[Therapeutic drug monitoring of antipsychotic drugs in routine psychiatric practice]. / Terapevticheskii lekarstvennyi monitoring antipsikhoticheskikh preparatov v povsednevnoi psikhiatricheskoi praktike.

OBJECTIVE: To evaluate the relationship between daily doses of antipsychotic drugs, their serum concentrations, and characteristics of patients treated for schizophrenia or schizophreniform disorder in day-to-day clinical practice. MATERIAL AND METHODS: A total of 187 patients were included in the study, 77 (41.1%) patients were on monotherapy, and 110 (58.9%) patients received two or more antipsychotics. Patients age was 27.8±8.1 years, and their body weight was 79.8±15.6 kg. The sample was represented mainly by young men (93.0%). The proportion of smokers was 37.4%. The appropriate HPLC-MS/MS method was used for the simultaneous analysis of 8 antipsychotics and its active metabolites. Serum concentrations of the drugs aripiprazole (ARI), chlorpromazine (CPZ), haloperidol (HAL), zuclopenthixol (ZUC), clozapine (CLO), risperidone (RIS), quetiapine (QUE), olanzapine (OLA), norclozapine (N-desmethylclozapine, NOR), 9-hydroxyrisperidone (9-OH-RIS), dehydroaripiprazole (DGA) were measured. The serum concentration/dose ratio (C/D) was employed as the primary outcome measure, as doses were not kept constant during the study. The active antipsychotic fraction (drug+active metabolite, active moiety - AM) was also evaluated for RIS and ARI. In addition, the metabolite/parent ratio (MPR) was evaluated for RIS and ARI. RESULTS: A total of 265 biological samples were obtained, 421 and 203 measurements of the concentration of drugs and their metabolites were carried out, respectively. Overall, 48% of antipsychotics levels were in the expected therapeutic ranges, 30% were below therapeutic ranges, and 22% were above them. A total of 55 patients underwent dose adjustments or drug changes due to ineffectiveness or side-effects. It has been found that smoking reduces the level of C/D for CLO (p<0.01, Mann-Whitney test). We have established that comedication with CLO significantly increases the C/D ratio of QUE (p<0.05, Mann-Whitney test). We have not revealed any influence of weight and age of the subjects on the C/D. The dose-concentration regression relationships are formalized for all AP. CONCLUSION: Therapeutical drug monitoring (TDM) is an essential tool to personalize antipsychotic therapy. Careful analysis of TDM data can contribute significantly to the study of the impact of individual patient characteristics on systemic exposure to these drugs.

[Therapeutic drug monitoring of aripiprazole as part of the individualization of the pharmacotherapy of schizophrenia]. / Provedenie terapevticheskogo lekarstvennogo monitoringa aripiprazola v ramkakh individualizatsii farmakoterapii shizofrenii.

OBJECTIVE: To personalize pharmacotherapy with aripiprazole in patients with schizophrenia via therapeutic drug monitoring (TDM). MATERIAL AND METHODS: TDM of aripiprazole (ARI) and its active metabolite dehydroaripiprazole (DHA) was performed for patients diagnosed with schizophrenia (ICD-10 F20.00; F20.01; F20.02). Thirty-six parameters were assessed. To carry out TDM, the method of high-performance liquid chromatography with mass spectrometry was chosen employing a validated method. RESULTS: TLM was performed in a group of young patients: 26.5±10.1 years old, average weight 77.2±16.2 kg, average PANSS score 81.4±21.4, UKU score 14.5±3.9. An average ARI concentration was 18.4±7.9 mg, serum ARI concentration 417.9±362.4 ng/ml, serum DHA concentration 117.5±116.1 ng/ml and the total concentration 535.4±478.5 ng/ml. Equations of correlation dependences of concentration on dose are obtained for ARI and DHA. CONCLUSION: The results show the significant metabolism of ARI. A combined determination of the main substance and its active metabolite DHA in the patient's blood serum is advisable for correct assessment of the TLM result in patients with mental diseases.

[Neopterin as a potential biomarker in neuropsychiatry]. / Neopterin kak potentsial'nyi biomarker v psikhonevrologii.

The importance of finding predictors or biomarkers of neuropsychiatric pathology, as well as methods of its prevention, treatment and early diagnosis is beyond question. The level of neopterin in body fluids is one of the possible biomarkers. Increased levels of neopterin in biological fluids (e.g., serum, cerebrospinal fluid or urine) are closely associated with various diseases associated with cellular immune response. The data presented in the review indicate the relevance of the study of neopterin concentrations in body fluids in patients with mental illness for the development of diagnostic and prognostic tests or as a pharmacodynamic marker of drug action.

Haloperidol Reduces the Activity of Complement and Induces the Anti-Inflammatory Transformation of Peritoneal Macrophages in Rats.

It is known that psychotropic substances affect the immune system. Unfortunately, chronic antipsychotic administration causes side toxicological effects, associated with oxidative stress. The mechanisms of these effects are still unclear. We investigated the impact of sub-chronic administration of haloperidol (Hal) on parameters of innate immunity and related systems in healthy rats and compared them with Hal content. Hal administration (0.5 mg/kg, 3 weeks) resulted in two-fold decrease of the activity of the complement system and hemostasis. Hal content correlated with the activity of the complement (r = -0.71), phagocytic activity of peritoneal macrophages (r = 0.78), leukocyte elastase (r = -0.71) and glutathione-S-transferase activity (r = -0.67). Hal fully blocked in vitro PMA-induced iNOS expression in macrophages and changed their morphology to "anti-inflammatory" phenotype. The comparison of in vivo and in vitro data showed that Hal has a direct effect on phagocytic component of innate immunity and an indirect effect on leukocyte elastase and antioxidant enzymes. The results obtained in the present study indicated that Hal significantly affects homeostasis and causes a number of complex biological transformations. Graphical Abstract.

[The content of N-acetylaspartate in depressed elderly patients during therapy with antidepressants and actovegin]. / Soderzhanie N-atsetilaspartata u pozhilykh patsientov s depressiei v protsesse terapii antidepressantami i aktoveginom.

AIM: To assess the plasma level of N-acetylaspartate (NAA) before and after combined therapy with antidepressants and actovegin in a group of elderly patients diagnosed with depression. MATERIAL AND METHODS: Nineteen patients, 7 men and 12 women, mean age 70.5±5.8 years, were studied using clinical examination and psychometric scales as well as computed tomography (CT). NAA plasma levels were determined. The duration of treatment with antidepressants (venlafaxine, fluvoxamine) and actovegin was 28 days, patients were examined at baseline and on the 28th day of treatment. RESULTS AND CONCLUSION: The NAA plasma level was reduced in patients compared to healthy volunteers. The increase of this indicator after treatment reflected a significant improvement on clinical and psychometric measures. The dynamics of NAA changes (increase or decrease) showed heterogeneity in the group of patients, which was not related to the efficacy of treatment but was correlated with comorbid diseases, in particular vascular diseases, and CT changes (leukoaraiosis). The authors consider the results of this study as preliminary.

[Therapeutic drug monitoring of risperidone and its active metabolite 9-hydroxyrisperidone in the treatment of schizophrenia]. / Terapevticheskii lekarstvennyi monitoring risperidona i ego metabolita 9-oksirisperidona pri terapii shizofrenii.

AIM: To conduct a routine therapeutic drug monitoring (TDM) and analyze its results for the optimization of pharmacotherapy. MATERIAL AND METHODS: Fifty-six inpatients (in total 68 samples) with various forms of schizophrenia were enrolled. High performance liquid chromatography with mass-spectrometric detection was used for quantitative determination of risperidone and 9-hydroxyrisperidone in the serum. RESULTS: Concentrations of risperidone and 9-hydroxyrisperidone were correlated with drug dose. Total concentrations in the blood at doses from 2 to 8 mg per day were distributed as follows: 44.1% were in the therapeutic, 29.4% in sub-therapeutic (<20 ng/mL) and 26.5% in conditionally toxic range (>60 ng/mL). CONCLUSIONS: Concentrations of risperidone and 9-hydroxyrisperidone did not follow the normal distribution. The results showed that monitoring of the total concentration of risperidone and its metabolite 9-hydroxyrisperidone was an effective tool for testing and quality control for the purpose of individualization of pharmacotherapy.

[N-acetylaspartate is a biomarker of psychiatric and neurological disorders].

N-acetylaspartate (NAA) is an amino acid abundant in the brain and claimed the role of a biomarker of neuropsychiatric disorders. The basic ways of NAA concentration measurement in the brain are magnetic resonance spectroscopy (MRS), magnetic resonance imaging (MRI) and chromatography. The review examined the relationship between NAA concentrations in different parts of the brain and biological liquids and neuropsychiatric disorders.

[Plasma levels of antipsychotics and the severity of side-effects in the treatment of schizophrenia exacerbation].

OBJECTIVE: To study a relationship between plasma levels of antipsychotics (AP) and severity of side-effects (SE) during the treatment of inpatients with exacerbation of schizophrenia. MATERIAL AND METHODS: The study included 39 patients treated with risperidone, haloperidol, zuclopenthixol, clozapine, aripiprazole or olanzapine as monotherapy or in combination of two AP. Blood sampling to measure the AP plasma level was performed twice (at 7-10 and 26-30 day from start of treatment), the levels of prolactin and glucose were determined once (at 26-30 day from start of treatment). Patients were assessed by psychometric scales PANSS and NSA and the side-effects scale UKU. RESULTS: The increased concentration of AP was noted in 33% of the patients. The high concentration of AP was significantly associated with akathisia and hyperkinesia (by UKU scale), NSA retardation factor and hyperprolactinemia. Patients with severe hyperprolactinemia were twice as likely to have a clinically significant depression. Increased blood glucose levels were observed in 18% of the patients, there was no significant association with AP plasma levels. Mental SE were most prominent, with a drift towards the neurological SE in the group with higher AP plasma levels. Chlorpromazine equivalent didn't significantly differ in the groups with normal, high and low AP concentrations. CONCLUSION: Elevated AP plasma levels, which were associated with some clinically significant SE and some negative symptoms, were found in most patients. In this regard, therapeutic drug monitoring is a promising method for the individualization of schizophrenia exacerbation treatment in routine clinical practice.

[Determination of homocysteine by tandem mass spectrometry with chemical ionization].

Homocysteine (Hcy) is an intermediate of methionine metabolism. High plasma Hcy concentrations are an independent risk factor for stroke, peripheral vascular disease, deep venous thrombosis, coronary disease, and cognitive deficiency. Apparently, it is a great importance to measure Hcy levels in human blood. A new method for the quantification of Hcy by means of reversed-phase LC/atmospheric pressure chemical ionization mass spectrometry has been developed. The MRM ion transition, m/z 136.0 ® 90.0 was used for Hcy quantification. The limit of detection was 0.4 mM, quantification was performed from 1 mM to 40 mM with coefficient of determination of R2=0,997. The method was applied successfully to Hcy determination in human blood.

[Biomarkers in the modern medical and biologic practice].

The lecture deals with biomarkers, a newly introduced direction in biomedical research. The following terms, definitions, and characteristics were proposed to describe biomarkers: diagnostic tools, clinical endpoints and surrogate endpoints. Examples of predictors for cardiovascular diseases, acute-phase of inflammation and malignant tumors are represented. The special attention is given to the characteristic of the widespread biomarkers: homocysteine, transthyretin and C-reactive protein. Modern methods of identification, qualitative and quantitative determination of biomarkers are considered: mass spectrometric methods, immunoassay. The relationships between the latest achievements in the field of genomics, proteomics, bioinformatics and biomarker's investigations are established. The perspectives of biomarkers are discussed.

[Clinical pharmacokinetics of para-aminosalicylic acid tablets].

Pharmacokinetic parameters of PAS-Akri coated tablets (Akrikhin, Russia) were investigated. The tablets contain paraaminosalicylic acid (PAS) as sodium dihydrate in an amount of 1000 mg. The single oral dose of the drug for healthy volunteers in the trial was 6, 9 or 12 tablets. In 7 days the dosage was changed. The blood samples were collected 0.25, 0.5, 0.75, 1, 2, 4, 6, 8 and 10 hours after the drug administration. The PAS serum levels were determined with HPLC. The trials will allow to optimize the dosing of PAS for providing efficient antituberculosis therapy.

[The effect of bromantane on the dopamin- and serotoninergic systems of the rat brain]. / Vliianie bromantana na dofamin- i serotoninergicheskie sistemy mozga krys.

The effect of acute and chronic administration (50 mg/kg, p.o.) of a new immunostimulator, bromantan exhibiting psychostimulant features on the content of NE, DA and 5-HT, and their metabolites are studied. Bromantan induced a significant increase in the 5-HT and 5-HIAA content in the frontal cortex and delayed an increase in their content in subcortical brain regions. A stable decrease in the 5-HT and 5-HIAA levels in the cerebellum is observed. The drug also affected the DA parameters of the brain thus suggesting an important role of dopaminergic system in the mechanism of pharmacological effects of the drug.

[A comparative study of the neurochemical profiles of carbidine stereoisomers]. / Sravnitel'noe izuchenie neirokhimicheskikh profilei stereoizomerov karbidina.

The effects of cis- and trans-isomers of atypical neuroleptic carbidine on the synthesis of dopamine and its autoreceptor regulation in the striatum and nucleus accumbens of rats were examined by blocking decarboxylase of L-aromatic amino acids and interrupting the nerve impulse flow in the dopaminergic neurons. The striatal release and metabolism of dopamine were studied in vitro by employing K(+)-stimulated efflux from isolated striata and in vivo by the microdialysis in freely moving rats. Carbidine trans-isomer, unlike its cis-isomer, was shown to enhance the biosynthesis of dopamine via blockade of presynaptic autoreceptors presumably located on the dopaminergic terminals. The trans-isomer was found to be much more potent by affecting the neurochemical parameters of dopaminergic neurotransmission, which are essential for the drug to produce its antipsychotic effect.

[Effect of ethanol on the levels of dopamine and its metabolites in the brain of rats with different degree of sensitivity to stress]. / Vliianie étanola na uroven' dofamina i ego metabolitov v mozge krys s razlichnoi chuvstvitel'nost'iu k stressu.

It was shown, that content of dopamine and its metabolites (DOPAC and HVA) are the same in two groups of rats with different time of immobilization in forced swimming test. One group of low active (LA) animals experienced the immobilization more than 300s, other high active (HA) rats for less than 120 s. Ethanol (2 g/kg per oris) increased the level of DA in the striatum and medial prefrontal cortex only in LA rats and besides, the concentration of dopamine after ethanol administration was higher in the n. accumbens of LA rats, than in that of HA rats. The authors suggest that differences in dopamine content between LA and HA rats are connected with different levels of voluntary alcohol consumption. The opportunity to use both groups of HA and LA rats for developing models of pathogenic heterogeneity of alcoholism is discussed.

Cognitive deficiency induced by the acute stress in rats: a possible role of brain catecholaminergic systems.

The evaluation of the male albino rats cognitive capacity was performed by placing the animals in glass cylinder plundged into water (22 degrees C.) In order to escape from that stress situation the rat should dive under the cylinder's edge, solving by this way the extrapolatory escape task (EET). Two groups of rats (A and B) have been selected and characterized within the total laboratory population. The A rats have shown a smaller number of attempts to achieve successful escape and a shorter latency of that reaction in comparison with the B animals. The latter displayed a higher behavioral activity in "open field" test. The combination of 100 mg/kg L-DOPA with 25 mg/kg of benzerazide (DOPA-BENZ) was shown to impair dramatically the cognitive capacity of the two groups of animals. DOPA-BENZ treated rats failed to demonstrate any correct solution of EET. The rats of the two groups were distinguished clearly in terms of dopamine contents and turnover rate measured in three brain areas by the HPLC technique. Among psychotropic drugs studied only haloperidol and fluphenazine were found to restore partially the animals capacity to cope with the EET after DOPA-BENZ administration.

[Effect of L-dihydroxyphenylalanine on rat behavior and on catecholamine metabolism of the brain in rats with different degrees of emotional-behavioral reactivity]. / Vliianie L-dioksifenilalanina na povedenie krys i metabolizm katekholaminov mozga krys s razlichnym urovnem émotsional'no-povedencheskoi reaktivnosti.

The effect of L-DOPA in combination with benserazide (Madopar), administered intraperitoneally on the rat behaviour and L-DOPA, DA, NE, DOPAC content in rat brain structures was studied depending on the level of the animals' emotional-behavioural reactivity. The results indicate that L-DOPA metabolism in striatum, n. accumbens and hypothalamus in intact animals with high emotional reactivity was the greatest. Administration of Madopar (50 mg/kg) induced significant behavioural disturbances in animals with less emotional-behavioural response patterns. In contrast, 125 mg/kg Madopar completely abolished individual differences in the rats' behaviour and DA, but not L-DOPA and DOPAC content. The correlation between behavioural and biochemical differences in two groups of animals is discussed in view of distinctions in L-DOPA and DA compartmentation process.

[Effect of carbidine, sulpiride and haloperidol on levels of monoamines and their metabolites in the brain structures of rats]. / Vliianie karbidina, sul'pirida i galoperidola na soderzhanie monoaminov i ikh metabolitov v strukturakh golovnogo mozga krys.

Haloperidol (1 mg/kg) was shown to increase significantly the dopamine (DA) turnover in n. accumbens and striatum and to a lesser degree in frontal cortex and hypothalamus of the rat brain; to decrease the noradrenaline content in hypothalamus. Sulpiride (50 mg/kg) slightly increased DA turnover in striatum and hypothalamus and lowered the serotonin (5-HT) content in frontal cortex. Carbidine (25 mg/kg) was found to increase DA turnover in frontal cortex, striatum and hypothalamus to a greater degree than haloperidol; 5-HT turnover was increased in all the cerebral regions. The results obtained indicated that the atypical neuroleptic drug carbidine exerts the predominant effect on the frontal cortex, the serotoninergic component being clearly pronounced.

[Role of monoamines in the recovery of the conditioned reflex activity of rats following extirpation of the frontal cortex]. / Rol' monoaminov v vosstanovlenii uslovnoreflektornoi deiatel'nosti krys posle ékstirpatsii lobnoi kory.

The influence of frontal cortex extirpation on the amount of monoamines in the brain structures was investigated in chronic experiments on rats trained according to the method of motor feeding reflexes with bilateral reinforcement. Monoamine levels were measured by high performance liquid chromatography with electrochemical detection. By the ninth day after the ablation serotonin (5-HT) and dopamine (DA) levels were significantly reduced in the cortex and the striatum, respectively, while noradrenaline ++ (NA), 5-HT, dihydroxyphenylacetic and 5-hydroxyindoleacetic acid levels in raphe nuclei and locus coeruleus were increased. The level of conditioned reflex reproduction was 39% on the light and 33% on the sound stimulus. The involvement of monoamines in the recovery of conditioned reflexes after frontal cortex extirpation is discussed.