Therapeutic and toxic concentrations of mirtazapine.
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Six cases involving the antidepressant mirtazapine were analyzed in detail at the San Diego County Medical Examiner's Office from 2004 to 2005. Mirtazapine was initially detected and confirmed in each of these cases by a liquid-liquid gas chromatography (GC)-MS basic drug screen. Following another liquid-liquid basic extraction, mirtazapine was quantitated by GC with nitrogen-phosphorus detection. For each case, mirtazapine concentrations in peripheral blood (pb), central blood (cb), vitreous (vit), and liver were determined against matrix specific calibration curves (limit of detection 0.01 mg/L; linear range 0.025-1.0 mg/L). In contrast with earlier studies of postmortem distribution of mirtazapine, we found concentrations in liver that were significantly higher. Mirtazapine was identified in the cause of death by the pathologist in three cases. In the drug-related deaths, mirtazapine concentrations (mean +/- S.D.) were 2.0 +/- 1.5 mg/L (pb), 1.6 +/- 1.0 mg/L (cb), 0.78 +/- 0.56 mg/L (vit), and 10 +/- 7.4 mg/kg (liver). Alternatively, concentrations considered therapeutic (three non-drug-related deaths) were (mean +/- S.D.) 0.18 +/- 0.22 mg/L (pb), 0.16 +/- 0.17 mg/L (cb), 0.12 +/- 0.16 mg/L (vit), and 0.73 +/- 0.68 mg/kg (liver). Although mirtazapine concentrations were elevated in blood and liver in three cases, it should be noted that other drugs were also found in toxic concentrations in each case. These data may further support the fact that mirtazapine is a relatively safe drug with respect to overdose. (+info)
Effect of mirtazapine on the CYP2D activity in the primary culture of rat hepatocytes.
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Our previous studies carried out on rats showed that mirtazapine given intraperitoneally at a dose of 3 mg/kg, twice a day for two weeks, increased the activity of CYP2D measured as ethylmorphine O-deethylation in liver microsomes. The aim of the present work was to find out whether the mirtazapine-induced increase in the CYP2D activity observed in vivo is connected with the central action of mirtazapine or the drug acts directly on hepatocytes. For this purpose, we studied the influence of pharmacological concentrations of mirtazapine (0.1, 1.0, 10 microM for 96 h) on the activity of CYP2D measured as the rates of ethylmorphine O-deethylation and dextromethorphan O-demethylation in the primary culture of rat hepatocytes. Additionally, we tested the ability of CYP isoforms to catalyze ethylmorphine O-deethylation, using cDNA-expressed CYPs and CYP inhibitors applied to liver microsomes. The obtained results indicate that mirtazapine applied at pharmacological concentrations can moderately increase the activity of rat CYP2D in hepatocytes, and CYP2D2 isoform contributes mostly to this effect. Similar result was previously obtained after in vivo administered mirtazapine in liver microsomes, but not in brain microsomes, the latter containing mainly CYP2D4 isoform. Mirtazapine appears to act directly on hepatocytes and its effect does not seem to depend on the central pharmacological action of the antidepressant. CYP2D2 is the main isoform catalyzing ethylmorphine O-deethylation while CYP2A2, CYP2C6 and CYP2C11 are of minor importance. (+info)
Honey bees communicate the location and desirability of valuable forage sites to their nestmates through an elaborate, symbolic "dance language." The dance language is a uniquely complex communication system in invertebrates, and the neural mechanisms that generate dances are largely unknown. Here we show that treatments with controlled doses of the biogenic amine neuromodulator octopamine selectively increased the reporting of resource value in dances by forager bees. Oral and topical octopamine treatments modulated aspects of dances related to resource profitability in a dose-dependent manner. Dances for pollen and sucrose responded similarly to octopamine treatment, and these effects were eliminated by treatment with the octopamine antagonist mianserin. We propose that octopamine modulates the representation of floral rewards in dances by changing the processing of reward in the honey bee brain. Octopamine is known to modulate appetitive behavior in a range of solitary insects; the role of octopamine in dance provides an example of how neural substrates can be adapted for new behavioral innovations in the process of social evolution. (+info)
An abbreviated version of the Connor-Davidson Resilience Scale (CD-RISC), the CD-RISC2: psychometric properties and applications in psychopharmacological trials.
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Resilience may be an important component of the prevention of neuropsychiatric disease. Resilience has proved to be quantifiable by scales such as the Connor-Davidson Resilience Scale (CD-RISC). Here, we introduce a two-item version of this scale, the CD-RISC2. We hypothesize that this shortened version of the scale has internal consistency, test-retest reliability, convergent validity, and divergent validity as well as significant correlation with the full scale. Additionally, we hypothesize that the CD-RISC2 can be used to assess pharmacological modification of resilience. We test these hypotheses by utilizing data from treatment trials of post-traumatic stress disorder, major depression, and generalized anxiety disorder with setraline, mirtazapine, fluoxetine, paroxetine, venlafaxine XR, and kava as well as data from the general population, psychiatric outpatients, and family medicine clinic patients. (+info)
A simpler and faster capillary electrophoresis method for determination of mianserin enantiomers in human serum.
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A stereospecific sample stacking capillary zone electrophoresis method is described for determination of S(+) and R(-) enantiomers of mianserin (1,2,3,4,10,14b-hexahydro-2-methyldibenzo[c,f]pyrazino[1,2-a]azepine) in human serum. The enantiomers of mianserin were extracted from human serum in one step extraction procedure using the mixture n-heptane:ethyl acetate (80:20, v/v). After separation of layers and freezing at -28 degrees C the organic layer was decanted and evaporated under a stream of nitrogen. The sample was dissolved in the mixture: water:methanol:acetonitrile (2:1:1, v/v/v). Separation was conducted in an aqueous solution of phosphoric acid (0.075M) adjusted to pH = 3.0 with concentrated triethylamine, and 2 mmole/L of 2-hydroxypropyl-beta-cyclodextrin. The analytes were measured by ultraviolet detection at 214 nm after separation on a Fused-Silica eCAP capillary. Clozapine was used as an internal standard. Recovery of the enantiomers from serum ranged from 82.94 to 90.37%. Total time of analysis was 49 minutes, whereas the other methods needed up to 100 minutes. (+info)
Development, validation and application of the HPLC method for determination of mianserin in human serum.
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A high performance liquid chromatography method for the determination of mianserin in human serum was developed and validated. Doxepin was used as an internal standard. Mianserin was extracted from human serum using a liquid-liquid extraction with hexane:isoamyl alcohol (99:1, v/v). The sample was then dissolved in 0.05 M phosphoric acid (pH=3.0), and after separation on a Hichrom RPB (250 x 4.6 mm, 5 mm) column, the analytes were measured by ultraviolet detection at 214 nm. The recovery ranged from 86.1 to 94.5% for mianserin. The method was specific and linear over the concentration range of 2.0-128.0 ng/mL. The limit of quantification (LOQ) was established at 2.0 ng/mL (CV=13.8%). The accuracy range was from 92.5 to 107.5%. The method was used to measure mianserin in human serum samples obtained from healthy volunteers who had received a single oral dose of 30 mg mianserin. Pharmacokinetic parameters obtained for the mianserin were in agreement with the existing data. (+info)
Mirtazapine in progressive multifocal leukoencephalopathy associated with polycythemia vera.
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Progressive multifocal leukoencephalopathy (PML) is a usually fatal cerebral white matter disease found in patients with human immunodeficiency virus infection and other immunocompromised states. We present the case of a 63-year-old woman with polycythemia vera who developed a progressive focal neurological deficit with white matter abnormalities on magnetic resonance images of the brain that was proved on biopsy to be PML. She was treated with the serotonin reuptake inhibitor mirtazapine and remains neurologically stable, with resolution of cerebral lesions, >2 years after diagnosis. We propose that mirtazapine should be investigated further for use in PML. (+info)
Simultaneous determination of nontricyclic antidepressants in human plasma by solid-phase microextraction and liquid chromatography (SPME-LC).
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A sensitive, selective, and reproducible solid-phase microextraction and liquid chromatographic (SPME-LC) method for simultaneous determination of mirtazapine, citalopram, paroxetine, fluoxetine, and sertraline in human plasma was developed, validated, and further applied to analyze plasma samples obtained from patients with depression. Important factors in the optimization of SPME efficiency are discussed, including the fiber coating, extraction time, pH, ionic strength, influence of plasma proteins, and desorption conditions. The limit of quantitation of the nontricyclic antidepressants in plasma varied from 25 to 50 ng/mL with a coefficient of variation lower than 5%. The response of the SPME-LC method for most of the drugs was linear over a dynamic range of 50 to 500 ng/mL, with all of them having correlation coefficients greater than 0.9970. The performance of the SPME-LC method allowed the nontricyclic antidepressants analyses in therapeutic levels. (+info)