Concentrations Of Mianserin Research Articles

Ventricular Fibrillation Caused by Mianserin Poisoning

Case: A 56-year-old man who revived after ventricular fibrillation was transferred to the emergency center at Kansai Medical University. The blood examination, computed tomography, and cardiac echocardiography at the time admission could not detect the cause of ventricular fibrillation. However, high-performance liquid chromatography revealed mianserin and aripiprazole in his serum. The concentration of mianserin (48.7 mg/L), especially, was found to be very high. Therefore, we believed that ingestion of a large amount of mianserin could have induced ventricular fibrillation.

The pharmacokinetics of mianserin suppositories for rectal administration in dogs and healthy volunteers: a pilot study.

BackgroundWe formulated mianserin suppositories for the treatment of delirium and evaluated their pharmacokinetics by measuring plasma drug concentrations in dogs and healthy human volunteers.MethodsMianserin suppositories were prepared by a melting technique using Tetramide® tablets and Witepsol H-15 as the suppository base. Pharmacokinetics of this 30-mg mianserin preparation were evaluated in three beagle dogs and three healthy adult males, in line with ethics committee approval. Plasma mianserin levels were determined using gas chromatography–mass spectrometry.ResultsIn dogs, the maximum plasma mianserin concentration (Cmax) was 1.3 ± 0.4 ng/mL, the time to Cmax (tmax) was 5.5 ± 4.3 h, and the area under the plasma concentration-time curve from 0 to 24 h (AUC0-24) was 18.9 ± 1.9 h・ng/mL. In humans, the Cmax was 14.6 ± 6.3 ng/mL, the tmax was 8 h, and the AUC0-24 was 266 ± 103 h・ng/mL.ConclusionsThe current study characterized the pharmacokinetics of mianserin suppositories in dogs and humans. As compared to oral administration, the suppositories produced a lower Cmax and a delayed tmax, although AUC0-24 values were comparable. It will be necessary to identify an appropriate dose that produces an adequate plasma mianserin concentration for effective and safe clinical use.Trial registrationUMIN000013853.

Disopyramide and Mianserin Intoxication: A Unique Fatal Case – Review of the Literature

Lethal occurrence is exceptional after disopyramide or mianserin poisoning. A case of intentional lethal intoxication with these drugs was reported, as well as a review of the literature. Pre- and postmortem blood concentrations of disopyramide or mianserin were assessed in a woman who died from acute cardiac failure after ingestion. The premortem blood concentration of disopyramide alone was considered lethal, and a toxic premortem concentration of mianserin was observed that may have increased cardiovascular failure induced by disopyramide because the metabolism of both drugs is mediated via cytochrome P450. Moreover, it was shown that the postmortem redistribution of disopyramide was limited, as pre- and postmortem concentrations were 48 and 65 mg/L, respectively. As regards mianserin, redistribution was observed after death with pre- and portmortem concentrations at 0.23 and 0.79 mg/L, respectively. This case illustrates that if postmortem blood concentration of disopyramide is known, the premortem concentration can be deduced.

P.3.015 Peak and trough dopamine D2 receptor occupancy for long-acting injectable risperidone a PET study

Altaraura, Alfredo Carlo, Fedele De Novellis, Massimo C. Mauri and Roberto Gomeni: Plasma and brain pharmacokinetics of mianserin after single and multiple dosing in mice. Prog. Neuro-Psychopharmacol. & Biol. Psychiat. 1987, 11: 23–33. 1.1. Pharmacokinetics parameters describing the time course of concentrations of mianserin (MIA) in plasma and brain and the relationship between plasma and brain concentrations were studied after acute and chronic administration of increasing doses of MIA in adult mice.2.2. There was a linear relationship between the area under the curve (AUC), the maximum concentration (Cmax) and doses, in plasma and brain, both during acute and chronic experiments (p < 0.05).3.3. A five-fold variation in plasma and brain terminal half-life (t 12) after chronic administration of the drug was observed, possibly due to a reduction in plasma drug clearance (CL).4.4. The values of Cmax and AUC in plasma and brain showed an increase of respectively about three and twelve times after chronic treatment.5.5. A very good correlation was observed between plasma and brain Cmax in both acute and chronic experiments; brain Cmax was 10.2 (±0.16) times higher than plasma Cmax after acute administration and 12.08 (± 1.33) times higher after chronic administration.

Effects of carbamazepine coadministration on plasma concentrations of the enantiomers of mianserin and of its metabolites.

Concentrations of the enantiomers of unconjugated and of total (unconjugated plus conjugated) mianserin, desmethylmianserin and 8-hydroxymianserin were measured in 12 patients before and after the introduction of carbamazepine. The dose of mianserin was 60 mg/d, carbamazepine was coadministered at 400 mg/d for 4 weeks, and blood samples were taken at weekly intervals after the introduction of carbamazepine. Each week, carbamazepine significantly decreased plasma concentrations of unconjugated and total (S)-mianserin (the more potent enantiomer) and of unconjugated and total (R)-mianserin. On average, plasma concentrations of unconjugated and total (S)-mianserin and of unconjugated and total (R)-mianserin were 55%, 56%, 66%, and 55%, respectively, of the corresponding values before introduction of carbamazepine. These results strongly suggest the involvement of CYP3A4, the major CYP enzyme induced by carbamazepine, in the metabolism of both enantiomers of mianserin. A strong decrease in the concentrations of (S)-8-hydroxymianserin was also measured (on average, the concentrations were 69% of the corresponding values before carbamazepine introduction). Conversely, plasma concentrations of unconjugated and of total (S)-desmethylmianserin, (R)-desmethylmianserin, and (R)-8-hydroxymianserin were only slightly modified by carbamazepine. From a clinical point of view, as a therapeutic window for (S)-mianserin has been recently suggested, the dose of racemic mianserin for a patient whose (S)-mianserin concentrations have been stabilized within this therapeutic window would need to be approximately doubled if carbamazepine, at 400 mg/d, is introduced as a comedication.

Correlation between steady-state plasma concentrations of mianserin and trazodone in depressed patients.

The correlations between steady-state plasma concentrations of mianserin and its active metabolite desmethylmianserin and those of trazodone and its active metabolite m-chlorophenylpiperazine (m-CPP) were examined in 19 depressed patients. Ten patients received first mianserin (30 mg per day) and second trazodone (150 mg per day), while 9 patients received these treatments in the opposite sequence, with at least 2-week intervals between the two phases. Blood was sampled at steady state, 1-3 weeks after initiation of each treatment. Plasma concentrations of mianserin, the separate enantiomers S(+)- and R(-)-mianserin, desmethylmianserin, trazodone and m-CPP were measured by means of high-performance liquid chromatography. There was a significant correlation between steady-state plasma concentrations of trazodone and total mianserin (r = 0.59) or S(+)-mianserin (r = 0.57), but not R(-)-mianserin (r = 0.33). The present study thus suggests that the metabolic capacity of mianserin, especially the more active S(+)-enantiomer, and that of trazodone correlate to each other. This finding supports the previous suggestions that cytochrome P4502D6 is involved in the metabolism of mianserin and trazodone.

Mianserin suppositories in the treatment of post-operative delirium

Mianserin suppositories (10–90 mg) were administered at bedtime to 16 patients with post-operative delirium (mean age 69·5 years). By the Delirium Rating Scale (DRS: Trzepacz et al., 1988), the average score decreased from 21·2 prior to administration to 14·5 on the first day of treatment and to 7·1 on the seventh day. Improvement was observed in all cases (marked in 85 per cent and slight in 15 per cent). The plasma concentration of mianserin was 65 ng/ml on day 1, 93 ng/ml on day 3 and 65 ng/ml on day 5, having reached therapeutic levels within 24 h of beginning treatment. Decreases in the free-3-methoxy-4-hydroxyphenyl(ethylene)glycol (MHPG) concentrations in plasma were observed after drug administration, but free-homovanillic acid (HVA) concentrations in plasma showed no significant change with the drug treatment. We consider mianserin suppositories to be an effective treatment for post-operative delirium. © 1997 John Wiley & Sons, Ltd.

Determination of the Enantiomers of Mianserin and its Metabolites in Plasma by Capillary Electrophoresis After Liquid--Liquid Extraction and On-Column Sample Preconcentration

Capillary electrophoresis has drawn considerable attention in the past few years, particularly in the field of chiral separations because of its high separation efficiency. However, its routine use in therapeutic drug monitoring is hampered by its low sensitivity due to a short optical path. We have developed a capillary zone electrophoresis (CZE) method using 2mM of hydroxypropyl -B- cyclodextrin as a chiral selector, which allows base-to-base separation of the enantiomers of mianserin (MIA), desmethylmianserin (DMIA), and 8-hydroxymianserin (OHMIA). Through the use of an on-column sample concentration step after liquid-liquid extraction from plasma and through the presence of an internal standard, the quantitation limits were found to be 5 ng/mL for each enantiomer of MIA and DMIA and 15 ng/mL for each enantiomer of OHMIA. To our knowledge, this is the first published CE method that allows its use for therapeutic monitoring of antidepressants due to its sensitivity down to the low nanogram range. The variability of the assays, as assessed by the coefficients of variation (CV) measured at two concentrations for each substance, ranged from 2 to 14% for the intraday (eight replicates) and from 5 to 14% for the interday (eight replicates) experiments. The deviations from the theoretical concentrations, which represent the accuracy of the method, were all within 12.5%. A linear response was obtained for all compounds within the range of concentrations used for the calibration curves (10-150 ng/mL for each enantiomer of MIA and DMIA and 20-300 ng/mL for each enantiomer of OHMIA). Good correlations were calculated between ((R) + (5))-MIA and DMIA concentrations measured in plasma samples of 20 patients by a nonchiral gas chromatography method and CZE, and between the (R)- and (S)-concentrations of MIA and DMIA measured in plasma samples of 37 patients by a previously described chiral high-performance liquid chromatography method and CZE. Finally, no interference was noted from more than 20 other psychotropic drugs. Thus, this method, which is both sensitive and selective, can be routinely used for therapeutic monitoring of the enantiomers of MIA and its metabolites. It could be very useful due to the demonstrated interindividual variability of the stereoselective metabolism of MIA.

The effect of mianserin hydrochloride on delirium

AbstractMianserin HCl (10–60 mg/day) was administered orally before bedtime to 46 patients (mean age: 63 years) with delirium at Kurume University Hospital. The therapeutic effects of mianserin were assessed pre‐ and post‐treatment using the Delirium Rating Scale (DRS: Trzepacz et al., 1988). The mean pre‐treatment DRS score was 21. This score decreased significantly (p&lt;0·05) to 14 on treatment day 1 and 10 on day 3. Mianserin was observed to be effective in 85 per cent of the cases (marked improvement in 67 per cent of the patients and slight improvement in 17 per cent). of the 46 patients, 28 were classified with delirium due to direct causes such as a brain tumour or cerebrovascular disease, and 18 due to facilitating factors such as hospitalization or physical restraint. In the former group, marked improvement was observed in 54 per cent of the patients, and slight improvement in 21 per cent. The latter group demonstrated marked improvement in 89 per cent of the patients, and slight improvement in 11 per cent. In control subjects receiving haloperidol, marked improvement was observed in 62 per cent of 17 delirious patients. The plasma concentration of mianserin reached a therapeutic level within 24 h of the initiation of treatment. Hence, based on these clinical results and on measurements of plasma mianserin concentrations, mianserin can be considered effective in the treatment of delirium in elderly patients due to its rapid onset and few side‐effects. Mianserin may offer an efficacy similar to that of haloperidol in the treatment of delirium while being safer.

Serum mianserin and ageing

1. 1. Mianserin is a tetracyclic antidepressant with relatively few anticholinergic and cardiovascular sideeffects. Its clinical efficacy is comparable to that of tricyclic antidepressants. It is widely used in Europe, especially in elderly outpatients. 2. 2. In the present studies, the authors have evaluated the efficacy of mianserin as well as the effects of ageing and concomitant psychotropic drugs on serum mianserin concentrations in 169 depressive psychiatric inpatients. 3. 3. In the patients the mean serum mianserin concentrations or their interindividual variations did not differ between the old, middle-aged, and young age groups. Furthermore, elderly women and men did not differ from each other for their dose-related drug concentrations. Neither were any differences found in serum mianserin concentrations between the older (≥75 years) and younger elderly (65–74). As is the case with TCAs, the co-administration of neuroleptics increased serum mianserin concentrations in the elderly. When comparing the therapeutic response and serum mianserin concentrations the authors found that the patients with good clinical improvement had higher mean serum mianserin concentrations than those without efficacy. 4. 4. There seem to be no clinically important changes in the phannacokinetics of mianserin with advancing age. The present results do not support the claim that the therapeutic profile of this drug is altered with advancing age. Mianserin can be regarded as an antidepressant with relatively few side-effects in the elderly.

Steady-State Plasma Concentrations of Mianserin and Its Major Active Metabolite, Desmethylmianserin

The steady-state plasma concentrations of mianserin and its major active metabolite, desmethylmianserin, were measured in 76 depressed patients receiving 30 mg of mianserin at bedtime. There were considerable inter-individual variations in the steady-state plasma concentrations of these compounds; the plasma concentrations of mianserin plus desmethylmianserin were within the therapeutic range suggested previously by us in only 43% of the patients. With advancing age, the plasma concentrations of mianserin increased significantly, while those of mianserin plus desmethylmianserin remained unchanged. Sex, smoking, and coadministration of benzodiazepines did not affect the drug's metabolism. There was no evidence that the kinetics of these compounds were nonlinear with increasing doses. The present study thus suggests that measuring the plasma concentrations of mianserin and desmethylmianserin contributes to rational treatment with this drug, that age, sex, smoking, and coadministration of benzodiazepines are not important factors in determining the dose, and that these compounds have linear kinetics.

Subjective side effects of mianserin in relation to plasma concentrations of mianserin and desmethylmianserin.

The main purpose of the present study was to examine the possibility that plasma concentrations of mianserin and its metabolite, desmethylmianserin, might be predicted by recording subjective side effects. In 44 depressed patients, subjective side effects during 3 weeks of treatment with 30 mg of mianserin were evaluated by the UKU Side Effect Rating Scale, and their relationships to plasma concentrations of mianserin and desmethylmianserin were analyzed. There was no significant relationship between plasma concentrations of these compounds and the occurrence of mianserin-induced side effects, except for dryness of mouth during week one. Our study, therefore, suggests that it is difficult to predict plasma concentrations of mianserin and desmethylmianserin based on the occurrence of subjective side effects.

Influence of changes in protein binding on the central activity of antidepressants.

The central effect (expressed as analgesic response), protein binding and brain uptake of mianserin were measured in mice receiving drug intraperitoneally. A significant decrease of the central effect of mianserin (30 mg kg-1) was seen in mice with experimental inflammation when compared with control animals (reaction time (s) = 12.12 +/- 1.22 vs 25.56 +/- 2.92; P less than 0.001) and the dose-analgesia response curve (10-60 mg kg-1) was significantly shifted to the right in mice with inflammation. In serum of mice with inflammation, unbound concentration of mianserin was decreased from 19.37 +/- 0.73 to 17.83 +/- 0.30% (P less than 0.05) and seromucoid levels were significantly increased (P less than 0.001). Following the intraperitoneal administration of 30 mg kg-1 of mianserin, brain uptake decreased in diseased mice when compared with control animals (P less than 0.02), suggesting that the decrease in analgesia was secondary to a decrease in drug delivery to the brain because of increased protein binding.

Effects of Carbamazepine on Serum Antidepressant Concentrations in Psychiatric Patients

The combination of carbamazepine and an antidepressant (doxepin, amitriptyline, mianserin) was given to 22 psychiatric inpatients with 29 measurements of their serum antidepressant concentrations. For comparison, sex-, age-, and dose-matched inpatients, treated with the antidepressant but not with carbamazepine, were selected as controls (N = 29). All the patients were treated with their routine daily dose for at least 7 days before the gas-chromatographic measurement of serum predose concentrations of the antidepressants. In patients with carbamazepine, serum doxepin and doxepin + nordoxepin concentrations (N = 17) were decreased significantly (p less than 0.05), on average to 46% and 45%, respectively, as compared to that in subjects without carbamazepine. Also in carbamazepine + amitriptyline patients, serum nortriptyline and amitriptyline + nortriptyline concentrations (N = 8) were significantly lower than in those not receiving carbamazepine (p less than 0.05). The mean serum antidepressant levels were decreased to 42% and 40%, respectively. The serum mianserin concentration of carbamazepine patients (N = 4) was reduced to 30% of that in patients not treated with carbamazepine (p less than 0.01). The percentage fractions of demethylated metabolites (nordoxepin, nortriptyline) from the total antidepressant levels were not influenced by carbamazepine. In patients treated with carbamazepine, serum total antidepressant concentrations remained more often below the suggested therapeutic ranges than in those patients without carbamazepine. The results suggest that serum antidepressant concentrations are reduced by concurrent carbamazepine therapy, and that the concentrations should be carefully monitored when carbamazepine is added to the antidepressant regimen.

Is there a therapeutic window for plasma concentration of mianserin plus desmethylmianserin?

AbstractThe relationship between clinical effects and plasma concentrations of mianserin and desmethylmianserin was studied in 29 cases of major depression during 3 weeks of mianserin treatment. The daily dose of mianserin was 30 mg in 27 cases and 20 mg in two cases. There was a significant U‐shaped relationship between the final Montgomery Åsberg Depression Rating Scale (MADRS) score and the steady‐state plasma concentration of mianserin (p&lt;0·05) or desmethylmianserin (p&lt;0·05). A much stronger relationship was observed for mianserin plus desmethylmianserin (p&lt;0·001). A theoretical therapeutic window (where a final MADRS score was expected to be 10 or less) was 71–128 nmol/1 for mianserin, 34–61 nmol/1 for desmethylmianserin, and 101–183 nmol/1 for mianserin plus desmethylmianserin. The proportion of responders was significantly higher inside than outside the window for mianserin plus desmethylmianserin (p=0·0033), but not for mianserin (p=0·063) or for desmethylmianserin (p=0·077). The occurrence of subjective side‐effects was not dependent on the plasma concentrations of these compounds. The present study suggests that desmethylmianserin contributes substantially to the overall antidepressant effects of mianserin treatment, and that the therapeutic response is most dependent on the combined plasma concentration of mianserin and desmethylmianserin, with an optimal therapeutic response occurring in the intermediate range.

Biphasic effects of mianserin and desipramine on serotonin-evoked current and Cl − efflux in Xenopus oocytes

Serotonin (5-HT, 1 μM) elicited two phases of Cl − inward current in Xenopus oocytes injected with rat brain mRNA: a transient current (T-current), which was generated rapidly (within 1 min), and a sustained current (S-current), which persisted for 10 min. Each type of 5-HT-evoked response was time-dependent after mRNA injection. The T-current was generated at 20-30 h and the S-current at 30–40 h. Although mianserin at 0.1 μ M completely inhibited the T-current, 10 μ M mianserin was required to suppress the S-current. 5-HT also caused Cl − efflux from oocytes preloaded with 36Cl −, Cl − efflux during 1 min, corresponding to the T-current, was inhibited by 0.1 μ M mianserin. A higher concentration of mianserin (10 μ M) was required to block the efflux for 10 min, corresponding to the S-current, as well as the current response. Desipramine selectively inhibited the T-current and Cl − efflux for 1 min. The mechanisms underlying the different sensitivity to mianserin of oocytes injected with rat brain mRNA are discussed.

Serum mianserin concentrations in psychiatric inpatients of different ages

One hundred and sixty-nine depressive psychiatric inpatients were treated with routine therapeutic doses of mianserin. Altogether 256 serum mianserin samples were measured gas-chromatographically in 3 age groups: 17 samples in patients under 35 years, 116 samples in patients between 35 and 65 years, and 123 samples in patients over 65 years. No differences in dose-corrected (calculated as mg/kg dose basis) mean serum mianserin concentrations were found between the age classes. Neither the interindividual variation nor the number of high serum mianserin concentrations was larger among elderly subjects than in the other age groups. Concurrent neuroleptic treatment significantly increased serum mianserin levels in the oldest patient group but not in the 2 others. The results suggest that mianserin dose should not be generally reduced with advancing age.

Variability in the elimination of mianserin in elderly patients.

1. Two studies of the elimination of mianserin are reported. 2. In the first study, the oral clearance of mianserin was measured in 15 elderly patients at steady state. In a sub-group of eight patients who completed studies at two different doses there was evidence of enhanced oral clearance at the higher dose. 3. In the second study, the elimination half-life was estimated in 12 patients who were observed to have disproportionately high mianserin concentrations with respect to dose. All had half-lives greater than or equal to 2.5 days with a mean of 6 +/- 2.8 (s.d.) days. In six of the patients the profile of elimination was suggestive of saturable elimination. 4. The sparteine oxidation status was measured in seven of the patients showing slow mianserin elimination. Only one was a 'poor oxidiser' of sparteine, suggesting no concordance with this phenotype. 5. It is concluded that there is marked variability in the elimination of mianserin in elderly patients.

Heterogeneous distribution of mianserin in rat brain during chronic continuous infusion.

The mianserin (MIS) distribution in 12 brain regions was investigated after 2- and 14-day continuous MIS infusion, starting with 19 mg/kg/day on the first day. There was no significant difference between the 2nd and 14th day with respect to MIS concentration, brain/serum concentration ratio in whole brain or MIS serum level. The MIS distribution was heterogeneous on the 2nd and 14th day and did not change with time. The concentrations were highest in cortex and hippocampus and lowest in cerebellum, hypothalamus, and bulbus olfactorious and septum. This distribution pattern differs from those found with tricyclic antidepressant drugs.

Electrophysiological studies on the effects of mianserin, a tetracyclic antidepressant agent, on isolated guinea-pig papillary muscle

We studied the effects of mianserin on the action potentials of papillary muscle from the guinea-pig. Mianserin (above 10μM) reduced the maximum rate of the rise (⊢otV max) of the action potential, and shifted the ⊢otV max E m relationship to more negative potentials. The compound also depressed the slow action potentials of K +-depolarized papillary muscles. It is concluded that relatively high concentrations of mianserin had an inhibitory action on the electrophysiological properties of both the fast- and slow-response fibers of the heart.