Pharmacogenomics and tailored polypharmacy: an 80-year-old lady with rosuvastatin-associated rhabdomyolysis and maprotiline-related Ogilvie's syndrome
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What is known and objectives: Multiple adverse drug reactions (ADRs) are expected, and thus should be prevented in the elderly comorbid patient on polypharmacy. Rosuvastatin is commonly prescribed for the treatment and prevention of atherosclerotic diseases, and in rare cases, is associated with rhabdomyolysis. Maprotiline is a tetracyclic antidepressant, infrequently used in the United States, but seemingly more broadly in European countries. Acute colonic pseudo-obstruction (Ogilvie's syndrome) caused by maprotiline has thus far, to our knowledge, not yet been described in the literature. CASE SUMMARY: We present a unique case of synchronous rhabdomyolysis and Ogilvie's syndrome in an 80-year-old lung cancer survivor following a recent ischemic stroke for which she was prescribed clopidogrel and rosuvastatin for secondary prevention, and maprotiline for post-stroke, new-onset insomnia and anxiety. The ADRs resolved on removal of the offending agents and initiation of conservative treatment. Retrospective pharmacogenetic testing of the patient's drug-metabolizing enzymes and transporters was performed to guide further management and prevent future potential drug interactions and ADRs. What is novel and conclusions: This is an interesting, albeit unfortunate, complex case that depicts the risk of rare adverse effects to medications and their potential relationship to pharmacogenetics. The impact of anticholinergic side effects of antidepressants on gastrointestinal motility, risk of myopathies with statins, increased susceptibility to ADRs caused by drug-drug interactions, and the utility of pharmacogenomic testing are discussed. The question whether commercially available pharmacogenomic tools are relevant for everyday use to direct patient care and reduce harmful drug-drug interactions is addressed and warrants further research.
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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.

Effect of maprotiline on Ca(2+) movement in human neuroblastoma cells.

In human neuroblastoma IMR32 cells, the effect of the anti-depressant maprotiline on baseline intracellular Ca2+ concentrations ([Ca2+]i) was explored by using the Ca2+-sensitive probe fura-2. Maprotiline at concentrations greater than 100 microM caused a rapid rise in [Ca2+]i in a concentration-dependent manner (EC50 = 200 microM). Maprotiline-induced [Ca2+]i rise was reduced by 50% by removal of extracellular Ca2+. Maprotiline-induced [Ca2+]i rises were inhibited by half by nifedipine, but was unaffected by verapamil or diiltiazem. In Ca2+-free medium, thapsigargin, an inhibitor of the endoplasmic reticulum Ca2+-ATPase, caused a monophasic [Ca2+]i rise, after which the increasing effect of maprotiline on [Ca2+]i was abolished. U73122, an inhibitor of phospholipase C, did not affect maprotiline-induced [Ca2+]i rises. These findings suggest that in human neuroblastoma cells, maprotiline increases [Ca2+]i by stimulating extracellular Ca2+ influx and also by causing intracellular Ca2+ release from the endoplasmic reticulum via a phospholiase C-independent manner.

La maprotilina anula las diferencias entre ratones machos y hembras en el laberinto de agua de Morris / Maprotiline removes differences between male and female mice in the Morris water maze

Se estudiaron los efectos de la administración subcrónica de maprotilina (15, 20 y 25 mg/kg) sobre el aprendizaje espacial con el laberinto de agua de Morris, así como sobre la actividad general, en ratones machos y hembras. En la dase de adquisición, la administración de maprotilina (15 y 25 mg/kg) deterioró el aprendizaje en los machos pero no en las hembras, y no se observaron diferencias de sexo en el grupo control. En la fase de retención, la maprotilina, en las tres dosis, anuló las diferencias de sexo. Sobre la actividad general, la maprotilina, en las tres dosis, tuvo un efecto supresor de la misma y anuló las diferencias de sexo. El efecto sexodimórfico del fármaco en la fase de adquisición están en la línea del encontrado en otros experimentos, en los que se han usado otros fármacos, tanto antidepresivos como antipsicóticos, y otras tareas de aprendizaje en ratones. Este sexodimorfismo consiste en que el efecto del fármaco se observa sólo en los machos o, si se observa en los dos sexos, es mayor en los machos que en las hembras. La anulación de las diferencias de sexo en la fase de retención puede ser debida a la acción anticoligérnica de la maprotilina (AU)

The effects of subchronic administration of maprotiline (15, 20 and 25 mg/kg) on spatial learning, utilising the Morris water maze, and on general activity were assessed in male and female mice. In the acquisition phase, maprotiline (15 and 25 mg/kg) impaired learning in males but not in females. Also in this phase, sex differences were not found in the control group. In the retention phase, all three levels of maprotiline removed the sex differences found in the control group. In the general activity test, all three doses of maprotiline decreased activity and removed the sex differences found in the control group. Sexual dimorphism in the effects of maprotiline on spatial learning agrees with findings in studies of the effects of antidepressants and antipsychotics on different learning tasks in mice. When this dimorphism is present, the drug effect is observed only in males or, if present in males and females, it is stronger in the former. The absence of sex differences in the maprotiline treated groups in the retention phase could be due to the anticholinergic properties of the drug (AU)

Evidence of the dual mechanisms of action of venlafaxine.

BACKGROUND: Indirect evidence suggests that the antidepressant venlafaxine hydrochloride selectively inhibits serotonin (5-HT) uptake at low doses, whereas at high doses, it inhibits both 5-HT and norepinephrine (NE) uptake. We hypothesized that, in vivo, both high and low doses would inhibit the 5-HT uptake of platelets but that the higher dose would differentially blunt the pressor response to tyramine, a marker for NE uptake. METHODS: Healthy male volunteers aged 18 to 45 years received either 75 mg or 375 mg of venlafaxine hydrochloride per day, the 5-HT uptake inhibitor sertraline hydrochloride (50 mg/d), or the NE uptake inhibitor maprotiline hydrochloride (150 mg/d) (n = 8 for each of 4 treatment groups). Changes in platelet 5-HT uptake and the pressor response to intravenous tyramine were assessed following the initial dose and after 1 and 2 weeks of drug administration. RESULTS: Platelet 5-HT uptake was inhibited by venlafaxine across the dose range and by sertraline but not maprotiline. Inhibition was competitive, related to increases in affinity and not related to capacity. Steady-state drug levels were associated with a 5-HT uptake inhibition of 87% or more in subjects taking venlafaxine or sertraline. The pressor response to tyramine differentially distinguished maprotiline from sertraline and the low dose of venlafaxine but not from the high dose of venlafaxine. CONCLUSION: This study provides the first in vivo evidence in healthy humans that both 5-HT uptake and NE uptake inhibition are mechanisms of action sequentially engaged by venlafaxine over its clinically relevant dose range.

Non-response to maprotiline caused by ultra-rapid metabolism that is different from CYP2D6?

CASE: We are reporting about a patient with major depression who failed to respond to pharmacotherapy due to ultra-rapid metabolism of maprotiline. Under daily oral doses of 175 mg maprotiline, the patient's metabolic ratio (MR) for maprotiline in plasma was 9.2 (expected MRp: 2.4) and the clearance of maprotiline (CLM) was 4190 ml.min-1 (expected CLM = 1220 in extensive metabolisers of CYP2D6). RESULTS: The patient's MRurine for sparteine was 0.5, which is within the range for extensive metabolisers of CYP2D6. Genotyping did not show a duplication of the CYP2D6L allele. The patient's caffeine half-life was 10 h, thus, precluding ultra-rapid metabolism for CYP1A2. The therapeutic regiment was changed to co-administration of 200 mg maprotiline and 20 mg fluoxetine once per day in order to inhibit metabolism via CYP2D6. Subsequently, MRP of maprotiline (4.9) and CLM were reduced (1900 ml.min-1; expected CLM in poor metabolisers: of CYP2D6 364). This regimen improved the clinical outcome of the underlying disease. CONCLUSION: We conclude that for the non-response seen with maprotiline, P450 isozymes other than CYP2D6 or CYP1A2 are responsible. As CYP2C19 is involved in the metabolism of a number of tricyclic antidepressants it may be a candidate for ultra-rapid metabolism in this patient.

Cardiovascular effects of fluvoxamine and maprotiline in depressed patients.

In the choice of an antidepressant drug the clinician must often consider the presence of a cardiovascular comorbidity in depressed patients. In the present study the cardiovascular effects of fluvoxamine and maprotiline were compared in a double-blind trial in which the quantitative changes in ECGs were assessed before and during a 3-week treatment. A total of 33 patients (mean age 44 years; range 20-65 years) with major depressive disorder (RDC) who were free from clinically relevant organic diseases were investigated. After a 7-day wash-out period, a 3 week treatment phase was started with 200 mg daily of either fluvoxamine (n = 18) or maprotiline (n = 15). On days 0, 7, 14 and 21 a 12-lead standard ECG was performed and the drug plasma levels were determined. All ECGs were analysed in a blind fashion by an internist. Maprotiline caused a significant prolongation of the PR interval (P < 0.001) and of the QRS interval (P < 0.01) was well as an increase in heart rate (P < 0.001). The QTc interval was only tendentially prolonged (P < 0.10) and the P-wave duration and T-wave amplitude were not affected by maprotiline. No significant changes in ECG parameters were observed during treatment with fluvoxamine; and there was a nonsignificant trend (P < 0.10) for a lower heart rate during treatment. Blood pressure was not affected by treatment with either antidepressant. In both groups no significant correlations were found between ECG findings and the plasma levels of the drugs. Our results confirm that fluvoxamine in therapeutic dose causes no alteration in surface ECG regarding cardiac conduction and repolarization. Conversely, maprotiline caused a significant prolongation of atrioventricular and intraventricular conduction and a rise in heart rate. Although these effects were not clinically relevant in our sample of patients without overt heart disease, they should be taken into account when treating depressed patients with concomitant cardiac disease.

Assay for maprotiline in human serum with improved sensitivity and selectivity.

The use of a photoreactor and fluorescence detection enables measurement of the tetracyclic antidepressant drug 3-(9,10-dihydro-9,10-ethanoanthracene-9-yl)-N-methylpropylamine (maprotiline) with a sensitivity of 100 pg/ml serum. This detection system is highly specific and enables the measurement of very low concentrations in the presence of high concentrations of other drugs that are often found in patient samples. The mean free portions of maprotiline and desmethylmaprotiline were found to be 2.2% and 1.5%, respectively.

Maprotiline metabolism appears to co-segregate with the genetically-determined CYP2D6 polymorphic hydroxylation of debrisoquine.

The plasma concentrations of the tetracyclic antidepressant maprotiline and its effect on histamine-induced bronchoconstriction were measured after single (50 mg) and multiple (50 mg twice daily) oral doses in healthy subjects. Histamine-induced bronchoconstriction was abolished after a single dose of maprotiline and this effect persisted throughout multiple dose treatment. The mean Cmax of maprotiline in six poor metabolisers (PM) of debrisoquine was 2.7-fold greater than that in six extensive metabolisers (EM) and the mean AUC(0,48 h) was 3.5 times higher. The duration of the pulmonary effect of maprotiline after cessation of multiple dose treatment in EM was less than 3 weeks compared with at least 4 weeks in PM.

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.

[Suicide with chloroquine combined with maprotiline and trimipramine]. / Suizid mit Chloroquin unter Beteiligung von Maprotilin und Trimipramin.

Report on suicide with chloroquine in combination with maprotiline and trimipramine. Chloroquine and his metabolite monodesethylchloroquine could be determined in organs and body fluids. The highest organ-concentrations of chloroquine were found in liver and kidney. The survival time and dose are discussed.

Pharmacokinetics of the antidepressant levoprotiline after intravenous and peroral administration in healthy volunteers.

To investigate the pharmacokinetics and the disposition of levoprotiline after i.v. and p.o. administration and to assess the absolute bioavailability, 12 healthy volunteers (11 women, 1 man) were given a 10 min i.v. infusion of 15 mg and a p.o. dose of 75 mg in a two-way crossover study. Blood and urine samples were collected after each dose. Unchanged levoprotiline and the sum of unchanged and glucuronidated levoprotiline (= total levoprotiline) were determined by a specific gas chromatographic-mass spectro-metric method. Intravenous levoprotiline was rapidly and extensively distributed into extravascular sites of the body; the steady-state volume of distribution was 18.81 kg-1. The elimination of levoprotiline from blood was independent of the dosing route, the half-life being 18.8 h. Only 1.8 and 0.6 per cent of the i.v. and p.o. dose, respectively, were excreted unchanged in the urine, whereas 57 per cent of each dose were renally excreted as total levoprotiline. The absolute bioavailability of p.o. levoprotiline was 40 per cent. About 60 per cent of the dose was subject to a first-pass effect in the liver. The systemic blood clearance of levoprotiline, determined after i.v. dosing, was 885 ml min-1, the renal blood clearance after i.v. and p.o. dosing was only 16.0 and 14.2 ml min-1, respectively. Presystemic and systemic clearance of levoprotiline occurred predominantly by direct glucuronidation.

[Nonspecific factors and variations in biological parameters studied in biological psychiatry]. / Facteurs non spécifiques de variations des paramètres biologiques étudiés en psychiatrie biologique.

Some studies found no connection at all between biological parameters and mental illness. There are many reasons for the discrepancies: populations and parameters investigated as well as the method used, widely differed. The discrepancies observed, could also be partly due to several non-specific factors such as age, sex, hormonal status, circadian or circannual variations, and washout period. The authors report here some data gathered in the course of a psychobiological research program on healthy volunteers. Their results indicate that human plateler MAO activity shows an apparent menstrual cycle related variation [3H] IMI binding in human platelets shows circadian variations in summer and some antidepressant drugs have a residual effect on serotoninergic parameters during one month. These studies oblige investigators to be cautious when interpreting biological data in psychiatry. Ideally longitudinal studies should be implemented at the various stages of mental illness.

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.

Dosagem plasmática e metabolismo dos antidepressivos tricíclicos / Plasma measurement and metabolism of tricyclic antidepressant drugs

Neste artigo é exposto sucintamente aspectos do metabolismo dos antidepressivos tricíclicos (desmetilaçao e hipdroxilaçao) que devem ser levados em conta na interpretaçao das dosagens plasmáticas e efeitos clínicos destes medicamentos

[Maprotiline poisoning in an eleven-month-old infant]. / Intoxication à la maprotiline chez un nourrisson de onze mois.

The authors report the case of an eleven-month old infant who was given maprotiline and clobazam. He was found in coma state and suffered from convulsions, that were treated with phenobarbital. The electrocardiogram showed a right bundle branch block and a left anterior hemiblock over 72 h. The child then recovered without sequelae.