[A comparison of the anxiolytic effect and tolerability of selank and phenazepam in the treatment of anxiety disorders].

Objective. To study the efficacy and tolerability of the new anxyolytic peptide selank in comparison with phenazepam. Material and methods. A comparative study of the anxiolytic effect and tolerability of selank and phenazepam was carried out in 60 patients with phobic-anxiety- and somatoform disorders (F40.2-9, F41.1-9, F45.0-1 by ICD-10) were examined. Results Pronounced anxiolytic and mild nootropic effects of selank were demonstrated. The anxiolytic effect lasted for a week after last receiving the peptide. Selank had a positive impact on the quality of life of the patients. Conclusion. The data obtained in the study extend therapeutic possibilities in the treatment of anxiety disorders.

[Neurotensin-like oligopeptides as potential antipsychotics: effect on dopamine system].

According to published data, peptide neurotensin is considered as endogenous antipsychotic agent. A series of oligopeptides have been synthesized based on the proposed active center of neurotensin. These oligopeptides (called neurotensin-like peptides, NLPs) have been studied on behavioral models, in which the functional state of the dopamine system of animals was modified by apomorphine injections. The results of verticalization, stereotypy, and yawning tests revealed NLPs that behave as antagonists of dopamine receptors. Radioligand analysis showed that these peptides compete for specific binding to these receptors with sulpiride, which is a D2-type selective antagonist of dopamine receptors. The high degree of NLPs efficiency manifested in the behavioral tests and radioligand analysis suggests that the their antipsychotic action can be mediated by dopamine receptors.

[Naloxone-induced suppression of the behavioral manifestation of serotoninergic system hyperactivation by beta-casomorphins-7 in mice].

The effect of human and bovine beta-casomorphins-7 on the behavior of mice under conditions of 5-hydroxytryptophan (5-HT) induced hyperactivation of the serotoninergic system (head twitch test) has been studied. Intraperitoneal administration of each peptide in a dose of 1 mg/kg was shown to suppress the head twitch response in mice approximately by half (p < 0.01). This effect was completely blocked by the opioid receptor antagonist naloxone (10 mg/kg), which did not alter the behavior of mice in the head twitch test by itself. Thus, the influence of casomorphins on the serotoninergic system in vivo has been demonstrated for the first time. The role of 5-HT and opioid receptors in the mechanism of casomorphin action is discussed.

[A comparative analysis of distribution of glyprolines administered by various routes].

The distribution of the glyprolines Pro-Gly-Pro and Thr-Lys-Pro-Arg-Pro-Gly-Pro (Selanc) was analyzed and compared in tissues of rat organs after different ways of their administration using the peptides uniformly labeled with tritium. Comparative data on changes in concentrations of the peptides in the rat organs after their intraperitoneal, intranasal, intragastric, and intravenous administration are given. The intranasal administration of both peptides was shown to be optimal for the delivery of glyproline molecules in the CNS. A high affinity of the studied glyprolines for gastric tissues was found for all the ways of their administration. We suggest that a high efficiency of action of glyprolines on homeostasis of the gastric mucous tunic was partially provided by accumulation of these peptides (to high concentrations) in gastric tissues.

[Immunomodulatory effects of selank in patients with anxiety-asthenic disorders].

The purpose of this article was to study the immunotropic effects of the new neurotrophic heptapeptide selank. The experiments in vitro revealed that the drug in concentration 10-7 M completely suppressed gene expression by peripheral blood IL-6 of patients with depression but not of the healthy controls. At the same time, the significant increase (p<0,05) of IL-6 concentration was observed in the cell culture of peripheral blood of patients in the presence of selank. The changes of the Th1/Th2 cytokine balance in vivo were found in the serum of patients with generalized anxiety disorder and neurasthenia who received Selank during 14 days. The dynamics of these changes had the significant inverse correlation dependence. The cytokine regulating effects revealed in the study suggest that selank can be used as a novel immunomodulator in patients with anxiety-asthenic disorders. Additionally, the adaptogenic properties of selank may be beneficial to its use in elderly people and people exposed to environmental stressors for the prevention of infectious diseases.

[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.

[Biological mechanisms of the individual variability of the anxiolytic action of opioids].

The opioid system is one in a number of peptidergic regulatory systems that support an appropriate anxiety level. The drugs that interact with the opioid system have been shown to influence anxiety, although there is a notable variability in their pharmacological effects. Biological mechanisms of this variability are considered to be the heterogeneity of opioid receptors, the ratio of the processes of their expression and desensitization, and the balance between the synthesis and degradation of endogenous opioid peptides. For instance, the anxiolythic effect of the synthetic derivate of enkephalin in rats was detected after stress-induced exhaustion of endogenous opioids, and its efficacy depended on the degree of delta- and mu-opioid receptor desensitization in some brain regions. The anxiolythic properties of the heptapeptide Selanc that has also been shown to affect the opioid system are most prominent in subjects with elevated activity of enzymes degrading endogenous opioid peptides. Thus, delicate correction of the opioid system with drugs of peptide nature is supposed to become a new approach to treatment of some forms of anxiety disorders accompanied with exhaustion of the endogenous opioid system and, in particular, of generalized anxiety disorder.

[Regulatory peptides and psychomotor development in infants].

Regulatory peptides (RP) are an important homeostatic factor. The maternal organism and placenta are substantial sources of RP for fetus during the prenatal period. Not only endogenous, but also exogenous RP play an important role during early postnatal period. In this study, the concentration of exogenous RP (casomorphins-7) and the activity of peptidases (enkephalinases) in the serum of breastfed and bottle-fed infants were estimated. Possible interrelation between these two parameters and the psychomotor development (PMD) of infants were evaluated. Using specially developed RIA, the investigators estimated the presence of human and bovine casomorphins immunoreactivity (CMir) in the serum of breastfed and bottle-fed infants. A distinct correlation of CMir with PMD was demonstrated. The activity of RP-degrading serum enzymes also correlated with PMD level. The role of endo- and exogenous peptides in normal PMD process and in the pathogenesis of early child autism is discussed in the article.

[Evenly tritium-labeled peptides and their in vivo and in vitro biodegradation].

Biologically active peptides evenly labeled with tritium were used for studying the in vitro and in vivo biodegradation of the peptides. Tritium-labeled peptides with a specific radioactivity of 50-150 Ci/mmol were obtained by high temperature solid phase catalytic isotope exchange (HSCIE) with spillover tritium. The distribution of the isotope label among all amino acid residues of these peptides allows the simultaneous determination of practically all possible products of their enzymatic hydrolysis. The developed analytical method includes extraction of tritium-labeled peptides from organism tissues and chromatographic isolation of individual labeled peptides from the mixture of degradation products. The concentrations of a peptide under study and the products of its biodegradation were calculated from the results of liquid scintillation counting. This approach was used for studying the pathways of biodegradation of the heptapeptide TKPRPGP (Selank) and the tripeptide PGP in blood plasma. The pharmacokinetics of Selank, an anxiolytic peptide, was also studied in brain tissues using the intranasal in vivo administration of this peptide. The concentrations of labeled peptides were determined, and the pentapeptide TKPRP, tripeptide TKP, and dipeptides RP and GP were shown to be the major products of Selank biodegradation. The study of the biodegradation of the heptapeptide MEHFPGP (Semax) in the presence of nerve cells showed that the major products of its biodegradation are the pentapeptide HFPGP and tripeptide PGP. The enkephalinase activity of blood plasma was studied with the use of evenly tritium-labeled [Leu]enkephalin. A high inhibitory effect of Semax on blood plasma enkephalinases was shown to arise from its action on aminopeptidases. The method, based on the use of evenly tritium-labeled peptides, allows the determination of peptide concentrations and the activity of enzymes involved in their degradation on a tg scale of biological samples both in vitro and in vivo.

[Leu-enkephalin homogeneously labeled with tritium in studying the Selank inhibiting effect on the enkephalin-degrading enzymes of human plasma]. / Odnorodno mechennyi tritiem [Leu]énkefalin v issledovanii ingibiruiushchego deistviia Selanka na énkefalindegradiruiushchie fermenty plazmy krovi.

A method of analysis of enkephalinase activity in blood plasma based on the application of Leu-enkephalin generally labeled with tritium at all its amino acid residues was developed. The method allows the simultaneous estimation of activity of several peptidases in microquantities of tissues. [G-3H]Leu-enkephalin was prepared by the method of solid phase catalytic isotope exchange (120 Ci/mmol) and subjected to proteolysis by the treatment with blood plasma. The resulting radioactive metabolites were separated by HPLC in the presence of the mixture of unlabeled fragments of Leu-enkephalin as internal standards. It was shown that aminopeptidases, dipeptidylaminopeptidases, and dipeptidylcarboxypeptidases respond for approximately 80%, 2%, and 10% of the total enzymatic activity, respectively. The new pathway of degradation of Leu-enkephalin by carboxypeptidase that provides for approximately 6% of the total enkephalin-degrading activity was discovered. Bestatin was shown to predominantly inhibit aminopeptidases and carboxypeptidases, whereas Selank is more specific for carboxypeptidases and dicarboxypeptidases. The English version of the paper: Russian Journal of Bioorganic Chemistry, 2004, vol. 30, no. 3; see also http://www.maik.ru.

[Effect of new peptide bioregulators livagen and epitalon on enkephalin-degrading enzymes in human serum]. / Vliianie novykh peptidnykh bioreguliatorov livagena i épitalona na énkefalindegradiruiushchie fermenty syvorotki krovi cheloveka.

The effect of new peptide bioregulators--Livagen (Lys-Glu-Asp-Ala) and Epitalon (Ala-Glu-Asp-Gly)--on endogenous opioid system was studied, particularly, their ability to change the activity of enkephalin-degrading enzymes from serum and interact with opioid receptors of the brain membrane fraction. Enkephalinase activity was assayed in vitro by the rate of 3H-Leu-enkephalin hydrolysis in the presence of the tested peptides. Livagen and Epitalon inhibited enkephalin-degrading enzymes from human serum. Livagen proved to be more efficient also as compared to well-known peptidase inhibitors such as puromycin, leupeptin, and D-PAM. The dose-inhibitory effect curves for Livagen and Epitalon were plotted; their IC50 equaled 20 and 500 microM, respectively. The interaction between the peptides and opioid receptors was estimated using a radioreceptor method with [3H][D-Ala2, D-Leu5]-enkephalin. No interaction was observed between the tested peptides and mu- or delta-opioid receptors of the membrane fraction from the rat brain.

[Semax and selank inhibit the enkephalin-degrading enzymes from human serum]]. / Ingibiruiushchee deistvie semaksa i selanka na énkefalindegradiruiushchie fermenty syvorotki krovi cheloveka.

A dose-dependent effect of synthetic heptapeptides Semax (Met-Glu-His-Phe-Pro-Gly-Pro) and Selank (Thr-Lys-Pro-Arg-Pro-Gly-Pro) on the enkephalin-degrading enzymes of human serum was demonstrated. The inhibitory effects of Semax (IC50 10 microM) and Selank (IC50 20 microM) are more pronounced than those of puromycin (IC50 10 mM), bacitracin, and some other inhibitors of peptidases. Beside the heptapeptides, their pentapeptide fragments also possessed an inhibitory effect; tri-, tetra-, and hexapeptide fragments did not display such an effect. As the above enzymes take part in degradation of not only enkephalins but also other regulatory peptides, it can be assumed that one of the mechanisms of biological activity of Semax and Selank is related to this inhibitory activity of theirs.

[Ednit effects on activity of renin-angiotensin-aldosterone system and renal function in hypertensive subjects with diabetes mellitus]. / Vliianie édnita na aktivnost' renin-angiotenzin-al'dosteronovoi sistemy i funktsiiu pochek u bol'nykh arterial'nymi gipertoniiami v sochetanii s sakharnym diabetom.

AIM: To evaluate effects of enalapril (ednit) therapy on activity and reactivity of renin-angiotensin-aldosteron system (RAAS) and renal function. MATERIALS AND METHODS: Ednit was given in a dose 5-10 mg/day to 30 patients with mild or moderate arterial hypertension (AH) in combination with moderate or severe non-insulin-dependent diabetes mellitus (NIDDM) in compensation or subcompensation of carbohydrate metabolism. RESULTS: Ednit lowered blood pressure after 6-7 days of treatment. Normal blood pressure was achieved on the treatment week 4-6. Antihypertensive effect of ednit resulted from a significant reduction in a total peripheral vascular resistance under unchanged cardiac output. Adequate hypoglycemic and antihypertensive therapy normalized carbohydrate metabolism. Renal elimination of nitrogen did not change much. Glomerular filtration rate in patients with hyper- and hypofiltration returned to normal. Proteinuria reduced, microalbuminuria was not registered. RAAS activity normalized. CONCLUSION: Ednit has both high antihypertensive activity and marked renoprotective effect with minor influence on carbohydrate metabolism in AH patients with NIDDM.