Mianserin Research Articles

In Search of the Most Stable Molecular Configuration of Heptakis(2,6-O-dimethyl)-β-cyclodextrin and Its Complex with Mianserin: A Comparison of the B3LYP-GD2 and M062X-GD3 Results.

Cyclodextrins are well known for their ability to form stable, highly soluble complexes with various substances, which makes them widely used as excipients in food, cosmetics, and pharmaceuticals. In this work, properties of heptakis(2,6-O-dimethyl)-β-cyclodextrin (DM-β-CD) in vacuo and in water, as well as its ability to bind the antidepressant drug mianserin (MIA) in aqueous solution, are investigated computationally. The results are shown to depend strongly on the density functional theory (DFT) applied. The most stable conformers of DM-β-CD found with the B3LYP-GD2 method differ from these indicated by M062X-GD3 and other functionals. According to the latter, two crystal structures, ZULQAY and BOYFOK03, optimized in vacuo and in water, respectively, have the lowest energy. Both the B3LYP-GD2 and M062X-GD3 results show that all tested inclusion and noninclusion complexes of MIA:DM-β-CD in stoichiometry 1:1 are stable in water. However, the structures and their energetic properties obtained with each method differ: in the most stable configurations, different aromatic rings of MIA are embedded inside DM-β-CD, and the corresponding complexation energies (calculated with the 6-31++G(d,p) basis set and corrected for the basis set superposition error) are −29.6 (B3LYP-GD2) and −23.9 (M062X-GD3) kcal/mol. The NMR spectra of DM-β-CD and MIA:DM-β-CD are also compared.

The Interaction of Heptakis (2,6-di-O-Methyl)-β-cyclodextrin with Mianserin Hydrochloride and Its Influence on the Drug Toxicity.

One tetracyclic antidepressant, mianserin hydrochloride (MIA), has quite significant side effects on a patients’ health. Cyclodextrins, which are most commonly used to reduce the undesirable features of contained drugs within their hydrophobic interior, also have the potential to alter the toxic behavior of the drug. The present paper contains investigations and the characteristics of interaction mechanisms for MIA and the heptakis (2,6-di-O-methyl)-β-cyclodextrin (DM-β-CD) system, and evaluated the effects of the complexation on MIA cytotoxicity. In order to assess whether there was an interaction between MIA and DM-β-CD molecules, isothermal titration calorimetry (ITC) have been chosen. Electrospray ionization mass spectrometry (ESI-MS) helped to establish the complex stoichiometry, and circular dichroism spectroscopy was used to describe the process of complex formation. In order to make a wider interpretative perspective, the molecular docking results have been performed. The viability of Chinese hamster cells were investigated in the presence of DM-β-CD and its complexes with MIA in order to estimate the cytotoxicity of the drug and the conjugate with the chosen cyclodextrin. The viability of B14 cells treated with MIA+DM-β-CD is lower (the toxicity is higher) than with MIA alone, and no protective effects have been observed for complexes of MIA with DM-β-CD in any ratio.

Antidepressants Differentially Regulate Intracellular Signaling from α1-Adrenergic Receptor Subtypes In Vitro.

Currently utilized antidepressants have limited effectiveness and frequently incur undesired effects. Most antidepressants are thought to act via the inhibition of monoamine reuptake; however, direct binding to monoaminergic receptors has been proposed to contribute to both their clinical effectiveness and their side effects, or lack thereof. Among the target receptors of antidepressants, α1‑adrenergic receptors (ARs) have been implicated in depression etiology, antidepressant action, and side effects. However, differences in the direct effects of antidepressants on signaling from the three subtypes of α1-ARs, namely, α1A-, α1B- and α1D‑ARs, have been little explored. We utilized cell lines overexpressing α1A-, α1B- or α1D-ARs to investigate the effects of the antidepressants imipramine (IMI), desipramine (DMI), mianserin (MIA), reboxetine (REB), citalopram (CIT) and fluoxetine (FLU) on noradrenaline-induced second messenger generation by those receptors. We found similar orders of inhibition at α1A-AR (IMI < DMI < CIT < MIA < REB) and α1D‑AR (IMI = DMI < CIT < MIA), while the α1B-AR subtype was the least engaged subtype and was inhibited with low potency by three drugs (MIA < IMI = DMI). In contrast to their direct antagonistic effects, prolonged incubation with IMI and DMI increased the maximal response of the α1B-AR subtype, and the CIT of both the α1A- and the α1B-ARs. Our data demonstrate a complex, subtype-specific modulation of α1-ARs by antidepressants of different groups.

The impact of β-cyclodextrin on biological and chemical properties of mianserin hydrochloride in aqueous solution

Mianserin hydrochloride (MIA), a drug, which belongs to a group of tetracyclic, noradrenergic and specific serotonergic antidepressants, is one of the commonly used psychotropic drugs. Despite its important uses and having a number of other potential utilizations, MIA has quite significant side effects on a patient health, including some cytotoxicity. The MIA toxicity could be reduced by drug encapsulation inside a non-toxic carrier, like β-cyclodextrin molecules (β-CD). Cyclodextrins are cone shaped supramolecules with hydrophobic interior, where hydrophobic parts of molecule can be included, and with hydrophilic rims consisting of primary and secondary hydroxyl groups, which can interact with water molecules. This study investigated the characteristic and mechanism for interaction of MIA with β-CD, and evaluated the effects of complexation on MIA cytotoxicity. Chemical shift differences for protons in mianserin hydrochloride and β-cyclodextrin molecules, induced by the formation of the inclusion complexes, have been determined by proton nuclear magnetic resonance spectroscopy. The other chemical properties of mianserin hydrochloride in aqueous solution in the presence of β-cyclodextrin has been examined at 298.15 K with the use of mass spectrometry and circular dichroism. The results showed that interaction of MIA with β-CD occurred through incorporation of MIA aromatic rings inside probably more than one β-CD molecules. The effects of β-cyclodextrin, mianserin hydrochloride and complexes thereof on the viability of Chinese hamster cells were investigated in order to estimate the cytotoxicity of the drug. The viability of B14 cells treated with MIA + β-CD is higher than with MIA and the protective effect is the highest for complexes of MIA:β-CD in a 1:4 ratio.

Dissolution Test for Mianserin Hydrochloride in Tablets

A dissolution test for mianserin hydrochloride in coated tablets containing 30 mg was developed and validated using a fast ultraviolet spectrophotometric method. The appropriate conditions were determinate after testing sink conditions, agitation spped and dissolution medium. The sink conditions tested showed that mianserin hydrochloride was soluble in 0.01 and 0.1 M hydrochloric acid (HCl), acetate buffer pH 4.1 and 5.0 and phosphate buffer pH 6.8. Then, dissolution tests were performed to investigate the drug release in each medium. Optimal conditions to carry out the dissolution test were 900 mL 0.1 M HCl and USP apparatus 2 (paddle) at 50 rpm stirring speed. The quantification method was also adapted and validated. The UV method showed specificity, linearity, precision and accuracy. The in vitro dissolution test can be used to evaluate the drug release profile and the data was used as an aid to establish a possible correlation with in vivo data.

A University Approach to Promoting the Proper Formulation and Use of Hospital Preparations

Hospital preparations (HPs) prepared by hospital pharmacists have contributed to advanced medical care which is custom tailored to various and individual medical needs. Advanced pharmaceutical knowledge and skills are needed to properly prepare HPs. Hospital pharmacists have inherited formulations and the skills to prepare them from their predecessors. However, there has been an ongoing decrease in the number of HPs prepared in hospitals due to an increase in the availability of commercial formulations. Despite this trend, it is not acceptable for hospital pharmacists to lack experience when a doctor requests an original HP. We often refer to "The Hospital Preparation Casebook" when HPs are prepared. However, evidence for drug management and clinical evaluation of HPs in the book are frequently insufficient; it is difficult to keep the information up to date. Therefore, we consider that it is the role of universities to support the supply and usage of HPs in cooperation with hospital pharmacists and pharmacies. Here we report a trial that adopted a physicopharmaceutical approach to developing a HP of a mianserin hydrochloride suppository.

Determination of olopatadine in human tears by hydrophilic interaction liquid chromatography-MS/MS method.

The objective of the study was development of hydrophilic interaction liquid chromatography-ESI/MS/MS method for the determination of olopatadine in tear matrix. Separation was performed on Acquity BEH amide column (2.1 × 100mm, 1.7μm). The mobile phase was consisted of 0.1% formic acid in water and acetonitrile. Mianserin hydrochloride was implemented as an internal standard. The artificial tear fluid was used as matrix. The tear samples were collected using Schirmer test strips. For the optimization of ultra pressure liquid chromatography conditions, Box-Benhken design was utilized. The optimal values of the ion source and collision cell parameters were found. Quantification was performed in multiple reaction monitoring mode. The optimized method was fully validated. The proposed method was utilized for monitoring of olopatadine in human tear.

Quantum chemical study and isothermal titration calorimetry of β-cyclodextrin complexes with mianserin in aqueous solution

β-Cyclodextrin (β-CD) is studied as a carrier of the drug mianserin (MIA). β-CD with MIA adducts with 1 : 1 and 2 : 1 stoichiometry are investigated in vacuo and in water using quantum chemical methods: PM6 and B3LYP/6-31G(d,p). An effect of the dispersion correction GD2 and the basis set superposition error on the complexation energies is also evaluated. Additionally, the interaction between MIA hydrochloride and β-CD in aqueous solution at 298.15 K is examined experimentally by isothermal titration calorimetry. Interaction parameters, such as the binding constant, enthalpy, entropy and Gibbs free energy, are presented. Analysis of the obtained data led to the following conclusions: the interaction of MIA with β-CD is rather strong; there is no significant energetic difference between the 1 : 1 complexes of β-CD with S-MIA and R-MIA enantiomers; the 2 : 1 (β-CD : MIA) adduct is energetically more favorable than 1 : 1; the complex formation of MIA + β-CD is enthalpy and entropy driven.

Biotransformation of Two Pharmaceuticals by the Ammonia-Oxidizing Archaeon Nitrososphaera gargensis.

The biotransformation of some micropollutants has previously been observed to be positively associated with ammonia oxidation activities and the transcript abundance of the archaeal ammonia monooxygenase gene (amoA) in nitrifying activated sludge. Given the increasing interest in and potential importance of ammonia-oxidizing archaea (AOA), we investigated the capabilities of an AOA pure culture, Nitrososphaera gargensis, to biotransform ten micropollutants belonging to three structurally similar groups (i.e., phenylureas, tertiary amides, and tertiary amines). N. gargensis was able to biotransform two of the tertiary amines, mianserin (MIA) and ranitidine (RAN), exhibiting similar compound specificity as two ammonia-oxidizing bacteria (AOB) strains that were tested for comparison. The same MIA and RAN biotransformation reactions were carried out by both the AOA and AOB strains. The major transformation product (TP) of MIA, α-oxo MIA was likely formed via a two-step oxidation reaction. The first hydroxylation step is typically catalyzed by monooxygenases. Three RAN TP candidates were identified from nontarget analysis. Their tentative structures and possible biotransformation pathways were proposed. The biotransformation of MIA and RAN only occurred when ammonia oxidation was active, suggesting cometabolic transformations. Consistently, a comparative proteomic analysis revealed no significant differential expression of any protein-encoding gene in N. gargensis grown on ammonium with MIA or RAN compared with standard cultivation on ammonium only. Taken together, this study provides first important insights regarding the roles played by AOA in micropollutant biotransformation.

Ultraviolet spectrophotometric method for analytical determination of mianserin hydrochloride in coated tablets and comparison with LC

abstract Ultraviolet spectrophotometric (UV) and Liquid Chromatographic (LC) methods for the determination of mianserin hydrochloride in pharmaceutical formulation were developed and validated. The various parameters, such as specificity, linearity, precision and accuracy were studied according to International Conference on Harmonization (ICH, 2005). For UV method, mianserin hydrochloride was determinate at 278 nm using HCl 0.1 M as the solvent. The response was linear in the concentration range of 20.0 - 140.0 µg/mL (r = 0.9998). Precision data evaluated by relative standard deviation was lower than 2%. The UV method was simple, rapid and low cost. Chromatographic analyses were performed in an Ace C18 column and the mobile phase was composed of methanol, 50 mM monobasic potassium phosphate buffer and 0.3% triethylamine solution adjusted to pH 7.0 with phosphoric acid 10% (85:15). LC method was specific, linear, precise, exact and robust. The results confirmed that the both methods are valid and useful to the routine quality control of mianserin hydrochloride in coated tablets. Statistical analysis by Student´s t-test showed no significant difference between the results obtained by UV and LC methods.

Effect of Jobelyn® on intruder- and isolation-induced aggressive behavior in mice

Aggression is a violent behavior emitted against another organism that may lead to its harm or death and thus is of public health significance, which necessitates the search for agents with anti-aggressive property. This study investigated the effect of Jobelyn® (JB), a unique African polyherbal formulation, on intruder- and isolation-induced aggressive behaviors in mice. Male mice that showed aggression after being housed individually with female counterparts for 3 weeks or kept in isolation for 4 weeks were treated orally (p.o.) with JB (5, 10 or 50 mg/kg), haloperidol (HP) (1 mg/kg), fluoxetine (FL) (10 mg/kg), p-chlorophenylalanine (PCPA) (20 mg/kg), mianserin (MS) (50 mg/kg) or distilled water (10 mL/kg) 60 min before being tested for aggression. Interaction studies involving oral administration of PCPA (20 mg/kg), FL (10 mg/kg) or MS (50 mg/kg) to aggressive mice that had received JB (5 or 10 mg/kg, p.o.) 30 min earlier were assessed. The effect of JB (5, 10 or 50 mg/kg, p.o.) on defensive behaviors was also evaluated. JB (5, 10 or 50 mg/kg) decreased aggressive behaviors without impairing the defensive mechanisms of mice. PCPA (20 mg/kg), an inhibitor of 5-hydroxytryptamine (5-HT) biosynthesis, increased aggressive responses and reduced the anti-aggressive effect of JB. FL (10 mg/kg), a 5-HT reuptake inhibitor, significantly suppressed aggression but did not alter the effect of JB on aggression. MS (50 mg/kg), a 5-HT receptor antagonist, reduced aggression and enhanced the effect of JB on aggression. These findings suggest that JB has anti-aggressive activity, which may be related to the enhancement of serotonergic system.

Density functional theory and vibrational studies of mianserin and its hydrochloride and hydrobromide salts

The molecular structure, linear and non-linear optical properties, and electronic properties of the anti-depressant drug mianserin (MIA) and its salts (MIA HCl and MIA HBr) have been investigated using the density functional theory (DFT/B3LYP) method with a 6-311G(d,p) basis set. The calculated first hyperpolarizability values are comparable with the reported values and are attractive objects for future studies of non-linear optics. FT-IR (4000–400cm−1) and FT-Raman (3500–50cm−1) spectra of mianserin HCl have been measured and analyzed. The assignment of bands observed in vibrational spectra have been made by comparison of their theoretical vibrational frequencies obtained using a B3LYP/6-311G(d,p) basis set. The scaled frequencies resulted in good agreement with the observed spectral patterns.

Micellar Electrokinetic Chromatographic Method for Mianserin Hydrochloride and Analysis of Degradation Products by Mass Spectrometry

A simple, stability-indicating micellar electrokinetic chromatography (MEKC) method was developed and validated for the analysis of mianserin hydrochloride in coated tablets. The method employed (hydroxymethyl)aminomethane (TRIS) 50 mM to which sodium dodecyl sulfate (SDS) 50 mM was added at pH 10.6 as the electrolyte and the voltage applied was 25 kV. The capillary used was 48.5 cm long (40.0 cm effective length and 50.0 µm i.d.) and the detection wavelength was 220 nm. Tetracycline was used as internal standard. The method was validated in accordance with the International Conference on Harmonization (ICH) requirements, which involved specificity, linearity, precision, accuracy and robustness. The stability-indicating capability of the method was established by enforced degradation studies combined with peak purity assessment using photodiode array detection. The degradation products formed under photolytic and oxidative conditions were investigated by electrospray ionization mass spectrometry. The method was linear over the concentration range of 50-130 µg/mL. The method was precise as demonstrated by an inter-day and intra-day relative standard deviation of less than 2.0%. The proposed validated MEKC method showed recoveries between 98.16 and 102.80% of the nominal contents. The Plackett-Burman design was applied for the robustness test in order to examine potential sources of variability by screening a large number of factors in a relatively small number of experiments.

ミアンセリン坐剤の院内製剤化へ向けた物理薬剤学的特性からのアプローチ

We tried to optimize the formulation for the hospital preparation of mianserin hydrochloride (MS) suppositories. MS as the raw material for the preparation was obtained from Tetramide tablets (MS-T), which were ground. The physicopharmaceutical properties of MS suppositories with bases of Witepsol H15 (H15), Witepsol W35 (W35) and Witepsol S55 (S55) were compared to choose the optimal base for the suppositories. The preparation strength correlated negatively among the three bases. The heat of fusion of MS-H15 suppositories was significantly low relative to MS-W35 and MS-S55 suppositories. The average drug release rate of MS-H15 suppositories exhibited the highest level on moment analysis. Comprehensive evaluation of the properties of MS suppositories, including the heat of fusion due to the solubility of the preparation and the drug release rate indicated that H15 was the optimal base for MS suppositories. Additionally, we examined the optimal mixing rate of ground MS-T and H15. The preparation strength positively correlated with an increased mixing rate of ground MS-T. The mean dissolution time (MDT) of suppositories was reduced with an increased mixing rate of ground MS-T. These results suggested that 0.10 g ground MS-T combined with 0.8 g H15 as the base was the optimal formulation for the hospital preparation of MS suppositories.

Management of non-motor complications in Parkinson’s disease

This paper summarizes the methods we devised for the treatment of psychosis, orthostatic hypotension, and mood disorders among the various non-motor complications of Parkinson's disease. Psychosis may not manifest when a patient believes in his/her delusions. If left untreated over a prolonged period, however, the delusions progress to paranoia that is very difficult to cure. Accordingly, enquiries should be made during routine examinations to detect the presence of psychosis and facilitate early discovery. Atypical antipsychotics are used when psychosis does not improve after reducing the doses of antiparkinson drugs. We achieved favorable results by using mianserin hydrochloride prior to this step, with efficacy being observed for hallucinations and mild delusions that often manifested at night. This drug does not act as a dopamine receptor blocker, so it has the advantage of not aggravating motor symptoms. With this therapy, it is also possible to improve motor symptoms without inducing psychosis by reducing the doses of antiparkinson drugs and locally stimulating the motor loop by deep brain stimulation of the subthalamic nucleus. We previously introduced leg-holding exercises for the treatment of orthostatic hypotension, through which blood pooled in the veins is returned to the systemic circulation by holding the knees. This can be done easily and is free of adverse reactions. Mood disorders are difficult to cope with in patients with Parkinson's disease, but may be treated by selecting an appropriate dopamine agonist while giving consideration to affinity for the dopamine D3 receptor. However, treatment becomes complicated when the dopamine receptor is overstimulated. Here we report on cases of successfully treated pathological gambling and dopamine dysregulation syndrome, which are considered difficult to manage. The solution may differ depending on a patient's environment, and it is not easy to prescribe therapy based on evidence-based medicine. The best therapy should be selected by maintaining communication with the patient and developing a relationship built on trust.

Determination of mianserin in human plasma by high performance liquid chromatography–electrospray ionization mass spectrometry (HPLC–ESI/MS): Application to a bioequivalence study in Chinese volunteers

This study aims to develop a standard protocol for the bioequivalence study of mianserin hydrochloride tablets—a tetracyclic antidepressant drug. For this purpose, a rapid, convenient and selective method using high performance liquid chromatography coupled with electrospray ionization mass spectrometry (HPLC–ESI/MS) has been developed and validated to determine mianserin in human plasma. Mianserin and the internal standard (I.S.), cinnarizine were extracted from plasma by N-hexane:dimethylcarbinol (98:2, v/v) after alkalinized with sodium hydroxide. LC separation was performed on a Thermo Hypersil-Hypurity C 18 (5 μm, 150 mm × 2.1 mm) with the mobile phase consisting of 10 mM ammonium acetate (pH 3.4)–methanol–acetonitrile (35:50:15, v/v/v) at 0.22 ml/min. The retention time of mianserin and cinnarizine was 3.4 and 2.1 min, respectively. Quadrupole MS detection and quantitation was done by monitoring at m/ z 265 [M+H] + for mianserin and m/ z 369 [M+H] + for cinnarizine. The method was validated over the concentration ranges of 1.0–200.0 ng/ml for mianserin. The recovery was 81.3–84.1%, intra- and inter-day precision of the assay at three concentrations were 9.6–11.4% with accuracy of 97.5–101.2% and the lower limit of quantitation (LLOQ) detection was 1.0 ng/ml for mianserin. The stability of compounds was established in a battery of stability studies, i.e., short-term and long-term storage stability as well as freeze–thaw cycles. This method proved to be suitable for the bioequivalence study of mianserin hydrochloride tablets in healthy human male volunteers.

Marchiafava‐Bignami disease treated by mianserin hydrochloride in short‐term evaluated by neuropsychological analysis

AbstractSince 1903, Marchiafava‐Bignami disease has been recognized as a rare syndrome with focal demyelination and necrosis in the corpus callosum, which is usually found in chronic alcoholics. It extends into the neighboring white matter and occasionally as far as the subcortical regions. We report a Japanese patient with Marchiafava‐Bignami disease associated with alcohol abuse, who had traveled around Western Europe, North America and China for more than 30 years. As he suffered extreme delirium in the early stages we administered a low dose (10 mg) of mianserin hydrochloride. He was very irritable and uncooperative on admission, after 20 days his delirium had disappeared and his temper had become very calm and mild. After 40 days, his intelligence level increased substantially as measured by various neuropsychological tests.

Analytical method development and validation of mianserin hydrochloride and its metabolite in human plasma by LC–MS

Mianserin is a tetracyclic antidepressant drug and administered as racemate of R (−) and S (+) mianserin hydrochloride in a dose of 30–90 mg/day in divided doses. Liquid chromatography-mass spectroscopy (LC–MS) is a tool, which is widely used for determination of drug and their metabolites in biological fluids because of its high sensitivity and precision. Here we describe a liquid chromatography mass spectroscopy method for simultaneous determination of mianserin and its metabolite, N-desmethylmianserin, from human plasma using a liquid–liquid extraction with hexane:isoamylalcohol (98:2) and back extraction with 0.005 M formic acid solution. This method is specific and linear over the concentration range of 1.00–60.00 ng/ml for mianserin and 0.50–14.00 ng/ml for N-desmethylmianserin in human plasma. The lowest limits of quantification (LLQ) is 1.00 ng/ml for mianserin and 0.50 ng/ml for N-desmethylmianserin. Intraday and interday precision (%C.V.) is <10% for both mianserin and N-desmethylmianserin. The accuracy ranges from 94.44 to 112.33% for mianserin and 91.85–100.13% for N-desmethylmianserin. The stability studies showed that mianserin and N-desmethylmianserin in human plasma are stable during short-term period for sample preparation and analysis. The method was used to assay mianserin and its metabolite, N-desmethylmianserin, in human plasma samples obtained from subjects who had been given an oral tablet of 30 mg of mianserin.

In Vitro Study of the Adsorption Characteristics of Drugs

The adsorption characteristics of eight adsorbents, cholestyramine, colestimide, aluminum silicate, sucralfate, aluminum hydroxide, calcium polystyrene sulfonate, carbon sphere and medicinal carbon, on the drugs such as methotrexate, antidepressants, mizoribine and ciprofloxacin hydrochloride were investigated in vitro. Medicinal carbon showed an excellent adsorption of all the tested drugs while the carbon spheres showed a high but slow adsorption characteristic. Cholestyramine and colestimide showed a higher adsorption in methotrexate than the other adsorbents. Aluminum silicate and calcium polystyrene sulfonate showed higher adsorption in four antidepressants, clomipramine hydrochloride, imipramine hydrochloride, mianserin hydrochloride and trazodone hydrochloride. In mizoribine, there were no adsorbents that showed higher adsorption except for the medicinal carbon. In ciprofloxacin hydrochloride, aluminum preparations and calcium polystyrene sulfonate showed higher adsorption characteristics. It is suggested that several adsorbents are potentially useful treatments for drug overdoses, but that these adsorbents have the possibility of decreasing the effects of the co-administered medicines.

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.