[The peptide analogue of neurotensin with antipsychotic and pro-cognitive effects: results of the pilot clinical trial]. / Peptidnyi analog neirotenzina s antipsikhoticheskimi i prokognitivnymi svoistvami: rezul'taty pilotnogo klinicheskogo issledovaniia.

OBJECTIVE: To evaluate the psychotropic specific spectrum activity of the novel peptide drug dilept and to find its effective doses in patients with schizotypal disorder. MATERIAL AND METHODS: The effects of dilept were studied in 25 patients (33.4±10.0 years old) with schizotypal disorder (F21.3) with predominance of obsessive-compulsive, hypochondriac, phobic symptoms, mild cognitive impairment and negative symptoms. Patients were treated with dilept 60, 120 and 200 mg daily for 14 days as monotherapy (with allowance of phenazepam up to 2 mg single doses for insomnia and anxiety) followed by combined treatment with phenazepam in the case of insufficient effectiveness of dilept monotherapy. The Positive and Negative Syndrome scale (PANSS), Psychopathological Symptom Severity scale, Clinical Global Impression scale (CGI) and Wechsler Adult Intelligence scale (WAIS-R) were used as outcome measures. RESULTS AND CONCLUSION: Dilept demonstrated the unique spectrum of psychotropic activity: antipsychotic with stimulating action, favorable effect on negative symptoms and cognitive dysfunction. Treatment action was the most evident when dilept was used in the dose 200 mg/day. There was no evidence of any side-effects known to be typical for antipsychotics. The efficacy of dilept and phenazepam combination is dependent on dilept's antipsychotic and pro-cognitive effects, while benzodiazepine lacks these effects.

[Results of a clinical study of a new anxiolytic, a blocker of central cholecystokinin receptors]. / Rezul'taty klinicheskogo issledovaniia novogo anksiolitika, blokatora tsentral'nykh kholetsistokininovykh retseptorov.

AIM: To evaluate anxiolytic action of GB-115, a low-affinity blocker of central cholecystokinin receptors, used in tablets in a dose of 1 mg for the treatment of patients with anxiety disorders in order to determine effective dose, safety, tolerability and efficacy in clinical settings. MATERIAL AND METHODS: The study included 31 patients (22 women, 9 men) diagnosed with generalized anxiety disorder (GAD, F41.1 according to ICD-10), aged from 22 to 53 years. The duration of treatment was 21 days. The Hamilton Anxiety Rating scale, Psychopathologic symptoms severity evaluation scale (PSSES), Spilberger State-Anxiety Inventory, Multidimensional Fatigue Inventory (MFI), Clinical Global Impression scale (CGI), computerized battery for evaluation of cognitive functions ('NS-Psychotest') were used. RESULTS AND CONCLUSION: The effective dose of GB-115 was determined at 6 mg per day. Drug action is characterized by fast onset of anxiolytic effect with stimulating properties and beneficial effect on sleep disturbances and autonomic symptoms. GB-115 treatment was associated with favorable changes in attention parameters, reaction time and overall performance. In contrast to first-line drugs for GAD treatment (SSRIs and SNRIs), GB-115 does not induce initial overactivation, anxiety and sleep disturbances. GB-115 is safe and has a good tolerability.

[Subjective evaluation of the effect of single test doses of phenazepam and placebo in patients with anxiety disorders: a relationship with objective pharmaco-electroencephalography characteristics]. / Sub''ektivnaia otsenka bol'nymi s trevozhnymi rasstroistvami deistviia odnokratnykh testovykh doz fenazepama i platsebo: sviaz' s ob''ektivnymi farmakoélektroéntsefalograficheskimi kharakteristikami.

AIM: To study the relationship between subjective evaluation (SE) of the effect of single test doses of benzodiazepine anxiolytic phenazepam and placebo and objective electroencephalography (EEG) characteristics in patients with anxiety disorders. MATERIAL AND METHODS: Forty patients, including 13 with generalized anxiety disorders (GAD, ICD-10 F41.1), 13 with anxiety-phobic disorders (AFD, ICD-10 F40.0) and 14 with anxiety-hypochondriac disorders (AHD, ICD-10 F45.2), were enrolled. The method of subjective evaluation of the effect of psychotropic drugs and EEG recording during wakeful rest and 2 hours after taking test doses of phenazepam (1 mg) and placebo were performed. RESULTS AND CONCLUSION: A trend towards the higher SE indices (tolerability and a wish to continue treatment with the drug) of the test dose of phenazepam in patients with GAD, its decrease in AFD and AHD, no differences in SE indices of placebo between different psychopathological patterns of disorders were identified. The changes in EEG specific for benzodiazepines were revealed in patients treated with phenazepam. Insignificant changes in the beta rhythm after taking placebo were found. Correlations between subjective assessments of the effect of test doses of phenazepam and placebo and EEG were observed. The results suggest that subjective assessments of the effect of anxiolytic drugs and objective indices of anxiolytic drug action are interrelated.

[Cognitive processes in patients with different structure of anxiety disorders]. / Osobennosti kognitivnykh protsessov u bol'nykh s razlichnoi strukturoi trevozhnykh rasstroistv.

AIM: To study the relationship between cognitive functions and psychopathological disturbances in anxiety disorders. MATERIAL AND METHODS: WAIS, the modified Witkin's Embedded figures test, a symptom scale (Yu.A. Aleksandrovsky et al. 1984) were administered to 111 patients, including 37 with generalized anxiety disorders (GAD, ICD-10 F41.1), 36 with anxiety-phobic disorders (AFD, ICD-10 F40) and 38 with anxiety-hypochondriac disorders (AHD, ICD-10 F45.2), and to 114 healthy people. RESULTS AND CONCLUSION: A distinct trend towards an increase of cognitive impairment depending on an increase in the complicity of psychopathological picture was observed as follows: GAD - AFD - AHD. A decrease in visual-motor coordination and visual attention was found in patients with GAD. In AFD patients, besides disturbances characteristic of GAD, there was a decrease on the WAIS Vocabulary subtest. In AHD patients, there was a decrease in analytic and synthetic abilities. The heterogeneity of changes in cognitive processes and the structure of their correlations with psychopathological symptoms in anxiety disorders was revealed as follows: a decrease in some parameters of cognitive processes in anxiety disorders with mild structure, an increase in cognitive dysfunction and in a number of correlations in anxiety disorders with more complex psychopathological picture, higher scores on the WAIS Block design task.

[Evaluation of the therapeutic efficacy and safety of the selective anxiolytic afobazole in generalized anxiety disorder and adjustment disorders: Results of a multicenter randomized comparative study of diazepam]. / Otsenka terapevticheskoi effektivnosti i bezopasnosti selektivnogo anksiolitika afobazola pri generalizovannom trevozhnom rasstroistve i rasstroistvakh adaptatsii: rezul'taty mnogotsentrovogo randomizirovannogo sravnitel'nogo s diazepamom issledovaniya.

AIM: to summarize the previously published results of a multicenter randomized clinical research phase III study trial of afobazole (INN: fabomotizole) versus diazepam in the treatment of patients with generalized anxiety disorder (GAD) and adjustment disorders (AD). SUBJECTS AND METHODS: Five investigating centers included 150 patients aged 18 to 60 years (60 patients with GAD and 90 with AD) a simple structure of anxiety disorders without concurrent mental, neurological or somatic disorders. Patients were randomized to take afobazole (30 mg/day; n=100) or diazepam (30 mg/day; n=50) for 30 days. Prior to drug administration, patients susceptible to placebo were excluded according to the results of its 7-day use. Withdrawal syndrome was evaluated within 10 days after completion of active therapy. The primary efficacy endpoint was the change of Hamilton Anxiety Rating Scale (HAMA) total score. The scores of the Clinical Global Impression (CGI) Scale and the Sheehan Scale as secondary efficacy endpoints  were analyzed. Drug safety was evaluated by assessment of adverse events. RESULTS: Afobazole and diazepam caused a significant reduction of HAMA total score. In the afobazole group, the reduction of anxiety  exceeded that in the diazepam group (the difference in the total score changes was 2.93 [0.67; 5.19]; p=0,01).The proportion of patients with reduction of disease severity was 72% in the afobazole group and 58% in the diazepam group. After therapy completion, the proportion of patients with no or mild disorder in the afobazole group was significantly higher than that in the diazepam group (69 and 44%, respectively; χ2=12.46; p=0,014). There was a trend toward a higher subjective patient-rated estimate of the afobazole effect using the Sheehan scale. There were a total of 15 and 199 adverse events in the afobazole and diazepam groups, respectively. No manifestations of afobazole withdrawal syndrome were found. Diazepam withdrawal syndrome was observed in 34 (68%) patients. CONCLUSION: Afobazole is an effective and safe drug to treat patients with GAD and AD and non-inferior than diazepam in the treatment of these disorders, however it is superior in terms of several variables, including the safety profile.

[The dynamics of behavioral and neuroreceptor effects after acute and long-term noopept administration in C57BL/6 and BALB/c mice].

The effect of acute, 7-fold and 14-fold noopept (1 mg/kg/day) administration on the dynamics of anxiolitic and nootropic behavioral effects in cross-maze, as well as their correlations with NMDA- and BDZ-receptor density was studied in inbred mice strains, differing in exploratory and emotional status--C57BL/6 and BALB/c. The dipeptide failed to affect the anxiety and exploration activity in C57BL/6 mice at each of 3 steps of experimental session. In this strain the B(max) values of [3H]-MK-801 and [3H]-Flunitrazepam binding changed only after single administration. In respect to BALB/c mice noopept induced both the anxiolitic and nootropic effects reaching their maximum on 7th day. In BALB/c strain the dynamics of hippocampal NMDA-receptor binding corresponds to the dynamics of exploratory efficacy whereas the dynamics of BDZ-receptors in prefrontal cortex was reciprocally to dynamics of anxiety level.

[Clinic pharmacokinetics of a new original antipsychotic drug Dilept].

The pharmacokinetic study of a new original antipsychotic drug Dilept in healthy volunteers was performed. Volunteers received Dilept as single 20, 40 or 60 mg tablets. The parent drug in the human blood plasma was detected in low concentrations and short-term time due to intensive biotransformation with formation of two metabolites N-caproyl-L-prolyl-tyrosin (M-1) and N-caproyl-L-prolin (M-2). After 20 and 40 mg of Dilept parent drug was detected in certain time points and after 60 mg for 1 h. M-1 and M-2 metabolites were registered in the blood plasma for 4 - 8 h. Theirs concentrations were 10 - 100 times higher of unchanged drug ones. Metabolites pharmacokinetics in the studied dosage range was nonlinear.

[The influence of piracetam on behavior and brain receptors in C57BL/6 and BALB/c mice: nootropic and anxiolytic effects].

The influence of acute and long-term piracetam administration on the dynamics of rapid (non-specific, anxiolytic) and slow (specific, nootropic) behavioral drug effects, as well as on their interrelation with NMDA- and BDZ-receptors was studied in inbred mice strains differing in cognitive and emotional status--C57BL/6 and BALB/c. The BALB/c strain contained 17% less [3H]-flunitrazepam binding sites in frontal cortex and 22% less [3H]-MK801 binding sites in hippocampus as compared to those in C57BL/6 mice. Based on these data, BALB/c strain was used as a model of psychopathology, combining increased anxiety and cognitive deficit. Under the action of single, 7-fold, and 14-fold piracetam i.p. injections (200 mg/kg body weight, daily), a fast increase in NMDA-receptor density and slow escalation of the specific nootropic effect was observed in BALB/c mice. Non-specific anxiolytic effects in these mice increased for the first 1 - 7 days without any changes in BDZ-binding and then decreased to initial values accompanied by decrement of brain receptor concentration. Thus, in BALB/c mice, a slowly manifested specific nootropic action of piracetam develops, following an increase in NMDA receptor density, whereas the non-specific anxiolytic effect precedes the fast-paced changes in BDZ-binding site density.

[Ladasten versus placebo effect self-evaluated by neurasthenia patients with different EEG alpha rhythm types].

The study was focused on the clinico-pharmacological analysis of differences between subjective and objective assessment of the effects of antiasthenic drug ladasten and placebo effects in patients with neurasthenia with different individual patterns manifested in their EEG alpha rhythms and MMPI findings. It is established that, in patients with neurasthenia characterized by reduced EEG alpha activity combined with emotional lability and inertness, the therapeutic action and effectiveness of ladasten and placebo was more robust (the subjective estimation was higher) than in patients with prominent alpha rhythm and sthenic personal traits. The self-assessment of the effect of single test doses of ladasten and placebo was independent of the individual differences of EEG alpha rhythm organization and personal traits with respect to tolerability, wish to continue the treatment, activating and calming effects. In long-term treatment, higher subjective estimations of the ladasten and placebo effect appeared in patients with reduced EEG alpha rhythm, and the difference corresponded to objective indices of the psychotropic action and effectiveness of the drug.

[The patterns of interzonal EEG relations and its relationship with the subjective assessment of single-dose action of phenazepam in patients with anxiety disorders].

The spectral-coherence analysis of phenazepam single-dose action in patients with anxiety disorder was performed. Significant changes in coherence parameters indicating the generalized character of reorganizations of interzonal connections with the involvement of delta, alpha, theta and beta-1 to beta-3 rhythms, including both their strengthening and weakening, were revealed. Correlations between the character of reorganizations of interzonal relations and subjective assessments of the drug effect were observed: activating and antianxiety drug effects were correlated with tolerability and the wish to continue treatment with the drug. Results suggest that drug effect on EEG spectra is more informative when subjective assessments are taken into account.

[Effect of phenazepam in various medicinal forms on psychophysical state of patients with anxiety disorders].

Differences between phenazepam formulations were found in the clinical study of drug effects on the psychophysiological state in patients with anxiety disorder. Phenazepam did not cause negative changes of psychophysiological parameters. In patients with anxiety disorders, the most significant positive therapeutic actionon psychophysiological state was observed in the case of using transdermal phenazepam formulation.

[Self-evaluation of single test doses and objective indices of ladasten vs. placebo efficacy in neurasthenic patients].

Self-evaluation of the effect of single-dose (15 mg) ladasten administration versus placebo has been studied in patients with neurasthenia diagnosis. Relationships between self-evaluation parameters and personal features, psychopathological and psychophysiological parameters of patients, drug action characteristics, and course treatment effectiveness have been analyzed. Results suggest that the self-rated high tolerability of ladasten treatment is comparable with that of placebo. No relationships are found between the self-evaluated single-dose effects of ladasten and personal features of patients. Correlations of the self-estimations and some psychopathological and psychophysiological parameters before treatment, main drug effects, and overall course treatment effectiveness are revealed, whereas the self-evaluation of placebo effect was related to personal features.

[Anxiolytic afobazole action self-evaluated by patients with anxiety-asthenic disorders].

Self-evaluation of single-dose (15 mg) action and course treatment (30 mg daily) results were studied in patients with anxiety and asthenic disorders treated with the new anxiolytic afobazole. Also, relationships between self-evaluated parameters and personal features, clinician-rated therapeutic changes, and treatment effectiveness were analyzed. The study was conducted according to formalized protocol using standard scales and methods. Results suggest that higher self-rated tolerability and patient acceptability were associated with afobazole treatment in comparison to benzodiazepines. The results revealed relationships between self-evaluated single-dose effects of afobazole and other parameters, personal features, cognitive impairments severity, main drug effects, and overall treatment effectiveness.

[Ladasten, the new drug with psychostimulant and anxiolytic actions in treatment of neurasthenia (results of the comparative clinical study with placebo)].

An aim of a randomized blind study was to assess therapeutic efficacy and safety of ladasten used as an antiastenic drug in patients with neurasthenia. Tasks of the study included the investigation of characteristics of therapeutical actions, efficacy of the drug comparing to placebo, possible side-effects and probability of the development of "withdrawal syndromes". The design of the study included a wash-out period, a monotherapy with ladasten and placebo during 28 days and a final 1-week period of receiving placebo. Standartisized objective and subjective methods of mental state evaluation in patients were administered. The results obtained suggest that a combination of psychostimulant and anxiolytic actions in the spectrum of psychotropic activity of ladasten determines the its high therapeutic efficacy in asthenic disorders. It has been found that ladasten is superior in the rate and degree of reduction of main symptoms of asthenic syndrome compared to placebo. The absence of "withdrawal syndrome" after the drug withdrawal reveals the lack of addictive potential in this drug.

[Therapeutic effect and pharmacokinetics of transdermal phenazepam preparation in patients with different anxiety disorders].

Clinical investigation of a transdermal phenazepam preparation (phenapercuten) in patients diagnosed with different anxiety disorders revealed an original therapeutic action of the new drug, which included both a selective anxiolytic effect and an activating (antiasthenic) component in the absence of undesired sedative and miorelaxant properties. It is shown that the specific action of phenapercuten is related to features of the pharmacokinetic profile of this transdermal drug that is characterized by a low levels of active compound in the blood plasma and by the absence of peak concentrations. TTS Phenapercuten was most effective in patients with anxiety disorders of simple structure.

[Clinical and electroencephalographic characteristic of noopept in patients with mild cognitive impairment of posttraumatic and vascular origin].

An effect of a new nootropic drug noopept on the dynamics of main EEG rhythms and narrow-band spectral EEG characteristics in patients with cerebral asthenic and cognitive disturbances caused by traumas or vascular brain diseases has been studied. Noopept caused the EEG changes characteristic of the action of nootropics: the increase of alpha- and beta-rhythms power and reduction of delta-rhythms power. The reaction of alpha-rhythm was provided mostly by the dynamics of its low and medium frequencies (6,7-10,2 Hz), the changes of beta-rhythm were augmented in frontal and attenuated in occipital areas. The analysis of frequency and spatial structure of EEG changes reveals that noopept exerts a nonspecific activation and anxyolytic effect. The differences in EEG changes depending on the brain pathology were found. The EEG indices of nootropic effect of the drug were most obvious in cerebral vascular diseases. The EEG changes in posttraumatic brain lesion were less typical.

[Characteristics of ladasten effect in neurasthenia patients with various EEG parameters].

Clinical and electroencephalographic (EEG) analysis ofladasten action in anxiety-asthenic patients with respect to their EEG-defined individual typological characteristics was carried out. Primary psychopathologic disorders and ladasten effects were assessed by objective classification methods (factor and cluster analyses), and individual EEG types characterized by marked or reduced alpha rhythm were determined. No significant correlations between baseline EEG results and the initial mental condition indices were found. Significant differences ofladasten action in patients with different EEG types were found. It was established that, in patients with marked alpha rhythm corresponding to asthenic personal traits, ladasten exhibits predominantly a psychostimulant action assessed by clinical rating scales, which is accompanied by high frequencies of alpha rhythm increase and beta 1 and beta 2 rhythms decrease. In patients with reduced alpha rhythm and the EEG type corresponding to asthenic personal traits, ladasten action was characterized by an increase of alpha-rhythm low frequencies and the opposite reaction of beta 1 and beta 2 rhythms, whose are typical for the EEG pattern of anxiolytic effect. These results may indicate that the effect of ladasten depends on the initial brain activity level, which varies in patients with different individual typological traits.

[Efficacy and possible mechanisms of action of a new peptide anxiolytic selank in the therapy of generalized anxiety disorders and neurasthenia].

Sixty-two patients with generalized anxiety disorder (GAD) and neurasthenia were studied. The effect of selank (30 patients) was compared to that of medazepam (32 patients). Patient's state was assessed with psychometric scales (Hamilton, Zung, CGI). Enkephalin activity in the blood serum was measured as well. The anxiolytic effects of both drugs were similar but selank had also antiasthenic and psychostimulant effects. The clinical-biological study revealed that patients with GAD and neurasthenia had the decreased level of tau(1/2) leu-enkephalin which was correlated with disease duration, severity of symptoms related to anxiety and asthenia and autonomic disorders. The increase of this parameter and stronger positive correlations with anxiety level were observed during the treatment with selank mostly in patients with GAD.