[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.

Effect of anthracene-9-carboxylic acid on the renal function of the unanesthetized rabbit.

Anthracene-9-carboxylic acid (9-AC) decreased the conductance to chloride in the isolated thick ascending limb of the loop of Henle and in the isolated perfused frog kidney (Greger, 1984; Oberleithner et al., 1983). The aim of this study was to study the in vivo effects of 9-AC in the unanesthetized rabbit. 9-AC decreased glomerular filtration rate, chloride and sodium clearances and urine volume. While glomerular filtration rate, chloride clearance and urine flow followed similar time courses for decreases and recoveries, and therefore seemed to be related, sodium clearance and fractional excretion of sodium showed an independent time course from the clearance of inulin and remained low throughout the experiment, suggesting a direct tubular effect. Values higher than unity for the fractional excretion of 9-AC, suggest that net tubular secretion of this acid occurs despite 9-AC is bound more than 80% to plasma proteins in the range of 10(-6) to 10(-3) M.

Sensitivity of normal human bone marrow myeloid progenitor cells to anthracycline, cisplatin, anthracene and flavone acetic acid derivatives, and its relevance for the prediction of human plasma concentrations of anticancer drugs.

Many in vitro investigations with anticancer agents are performed at concentrations equal to the peak concentrations or fractions of the peak concentrations achieved in human plasma after administration of these agents. In an effort to develop an in vitro test capable of predicting these peak plasma concentrations prior to the completion of pharmacokinetic studies, the effect of several classes of anticancer agents against normal human bone marrow myeloid progenitor cells (CFU-GM) was studied. The investigated agents included anthracycline antibiotics, cisplatin and its analogs, anthracene derivatives and two flavone acetic acid derivatives. The CFU-GM were exposed to these agents for 30-60 min. An exponential relationship between drug concentration and CFU-GM growth was observed for all compounds with the exception of the flavone acetic acid derivatives which were inactive. For the latter two compounds, an inhibition of CFU-GM growth was observed after continuous exposure. When compared to the plasma concentrations after parenteral administration of these agents, there was a very good agreement between 1/10 of the peak plasma concentration and the concentration inducing a 90% inhibition of the CFU-GM growth for the anthracycline antibiotics and anthracene derivatives. In contrast, for cisplatin and its analogs, there was a better agreement between 1/10 of the peak plasma concentration and the concentration inducing a 10% inhibition of CFU-GM growth. The combination of concentrations inducing inhibitions of 10 and 90% of the CFU-GM growth provides a range of concentrations that predict reasonably well the peak plasma concentrations of several anticancer agents and that could be used as guides for other in vitro investigations.

Fluorimetric determination of levoprotiline in human plasma after thin-layer chromatographic or high performance liquid chromatographic separation.

The quantitative determination of the new antidepressant drug levoprotiline, the R-(-)-enantiomer of oxa-protiline (a-[methylamino)methyl)-9,10-ethanoanthracene-9(10H)-ethanol), in human biological material is described. Analysis is performed by alkaline extraction with n-heptane-isopropanol, subsequent fluorescence derivatisation with NBD chloride (4-chloro-7-nitrobenzofurazan), thin layer or high performance liquid chromatography, and fluorimetric measurement of the derivatisation product (lambda max ex. = 470 nm, lambda max em. = 525 nm). The sensitivity of the procedure (detection limit less than 1 ng/ml) permits the performance of pharmacokinetic studies after therapeutic doses.

Serum levels of maprotiline and its adverse effects on depressed patients.

The relationships between the side effects of maprotiline (MPT) and the serum concentration of MPT and desmethylmaprotiline (DMPT) were investigated with 27 blood samplings in 15 depressed inpatients. There were significant correlations between the side effects and serum levels of MPT and DMPT. Mild side effects frequently occurred at levels of more than 130 ng/ml of MPT and 70 ng/ml of DMPT. At more than 220 ng/ml of the MPT levels and 110 ng/ml of DMPT levels, severe side effects occurred. Nearly sigmoidal serum level/side effect response curves occurred with both compounds.

A comparison of maprotiline and its desmethylated metabolite serum concentrations in outpatients and inpatients.

An investigation was conducted on drug defaulting in 26 depressed patients (11 outpatients and 15 inpatients) treated with maprotiline (MPT), using the interrogation methods and measurements of drug serum levels. All the outpatients visited the clinic regularly and complied with taking the prescripted drugs as directed. The results were as follows: (1) The relationships between the MPT and desmethylmaprotiline (DMPT) serum levels and the daily MPT doses showed highly linear regressions in all the patients, and in the inpatients and outpatients separately. There were significant differences between the regression coefficients obtained in the outpatients and inpatients with respect to MPT (P less than 0.01) and DMPT (P less than 0.001). There was a discrepancy between the results from the patients' reports and measurements of the drug serum levels. This finding indicated noncompliance by the outpatients. (2) Comparing various factors of the outpatients to those of the inpatients, the DMPT/MPT ratio of the former was higher than that of the latter (P less than 0.05). This was also due to the patients' noncompliance, and this ratio, therefore, was considered to be a sensitive marker for checking the compliance of the patients treated with MPT.

Plasma levels of maprotiline and zimelidine and their relationship to clinical response in depressed patients.

Plasma levels of maprotiline, zimelidine, and their respective demethylated metabolites were analyzed, and their relationship to the clinical response was examined, in 60 depressed patients given the drug treatment for 4 weeks. Significant correlation was found between zimelidine and norzimelidine levels (r = 0.531; p less than 0.05) as well as between the steady-state levels of total zimelidine and concentration of the drug 12 h after a single dose (r = 0.753; p less than 0.001). The ratios of drugs and their metabolites in individual patients remained remarkably constant throughout the study. Significant correlations between Hamilton Depression Rating Scale (HAMD) scores and plasma levels of total maprotiline (r = 0.613; p less than 0.05) or norzimelidine (r = -0.552; p less than 0.05) were observed in subgroups of retarded depressives on day 14, and between HAMD scores and norzimelidine levels in retarded depressives (r = 0.703; p less than 0.02) and all patients (r = 0.436; p less than 0.02) on day 28. Both maprotiline and zimelidine produced marked decreases in mean HAMD scores by the end of treatment, but the overall clinical response between the various subgroups was not significantly different (x2 = 3.15; df = 3). Responders and nonresponders to treatment could not be distinguished by mean plasma levels of drugs or their metabolites when all patients were considered. However, a significant difference was found in maprotiline levels between responders and nonresponders within a subgroup of retarded depressives.

Clinical pharmacokinetics of 9, 10-anthracenedicarboxaldehyde-bis [(4,5-dihydro-1 H-imidazol-2-yl)hydrazone]dihydrochloride.

We studied the clinical pharmacokinetics of the anthracene derivative bisantrene using high-performance liquid chromatographic analysis. We administered the drug to ten patients at 120-250 mg/m2 IV; one of these patients also received a second dose of 120 mg/m2 6 weeks later, and another received 150 mg/m2 weekly for three doses. Bisantrene disappeared from the plasma biphasically, with an initial t1/2 of 0.6 +/- 0.3 h and a terminal t1/2 of 24.7 +/- 6.9 h after single doses. The apparent volume of distribution according to the area under the curve was 42.1 +/- 5.9 l/kg, and the total clearance was 1045.5 +/- 51.0 ml/kg/h. The 96-h cumulative urinary excretion was 3.4% +/- 1.1% of dose; thus, renal excretion was a minor route of elimination for this agent. Bisantrene pharmacokinetics in the patient who received a second dose after 6 weeks showed insignificant changes. However, in the patient who was given this drug weekly for 3 weeks, the plasma t1/2 of the drug during the terminal phase became increasingly longer, while the total clearance was significantly reduced. These results suggest that bisantrene may accumulate in the body and that caution is essential in the event of frequent administration.

Tissue deposition of bisantrene in B16 melanoma tumor-bearing mice.

Single doses of 14C-labeled bisantrene, a new antitumor agent, were administered intravenously at 10 and 100 mg/kg to mice bearing intraperitoneally implanted B16 melanoma. At 24 hr after dosing, the tumors contained relatively high drug concentrations as compared to most of the other tissues. The concentrations averaged 2.4 and 28.3 micrograms/g tumor and the tumor/blood concentration ratios were 40/1 and 29/1 for the low and high doses, respectively.

Regional targeting of bisantrene by directed intravascular precipitation.

Targeting of anticancer drugs to specific organs by directed intravascular precipitation was studied in calves using 9-10 anthracenedicarboxyaldehyde bis [(4,5-dihydro-lH-imidazol-2-yl) hydrazone] dihydrochloride (Bisantrene), a clinically active anticancer drug with limited solubility at physiological pH. Rapid injection of Bisantrene in solution at pH 4.5 into the internal iliac artery resulted in concentrations of drug in the urinary bladder wall supplied by the artery that were more than 1000 times those in the same tissue following injection of the same dose of drug IV, the route of administration used clinically. Localization of the orange fluorescent drug to the ipsilateral bladder wall was easily seen. Fluorescence microscopy revealed deposits of drug along the walls of the arteriolar and capillary bed supplied by the artery into which it had been injected. Concentrations of drug in the systemic circulation and in tissues not supplied by the internal iliac artery used for drug injection were lower after intraarterial (IA) drug administration than after IV administration. Pathological studies of the tissues of calves sacrificed at intervals up to four weeks following rapid injection into the internal iliac artery of the same doses of Bisantrene used IV in cancer patients did not reveal evidence of extensive cytotoxicity to the infused organs.

Blood and tissue concentrations of Bisantrene measured by a simple fluorometric assay.

We have developed a simple sensitive fluorometric assay for the measurement of total Bisantrene in plasma, red blood cells, and tissues to facilitate preclinical and clinical pharmacologic assessment of this active anticancer agent. The assay was used to measure the plasma disappearance and tissue concentrations of Bisantrene in the rabbit. Results are comparable to those reported with HPLC assays and with measurement of radioactivity in combusted tissue following IV administration of radiolabeled Bisantrene. We demonstrated that when a plasma concentration of approximately 50 micrograms/ml is not exceeded, Bisantrene remains in solution at that concentration. If Bisantrene is introduced into plasma at a concentration exceeding 50 micrograms/ml, precipitation of the drug is initiated and continues until the plasma concentration is no greater than 15 micrograms/ml. This finding supports our previous recommendation that in clinical trials Bisantrene should be administered at low concentrations over prolonged periods of time to maximize the bioavailability of the drug by minimizing precipitation of the drug in plasma.

Measurement of maprotiline and oxaprotiline in plasma by high-performance liquid chromatography of fluorescent derivatives.

The antidepressant maprotiline and its hydroxylated analogue oxaprotiline were assayed in plasma by solvent extraction and formation of fluorescent derivatives, which were purified by thin-layer chromatography and quantitated by high-performance liquid chromatography with fluorescence monitoring. The procedure possesses a high sensitivity, accuracy and reproducibility, and metabolites of the drugs did not interfere.

Comparison of UV and fluorescence spectrophotometry for the quantification of a potent myotonia inducer: anthracene-9-carboxylic acid, in plasma, urine, and saline perfusion fluids.

UV and fluorescence spectrophotometry were used to establish the analytical profile of a potent myotonia inducer, anthracene-9-carboxylic acid (I). UV spectrophotometry is useful for the determination of I when it is dissolved in physiological solutions (Ringer's, Tyrode's, etc). In these fluids there is a linear relationship between UV absorption and I concentration between 500 and 2000 ng/ml (2.25-9.0 X 10(-6)M). However, in biological fluids there are interferences in the UV absorption due to organic substances. On the other hand, fluorescence spectrophotometry is more sensitive than UV for determinations in plasma and urine. Within the range of 200-1000 ng/ml (0.9-4.5 X 10(-6) M) fluorescence intensity increases linearly with concentration. Furthermore, when both emission and excitation spectra are combined there are no interferences due to organic substances normally present in those fluids. An extraction procedure of I from plasma and urine is also described, and the importance of I determinations in relation to the problem of this myotonia-inducing aromatic monocarboxylic acid is discussed.

Characterization of the pharmacokinetics of bisantrene (NSC-337766).

The pharmacokinetics of bisantrene, 9,10-anthracenedicarboxaldehyde bis [4,5-dihydro-1 H-imidazol-2-yl) hydrazone) dihydrochloride were evaluated during a Phase I clinical investigation. Bisantrene at doses of 20 to 280 mg/m2 was administered by variable infusion rates to nine patients with advanced metastatic cancer. Bisantrene's plasma clearance followed a triexponential pattern with a harmonic mean terminal half-life (t1/2 gamma) of 26 h. The steady state volume of distribution (Vdss) was large, averaging 627 l/m2. Plasma clearance averaged 42.6 +/- 6.7 l/h/m2. The cumulative urinary excretion of bisantrene was 3.6 +/- 1.6% at 48 h.

Liquid chromatographic separation of antidepressant drugs: II. Amoxapine and maprotiline.

The simultaneous serum analysis of amoxapine (AMOX) and its major metabolite 8-hydroxyamoxapine (8-OH AMOX), and maprotiline (MAP) and its major metabolite desmethylmaprotiline (D-MAP) by high-performance liquid chromatography (HPLC) and ultraviolet detection is described here. AMOX and 8-OH AMOX were detected at 254 nm at 0.01 absorbance units full scale (AUFS). MAP and D-MAP were detected at 214 nm at 0.05 AUFS. Serum (1.0 ml collected in plastic) extraction was by Bond-Elut C18 columns. The compounds of interest were eluted from the columns with 10 mM methanolic ammonium acetate. The eluates are evaporated at 56-58 degrees C and reconstituted with 200 microliter of mobile phase. The mobile phase was absolute ethanol-acetonitrile-tert-butylamine (98:2:0.05, vol/vol), and the flow rate was 2.0 ml/min. Absolute recoveries range from 97 to 100% for all compounds. HPLC was done on a 5-micron (4.6 X 250 mm) silica-packing column (normal phase). Separations on a 10-micron silica column (3.9 X 300 mm) are also discussed. Peak height ratios using trimipramine as the internal standard were linear for each drug between 25 and 1080 ng/ml. AMOX and 8-OH AMOX ratios with promazine as the internal standard were linear between 25 and 1080 ng/ml. Detection limits were 3 ng/ml for AMOX and 8-OH AMOX, 12 ng/ml for D-MAP, and 15 ng/ml for MAP. Coefficients of within-day and day-to-day variation at three concentration levels were less than 10.8% and 10.5%, respectively, for all compounds. Correlations of AMOX, 8-OH AMOX, and MAP sample assays using gas chromatography (or gas chromatography-mass spectrometry) and this method were compared. Steady-state daily dosages and corresponding serum levels are presented for seven patients. AMOX and 8-OH AMOX concentrations for 37 patients are given; these show that the ratios of these compounds are highly variable between patients. MAP and D-MAP concentrations for 30 patients show that D-MAP can be a significant fraction of the circulating drug. Assay time for 8-OH AMOX/AMOX was 6.5 min and less than 13 min for D-MAP/MAP.(ABSTRACT TRUNCATED AT 250 WORDS)

Analysis of amoxapine, 8-hydroxyamoxapine, and maprotiline by high-pressure liquid chromatography.

Two high-pressure liquid chromatography procedures are presented for the routine analysis of two new antidepressant drugs, amoxapine (Asendin) as well as its active metabolite and maprotiline (Ludiomil). Recovery rates were excellent with both methods of extraction. Method 1, for amoxapine and its metabolites, was linear up to 1,000 ng/ml. Sensitivity for the parent drug was 10 ng/ml and, for the active metabolite, 25 ng/ml. Within-run coefficients of variation (CV) were 4.57% for 8-hydroxyamoxapine and 3.84% for amoxapine. Method 2, for maprotiline, was linear from 10 to 1,000 ng/ml. Intraassay CV was 3.2%. Reliable, yet simple, methods for monitoring these drugs are needed in order to establish firmly the pharmacological data important to appropriate patient therapy.