Carlos Lima

Effect of age and gender on citalopram and desmethylcitalopram steady-state plasma concentrations in adults and elderly depressed patients.

The effect of aging on steady-state plasma concentrations of citalopram (CIT) and desmethylcitalopram (DCIT) was investigated in 128 depressive patients treated with 10-80 mg/day CIT. They were separated into three groups, with age up to 64 years (mean age+/-S.D.: 47+/-12 years; n=48), between 65 and 79 years (72+/-1 years; n=57), and from 80 years or older (84+/-1 years; n=23). Body mass index (BMI), renal and hepatic functions were similar in the three groups. A large interindividual variability of plasma levels of CIT (16-fold) and DCIT (12-fold) was measured for a given dose. The mean plasma levels of CIT corrected for a 20 mg daily dose were 55% higher in the very elderly (>=80 years) patients (65+/-30 ng/ml; p<0.001) and 38% higher in the elderly (65-79 years) patients (58+/-24 ng/ml; p<0.001) when compared to the adult patients (42+/-17 ng/ml). DCIT mean plasma level was 38% higher (p<0.05) in the group of very elderly patients (22+/-10 ng/ml) when compared to the adult patients (16+/-9 ng/ml). As a consequence, the mean plasma concentration of CIT+DCIT was 48% higher in the very elderly patients (86+/-36 ng/ml; p<0.001) and 33% higher in the elderly patients (77+/-28 ng/ml; p<0.001) when compared to the adult patients (58+/-21 ng/ml). Age correlated significantly with CIT (r=0.43, p<0.001), DCIT (r=0.28, p<0.01), and CIT+DCIT plasma levels (r=0.44, p<0.001), and thus accounts for 18% of the variability of CIT plasma levels, with no influence of gender. The recommended dose reduction of CIT in elderly patients seems therefore justified.

Steady state concentrations of the enantiomers of mianserin and desmethylmianserin in poor and in homozygous and heterozygous extensive metabolizers of debrisoquine

Steady state concentrations of (S)- and (R)-mianserin and desmethylmianserin were measured in 21 homozygous extensive metabolizers (as determined by genotyping for mutations 3 [or A] and 4 [or B]), in seven heterozygous extensive metabolizers and in one poor metabolizer of debrisoquine, as well as in one patient receiving very high doses of mianserin (360 mg/day) and fluoxetine (160 mg/day), a strong cytochrome P450IID6 inhibitor. The mean dose of mianserin was (mean +/- SD, range: 67 +/- 63, 10 to 360 mg/day). High dispersions of the (S)/(R)-mianserin and desmethylmianserin ratios were observed (mean +/- SD, range: 2.10 +/- 1.01, 0.64 to 4.76, and 0.29 +/- 0.14, 0.08 to 0.57, respectively). The highest (S)/(R)-mianserin ratio was calculated for the poor metabolizer (4.76) agreeing with those results of a single-dose study with poor and extensive metabolizers of debrisoquine, in that the cytochrome P450IID6 is probably involved in the metabolism of mianserin with an enantioselectivity for the (S)-enantiomer. Nevertheless, the mean concentration-to-dose ratios for (S)- or (R)-mianserin or desmethylmianserin were not significantly different between homozygous and heterozygous and extensive metabolizers, and no particular values were measured in the poor metabolizer nor in the patient receiving fluoxetine. Furthermore, the (S)/(R)-mianserin ratio measured in the PM was only slightly higher than the second highest ratio (3.85) of an homozygous extensive metabolizer, whereas no particular value (2.92) was calculated for the patient taking fluoxetine. Finally, no significant differences in (S)/(R)-mianserin or (S)/(R)-desmethylmianserin were calculated between homozygous and heterozygous extensive metabolizers. Although the number of patients included in this study is too low to allow definite conclusions, the results suggest that the debrisoquine genotype has only a moderate influence on the steady state concentrations of the enantiomers of mianserin and desmethylmianserin.

Multicenter study on the clinical effectiveness, pharmacokinetics, and pharmacogenetics of mirtazapine in depression.

Abstract Pharmacogenetic tests and therapeutic drug monitoring may considerably improve the pharmacotherapy of depression. The aim of this study was to evaluate the relationship between the efficacy of mirtazapine (MIR) and the steady-state plasma concentrations of its enantiomers and metabolites in moderately to severely depressed patients, taking their pharmacogenetic status into account. Inpatients and outpatients (n = 45; mean age, 51 years; range, 19–79 years) with major depressive episode received MIR for 8 weeks (30 mg/d on days 1–14 and 30–45 mg/d on days 15–56). Mirtazapine treatment resulted in a significant improvement in mean Hamilton Depression Rating Scale total score at the end of the study (P < 0.0001). There was no evidence for a significant plasma concentration–clinical effectiveness relationship regarding any pharmacokinetic parameter. The enantiomers of MIR and its hydroxylated (OH-MIR) and demethylated (DMIR) metabolites in plasma samples on days 14 and 56 were influenced by sex and age. Nonsmokers (n = 28) had higher mean MIR plasma levels than smokers (n = 17): S(+)-enantiomer of MIR, 9.4 (SD, 3.9) versus 6.2 (SD, 5.5) ng/mL (P = 0.005); R(−)-enantiomer of MIR, 24.4 (SD, 6.5) versus 18.5 (SD, 4.1) ng/mL (P = 0.003). Only in nonsmokers, plasma levels of S(+)-enantiomer of MIR and metabolites depended on the CYP2D6 genotype. Therefore, high CYP1A2 activity seen in smokers seems to mask the influence of the CYP2D6 genotype. In patients presenting the CYP2B6 *6/*6 genotype (n = 8), S-OH-MIR concentrations were higher those in the other patients (n = 37). Although it is not known if S-OH-MIR is associated with the therapeutic effect of MIR, the reduction of the Hamilton scores was significantly (P = 0.016) more pronounced in the CYP2B6 *6/*6–genotyped patients at the end of the study. The role of CYP2B6 in the metabolism and effectiveness of MIR should be further investigated.

Concentrações plasmáticas de paroxetina em pacientes adultos e idosos com depressão

INTRODUCTION: The effect of aging on steady-state plasma concentrations of paroxetine was investigated in 136 depressive patients treated with paroxetine 10-120 mg/day. METHODS: The patients were divided into three groups: aged up to 64 years (mean age ± standard deviation: 41.7±12.6 years; n = 44), between 65 and 79 years (72.8±4.7 years; n = 64), and 80 years or older (82.8±3.3 years; n = 28). Paroxetine doses were normalized to 20 mg/day. Blood samples were collected under steady-state conditions. Paroxetine plasma levels were measured by gas chromatography/mass spectrometry. Hepatic and renal functions were measured by standardized clinical laboratory tests. RESULTS: A large interindividual variability of paroxetine plasma levels (37-fold) was measured for a given dose. The mean plasma levels of paroxetine corrected for a 20 mg daily dose were 87% higher in the very elderly (≥ 80 years) patients (56.4±64.1 ng/mL; p < 0.05) and 57% higher in the elderly (65-79 years) patients (46.7±33.4 ng/mL; p < 0.001) when compared to the adult patients (< 64 years) (29.9±11.9ng/mL). Age correlated significantly with paroxetine plasma levels (r = 0.21, p < 0.05). CONCLUSION: Recommended dose reduction of paroxetine in elderly patients seems therefore justified.

Foix-Alajouanine syndrome mimicking a spinal cord tumor

Subacute necrotizing myelopathy (SNM) or Foix-Alajouanine syndrome is a rare disease characterized by progressive neurological dysfunction caused by a spinal dural arteriovenous fistula (AVF). Radiological diagnosis is usually suspected when there is intramedullary nonspecific enhancement and perimedullary flow voids. Ring-enhancement is rarely reported in the scope of AVF, which poses a diagnostic challenge and raises the suspicion of a spinal cord tumor. In such situations, biopsy can be required and delay proper diagnosis. We report the case of a patient with SNM, who underwent biopsy on the assumption of it being a spinal cord tumor.

B-Coloring Graphs with Girth at Least 8

A b-coloring of a graph is a proper coloring of its vertices such that every color class contains a vertex that has neighbors in all other color classes. The b-chromatic number of a graph is the largest integer b(G) such that the graph has a b-coloring with b(G) colors. This metric is upper bounded by the largest integer m (G) for which G has at least m (G) vertices with degree at least m (G) —1. There are a number of results reporting that graphs with high girth have high b-chromatic number when compared to m(G). Here, we prove that every graph with girth at least 8 has b-chromatic number at least m(G) 3 - 1. This proof is constructive and yields a polynomial time algorithm to find the b-chromatic number of G. Furthermore, we improve known partial results related to reducing the girth requirement of our proof.

Psychotropic drug prescriptions in hospitalized elderly psychiatric patients: comparison with adult psychiatric patients

Background:  Drug prescriptions were studied in two samples of inpatients that differentiated by their ages (patients 18–64 years vs elderly patients >64 years), in order to compare the use of psychotropic and non‐psychiatric drugs, and the proportion of newer versus classical antidepressants or antipsychotics.