[Evidence-based treatment of acute psychotic episode and schizophrenia in children and adolescents]. / Dokazatel'naia farmakoterapiia ostrogo psikhoticheskogo épizoda i shizofrenii u detei i podrostkov.

Children and adolescents are a special group in the context of psychopharmacotherapy. Given the limited choice of registered antipsychotics permitted in childhood, caution should be exercised in the choice of medication. This literature review reviews the current evidence base for pharmacotherapy of acute psychotic episode and schizophrenia in children and adolescents. The results of major systematic reviews and meta-analyses are compared. Meta-analyses of pharmacotherapy studies of the first psychotic episode are considered separately. Antipsychotics of the first and second generation are comparable in effectiveness for children and adolescents with acute psychotic episode. Olanzapine demonstrates higher efficacy in reducing negative symptoms. Ziprasidone and asenapine are less effective in treating schizophrenia in children and adolescents than other antipsychotics. Compared to adults, children and adolescents are at higher risk of metabolic impairments when taking antipsychotics.

EFFECT OF CARBAMAZEPINE ON THE ACTIVITY OF CYP3A4 ISOENZYME IN PATIENTS WITH ALCOHOL ADDICTION.

According to literature data, isoenzyme CYP3A4 of cytochrome P450 is involved in biotransformation of drugs.,At the same time, there is evidence that carbamazepine induces CYP3A4 activity. The purpose of the study was to evaluate the effect of carbamazepine on the CYP3A4 activity in patients with alcohol addiction. The study was performed on a group of 25 men with alcohol abuse, which received haloperidol during the exacerbation of addiction. The activity of CYP23A4 was evaluated using high performance liquid chromatography with mass spectrometry (HPLC-MS/MS) for determining 6-beta-hydroxycortisol conversion to cortisol in urine. The results were used to construct a plot and derive an equation of logarithmic regression reflecting the dependence of CYP3A4 activity on the dose of carbamazepine: y = (5.5 - 9.1) x 10⁻5 - ΔΔx². These data demonstrate a statistically significant effect of carbamazepine on the activity of CYP3A4 isoenzyme in patients with alcohol addiction treated by haloperidol.

CYP3A4 activity and haloperidol effects in alcohol addicts.

BACKGROUND: Haloperidol is one of the most commonly used typical antipsychotics [2]. It has a powerful antipsychotic activity blocking mesolimbic postsynaptic dopamine receptors. Unwanted adverse effects accompany the use of haloperidol. Therefore alcohol abusers' attitudes towards haloperidol are ambiguous and often negative, which sometimes limits it's use in patients with addictive disorders [3]. Cytosolic carbonyl reductase reduces haloperidol to reduced form, which has 10-20% of the activity of the parent molecule. It is further metabolized by CYP3A4 to a tetrahydropyridine and then conjugated by glucuronidation and sulphation. Reduced haloperidol is back-oxidized to haloperidol by CYP3A4 and CYP2D6. Haloperidol is N-dealkylated by CYP3A4 and CYP2D6 to 4-chlorophenyl-4-hydroxypiperidine and p-fluorobenzoyl propionic acid. The correlation between CYP2D6 and CYP3A4 activity and the rate of biotransformation of haloperidol was demonstrated in a number of studies on patients with schizophrenia [1, 2, 5]. At the same time other studies deny or disaffirm this correlation [4]. OBJECTIVE: To estimate the correlation between CYP3A4 isoenzyme activity and the efficacy and safety of haloperidol in patients with alcohol abuse during the exacerbation of the addiction. METHODS: The study involved 15 men, alcohol abusers, in exacerbation of their addiction, who were hospitalized in Moscow Research and Practical Centre for Narcology of the Departament of Public Health. All 15 patients received haloperidol in tablets and injections. Determination of CYP3A4 activity was performed using high performance liquid chromatography with mass spectrometry (HPLC/ MS) by determination of endogenous substrate of this isoenzyme and its metabolite in urine - the ratio: cortisol/6-beta-hydroxycortisol. We used international psychometric scales to assess efficacy of haloperidol (the scale of determining the severity of addiction of The National Research Center on Addictions of the Ministry of Health Of Russia, Hamilton Anxiety Research Scale (HARS)). The safety of haloperidol was estimated by the UKU Side-Effect Rating Scale. Scales express the clinical picture of the abuse. The higher the score, the more pronounced the addiction is. Calculating the differences in scores of the scales allowed for clinical assessment of haloperidol effects. The larger the difference in scores was, the more pronounced were the changes in clinical picture of abuse, and the higher the efficacy of therapy was assumed. Statistical analysis of the results of the study was performed by non-parametric statistics by the program STATISTICA v10.0 («StatSoft Inc.¼, USA). The normality of sample distribution was estimated by Shapiro-Wilk's W-test, and the homogeneity of dispersion, that was estimated by Fisher's T-test (in case of comparison of two samples). The differences were evaluated as significant in case of p < 0,05 (statistic power >80%). To determine the correlation between the quantitative characteristics Spearman rank R coefficient was calculated. The value of correlation coefficient r from 0,3 to 0,7 (p < 0,05) indicated positive moderate, but significant correlation between the characteristics, r>0,7 (p < 0,05) - strong and significant correlation, negative value of r indicated inverse correlation. RESULTS: Data analysis demonstrated a correlation between the activity of isoenzyme CYP3A4 and the scores of pathological addiction (r1 = -0,36), HARS (r2 = -0,45), UKU Side-Effect Rating Scale (r3 = -0.15) in the entire group (p < 0.05). In a group of patients, who received the higher doses of haloperidol (more than 7.5 mg per day in tablets or 5 mg per day in injections), the following results were received in the same groups of data: r1 = -0.68, r2 = -0.71, r3 = -0.76 (p < 0.05). CONCLUSIONS: The results demonstrate the correlation between CYP3A4 activities and the efficacy and safety of haloperidol in alcohol abusers during the exacerbation of the addiction. The inverse correlation indicates that the higher the activity of CYP3A4 is, the lower the efficacy of haloperidol is. Also it can be assumed that the presence of strong correlation between the activity of CYP3A4 and the efficacy of haloperidol in group of patients, who received higher doses of haloperidol, may indicate that CYP3A4 is involved in haloperidol metabolism when it is used at higher doses. LIMITATIONS OF THE STUDY: It should be noted that in this research the activity of CYP3A4 was determined using high performance liquid chromatography with mass spectrometry (HPLC/MS) by determination the ratio of cortisol/6-beta-hydroxycortisol for the fist time. To increase the level of our confidence in the results further studies with a larger number of people are necessary.

[The treatment of patients with toxic encephalopathy caused by using surrogate psychoactive manganese-containing compounds].

Toxic encephalopathy caused by using surrogate psychoactive manganese-containing compounds was characterized clinically by a combination of parkinsonian, dystonic and pseudobulbar syndromes, eye-movement disturbances, autonomic insufficiency, affective disorders and moderate intellectual and memory impairment. Pharmacotherapeutic efficacy of mexidol has been studied. The results of the study showed that mexidol therapeutic course has a moderate effect on the expression of movement disorders and intellectual and memory impairment. Mexidol treatment significantly reduced severity of affective disorders and improved quality of life and daily activity of patients.

[Hepatopancreatic syndrome in chronic alcoholism]. / Gepatopankreaticheskii sindrom pri khronicheskom alkogolizme.

The results of puncture biopsy of the liver, ultrasonic and angiographic investigation of the liver and pancreas in 114 patients with chronic alcoholism revealed an increment of changes in these organs in parallel with an increase in the duration of chronic alcoholic intoxication. A simultaneous study of immunoreactive insulin (IRI) and C-peptide showed that an increase in the IRI basal level in the patients suffering from alcoholism up to 10 yrs was determined mainly by an increase in the activity of beta-cells. In a long period of alcoholism an increase in the IRI basal level resulted from a decrease in the rate of insulin degradation in the liver as assessed by a lower level of C-peptide. In liver cirrhosis a noticeable decrease in pancreatic incretory function was combined with noticeable disturbance of insulin degradation in the liver. The above investigations showed that there were morphological, functional and clinical signs of the "hepatopancreatic syndrome" in chronic alcoholism.

[Relationship between the cyclic nucleotide content of blood plasma and the clinical course of chronic alcoholism]. / Issledovanie zavisimosti mezhdu soderzhaniem tsiklicheskikh nukleotidov v plazme kvori i klinicheskim techeniem khronicheskogo alkogolizma.

In patients with chronic alcoholism out of abstinence the plasma cAMP concentration was shown to decrease and that of cGMP to increase, cAMP/cGMP ratio was 1.8 in contrast to control value of 4.2. During abstinence the plasma cAMP level was higher and cAMP/cGMP ratio in patients with abstinence was 3.1. In patients with acute hallucinosis the plasma cAMP level was lower but during delirium, on the contrary, as well as the plasma cGMP level, higher than in control. The treatment of alcoholic patients relieved clinical symptoms of abstinence but the plasma cyclic nucleotide levels didn't change significantly. In most patients after cessation of delirium the plasma cAMP level was significantly lower as compared with pretreatment level.