeutic efficacy achieved with notriptyline plasma levels between 50-175 ng/ml. The evidence for imipramine supports a linear relationship between plasma levels of imipramine plus desmethylimipramine and clinical response in nondelusional endogenously depressed tricyclic responsive inpatients. For amitriptyline, the picture is less clear. However, with the exception of one well-controlled study, the available evidence suppprts some significant relationship between amitriptyline plus nortriptyline plasma levels and antidepressant efficacy in tricyclic respoonsive endogenously depressed patients, but it is not clear as to whether this is a linear relationship or a curvilinear one. For the other antidepressants: protriptyline, desmethylimipramine, doxepin, clomipramine, maprotiline, and butriptyline, a significant relationship (if any) awaits further elucidation. It is important to point out that these plasma level relationships probably do no generalize to other types of depressions (e.g. neurotic, characterological, delusional, acute situationa, etc.) and clearly do not apply to every endogenous tricyclic responsive patient. /owever, it appears that, in general, a clinician will obtain therapeutic efficacy for endogenously depressed patients if these guidelines are followed. The actual therapeutic levels will depend on the assay's sensitivity and specificity and may vary from center to center, illustrates the importance of each center defining its own therapeutic limits, or conversely all centers adoptina a universal reproducible assay methodology for each compound measured. Despite these limitations, these reviewers feel that routine monitoring of plasma levels of the tricyclic antidepressants is a useful method to maximize therapeutic efficacy and prvent undue side effects, as well as to insure good medication compliance.

Depression in the elderly: pharmacologic considerations in treatment.

The pharmacologic treatment of depression in the aged is complicated by an increased frequency of concurrent medical disease and multiple drug use. In addition, age-related physiologic changes may alter the pharmacokinetics and pharmacodynamics of the antidepressant medications. As a consequence, the variability of response and the incidence of adverse effects are increased in the elderly. The clinical implications of these factors and guidelines for the use of antidepressants in the elderly are discussed.

Plasma concentrations of fluvoxamine and maprotiline in major depression: implications on therapeutic efficacy and side effects.

We examined the relationship between plasma concentrations of specific acting antidepressants (fluvoxamine/maprotiline) and clinical improvement as well as the impact of the magnitude of the plasma concentration of these antidepressants on side effects. Patients (32 patients with major depression) were treated within a double-blind parallel trial for four weeks and plasma concentrations were obtained before, on days 8 and 28 of the trial. Although there was a fixed-flexible dosage design it was apparent that 16 patients (89%) of the fluvoxamine group and all patients of the maprotiline group received a dosage between 200 and 300 mg/day in the last week of the trial. Plasma concentrations (mean +/- SD micrograms/l) of fluvoxamine were 125 +/- 91 and 142 +/- 108 on days 8 and 28, respectively and the range of fluvoxamine plasma concentrations on day 28 was from 20 to 417 micrograms/l. Plasma concentrations (mean +/- SD micrograms/l) of maprotiline were 146 +/- 62 and 202 +/- 134 on days 8 and 28, respectively and the range of maprotiline plasma concentration on day 28 was from 12 to 428 micrograms/l. There was no linear relationship between plasma concentrations of both antidepressants (fluvoxamine/maprotiline) and oral dosage. Whereas there was no correlation between fluvoxamine concentration and clinical response there was a tendency that higher maprotiline concentrations were associated with a better antidepressive efficacy at the end of the trial. Higher concentrations of fluvoxamine as well as of maprotiline were significantly (P < 0.05) associated with more side effects.

Maprotiline in affective illness. Plasma concentration and clinical response.

Twenty patients suffering from endogenous depression were treated with maprotiline for 4 weeks. Blood samples were collected at weekly intervals and severity of depression assessed using the Hamilton Depression Rating Scale. No simple relationship between plasma maprotiline concentration and amelioration score was observed at week 3 (rs = 0.25) or week 4 (rs = -0.05). No significant difference in plasma concentrations between responders and non-responders was observed at week 4. Maprotiline was effective as an antidepressant in some patients.

GLC-mass spectrometric determination of maprotiline and its major metabolite using stable isotope-labeled analog as internal standard.

A quantitative GLC-mass spectrometric assay was developed for the determination of maprotiline and its major metabolite, desmethylmaprotiline, in animal and human plasma. The assay utilizes selective-ion focusing to monitor, in a GLC effluent, the fragment ions and the base peaks of maprotiline and desmethylmaprotiline trifluoroacetamides generated by electron-impact ionization. Maprotiline-d3 was the internal standard. The assay can measure 2 ng of maprotiline (and the metabolite)/ml of plasma with approximately 5% precision. The curves relating the amounts of maprotiline and the metabolite added versus the amounts experimentally found over a large concentration range were linear with nearly zero intercepts and slopes of 0.99 +/- 0.01 and 0.98 +/- 0.02, respectively. The method was used to study the pharmacokinetic pattern of the drug in rabbits as well as to analyze intact maprotiline and the metabolite in patients maintained on therapeutic doses of maprotiline. Assay specificity was confirmed by complete consistency of the mass spectra of maprotiline and desmethylmaprotiline with those of the authentic materials.

Pharmacokinetics of maprotiline and its demethylated metabolite in serum and specific brain regions of rats after acute and chronic administration of maprotiline.

The concentrations of maprotiline (MAP) and its demethylated metabolite desmethylmaprotiline (DMAP) in the serum and specific brain regions were determined periodically after acute or chronic administration of 20 mg/kg of MAP in rats. MAP was eliminated in a biexponential manner from the serum and monoexponentially from the brain. The DMAP declined monoexponentially from the serum and brain regions. No significant difference was observed in elimination among the eight brain regions examined. In the brain, MAP distributed unevenly after chronic administration, whereas DMAP showed an even distribution. In the acute administration, the AUCbrain: AUCserum ratio of MAP was similar to that of DMAP, and the AUCDMAP: AUCMAP ratio in the serum was almost equal to that in the brain, indicating equivalent ability of MAP and DMAP to penetrate into the brain. After chronic administration, the AUCDMAP value in the serum increased 4.1 times, whereas no marked change was observed for MAP. There was no evidence of enhanced N-demethylation activity from in vitro metabolism study, suggesting that the enhanced AUCDMAP value was not attributable to the enhancement of drug metabolizing activity. Although the AUCMAP value in the brain, as well as in the serum, increased slightly, the AUCDMAP in the brain increased 2.3 times, showing less increase than that in the serum. These findings suggest inhibited distribution of DMAP into tissue, including brain regions, after chronic administration. The pharmacokinetics of the demethylated metabolite DMAP is affected more than that of MAP by chronic administration of MAP.

Pharmacokinetic analysis of maprotiline and its demethylated metabolite in serum and brain of rats after acute and chronic oral administration of maprotiline.

Compartmental model analysis by simultaneous curve fitting was used to ascertain the pharmacokinetic relationship between maprotiline (MAP) and its demethylated metabolite desmethylmaprotiline (DMAP) in the serum and brain of rats after single or multiple oral administrations of MAP. The extent of bioavailability and the fraction metabolized to DMAP after acute oral administration were 0.202 and 0.065, respectively, indicating first-pass metabolism of MAP. Although the estimated transfer rate constants to and from the brain (k(in) and k(out)) of MAP were higher than those of DMAP, the k(in):k(out) ratio for MAP was similar to that for DMAP. These findings indicate the equivalent ability of MAP and DMAP to penetrate into the brain after acute oral administration. The estimated values of bioavailability and fraction metabolized to DMAP increased 2.6 and 1.7 times, respectively, after chronic administration of MAP. These findings are attributable to inhibited distribution in tissue. The k(in) and k(out) values of MAP decreased, whereas those of DMAP showed no marked change. Therefore, the k(in):k(out) ratio for MAP decreased, whereas that for DMAP did not change. These results suggest that the permeability of MAP into the brain might be affected and that of DMAP is not modified by chronic administration of MAP.

Simultaneous quantification of citalopram, clozapine, fluoxetine, norfluoxetine, maprotiline, desmethylmaprotiline and trazodone in human serum by HPLC analysis.

We describe an analytical procedure for the simultaneous quantification of citalopram (seropram), clozapine (leponex), fluoxetine (fluctine), norfluoxetine, maprotiline (ludiomil), desmethylmaprotiline and trazodone (trittico) in human serum within a period of 11.5 minutes using reversed phase HPLC. After 2 liquid/liquid extractions in the sample preparation phase, the drugs and metabolites were separated on a C18 column using a mobile phase consisting of acetonitrile/buffer (30/70, v:v) at 70 degrees C, a flow rate of 1.5 m/min and haloperidol as internal standard. Absorption and native fluorescence signals of the eluted compounds were detected simultaneously at 260 nm and 227/300 nm (excitation/emission), respectively. The calibration ranges for citalopram, clozapine, fluoxetine, norfluoxetine, maprotiline, and desmethylmaprotiline ranged from 50-400 microg/l and for trazodone from 50-3,200 microg/l. The CVs varied between 0.6% and 5.5% (within-run) and between 3.2% and 7.1% (between-run). Recoveries were > 90% for all pharmaceuticals. We noticed no interferences from several commonly used drugs.

A simple automated procedure for the detection and identification of peaks in gas chromatography--continuous scan mass spectrometry. Application to systematic toxicological analysis of drugs in whole human blood.

Gas chromatography-mass spectrometry (GC-MS), which combines the separation power of GC with the power of MS for the identification of unknown compounds, possesses high potential in systematic toxicological analysis (STA). Different factors, however, do not allow this potential to be fully exploited. Between them, the low selectivity of the mass spectrometer operating in continuous scan plays a critical role, in many cases precluding the possibility of selecting mass spectra in the total ion chromatogram (TIC) sufficiently clean for a positive identification by library search, even when using reverse search algorithms. Moreover, the large amount of information contained in GC-MS data file that results from the analysis of a biological extract makes the efforts of manual search almost useless and requires the availability of reliable methods for the automated detection and identification of peaks in a TIC. In this paper, a simple procedure that improves the performance of a bench-top GC-MS system in the purification of mass spectra of coeluting compounds and that can be easily combined with the automated processing of a GC-MS data file is described. It is based on the subtraction of the intensities of successive pairs of scans in the TIC, on the detection of positive and negative peaks in the transformed chromatograms, and on the search of the corresponding background-subtracted electron ionization mass spectra against reference libraries. In order to evaluate the proposed procedure, GC-MS data files obtained for the analysis of extracts of blank whole blood spiked with more than 100 drugs, poisons, and their metabolites at a concentration of 0.5 mg/L were used. Compared with the search of the raw TICs, the proposed procedure increased the number of identified substances and, in many cases, obtained higher match quality values for identification.

Simple analysis of tetracyclic antidepressants in blood using headspace-solid-phase microextraction and GC-MS.

A simple and sensitive method for analysis of three tetracyclic antidepressants, maprotiline, mianserin, and setiptiline, in human whole blood was developed using headspace-solid-phase microextraction (SPME) and gas chromatography-mass spectrometry (GC-MS). A vial containing a blood sample, sodium hydroxide, and imipramine as an internal standard was heated at 120 degrees C. The extraction fiber of the SPME was exposed for 45 min in the headspace of the vial. The compounds absorbed on the fiber were desorbed by exposing the fiber in the injection port of a GC-MS. The calibration curves, using an internal standard method, demonstrated good linearity throughout the concentration range from 0.005 to 5.0 microg/g for mianserin and setiptiline and from 0.025 to 25 microg/g for maprotiline. No interferences were found, and the time for analysis was 60 min for one sample. In addition, this proposed method was applied to a medicolegal case in which the cause of death was suspected to be acute setiptiline poisoning. Setiptiline was detected in the left and right heart blood samples of the victim at concentrations of 1.77 and 0.78 microg/g, respectively.

Efficacy, side-effects, plasma and blood levels of maprotiline (Ludiomil).

Two trials of maprotiline (Ludiomil) were performed in general practice. In the first study depressed patients were given either 75 mg of maprotiline in a single dose or 25 mg three times daily. Assessments of the severity of depression and of side-effects were made initially and following 1, 2 and 4 weeks' treatment. At each assessment measurements of plasma levels of maprotiline were made. A second trial was performed in which some patients receiving 75 mg single dose of maprotiline had whole blood levels of maprotiline assayed. Steady-state levels of maprotiline were achieved after one week but these levels showed considerable individual variability. No clear correlation emerged between clinical response, side-effects and plasma or blood levels. Some of the factors which may be responsible are discussed.

[Blood concentrations of maprotiline in depressive patients]. / Etude des concentrations sanguines de maprotiline chez des patients déprimés.

Blood levels of Maprotiline were analysed and their relationship to the clinical response was examined in 89 depressed inpatients, according DSM III criteria for Major Depressive Episode, given the drug treatment for 3 weeks. Maprotiline produced marked decreases in mean MADRS and COVI scale scores by the end of treatment. On day 21, no correlation between blood levels of Maprotiline and MADRS or COVI scores were found when all patients were considered. Nevertheless, significant correlations were observed on day 14 (r = .22; p less than .05 for MADRS and r = .23; p less than .05 for COVI scale). In addition, a significant correlation between MADRS or COVI scale scores and Maprotiline blood levels were observed on days 14 and 21 in subgroups of young patients, severe depression (high scores to clinical global investigations), during of at least 3 months, treated without other drug than Maprotiline and good responders.

Comparative evaluation of positron emission tomography radiotracers for imaging the norepinephrine transporter: (S,S) and (R,R) enantiomers of reboxetine analogs ([11C]methylreboxetine, 3-Cl-[11C]methylreboxetine and [18F]fluororeboxetine), (R)-[11C]nisoxetine, [11C]oxaprotiline and [11C]lortalamine.

We have synthesized and evaluated several new ligands for imaging the norepinephrine transporter (NET) system in baboons with positron emission tomography (PET). Ligands possessing high brain penetration, high affinity and selectivity, appropriate lipophilicity (log P = 1.0-3.5), high plasma free fraction and reasonable stability in plasma were selected for further studies. Based on our characterization studies in baboons, including 11C-labeled (R)-nisoxetine (Nis), oxaprotiline (Oxap), lortalamine (Lort) and new analogs of methylreboxetine (MRB), in conjunction with our earlier evaluation of 11C and 18F derivatives of reboxetine, MRB and their individual (R,R) and (S,S) enantiomers, we have identified the superiority of (S,S)-[11C]MRB and the suitability of MRB analogs [(S,S)-[11C]MRB > (S,S)-[11C]3-Cl-MRB > (S,S)-[18F]fluororeboxetine] as potential NET ligands for PET. In contrast, Nis, Oxap and Lort displayed high uptake in striatum (higher than in thalamus). The use of these ligands is further limited by high non-specific binding and relatively low specific signal, as is characteristic of many earlier NET ligands. Thus, to our knowledge (S,S)-[11C]MRB remains by far the most promising NET ligand for PET studies.

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.

Estimation of maprotiline in serum by gas-chromatography, with use of a nitrogen-specific detector.

We describe a gas-chromatographic procedure for estimating therapeutic concentrations of maprotiline, a new tetracyclic antidepressant, in serum by use of a nitrogen-specific detector. Desmethyldoxepin, a secondary amine similar in structure to maprotiline, is added as a mass internal standard to the specimen before extraction, to obviate the need for accurate measurements of volumes during extraction and analysis. Both maprotiline and the internal standard are converted to acetyl derivatives, to avoid the adsorption of secondary amines on the column. A highly selective liquid phase is used, which allows a very good separation of desmethyldoxepin, maprotiline, desmethylmaprotiline, and the interferences from serum and reagents.