[Observational study of the efficacy and safety of the drug Ampasse in patients with moderate cognitive impairment in chronic cerebral ischemia]. / Nablyudatel'noe issledovanie effektivnosti i bezopasnosti primeneniya preparata Ampasse u patsientov s umerennymi kognitivnymi narusheniyami pri khronicheskoi ishemii golovnogo mozga.

OBJECTIVE: The study of the efficacy and safety of drug Ampasse in the treatment of mild cognitive impairment syndrome (MCI) in patients with chronic cerebral ischemia (CCI) and as an adjuvant therapy in the treatment of chronic pain syndromes of various origins. MATERIAL AND METHODS: 50 patients with an average age of 67±7.4 years with MCI syndrome against the background of CCI, suffering from chronic pain syndromes of various origins, received the drug Ampasse at a dose of 25 mg per day intravenously by bolus for 15 days. At the screening visit, day 15 of therapy, day 30, and day 180 of the observation period, cognitive functions, emotional sphere, severity of pain syndrome, sleep quality, and quality of life were assessed. RESULTS: In 95% of patients during therapy, an improvement in cognitive functions was noted (increase by 2 points on scales MoCA and MMSE, p<0.05). The maximum severity of cognitive improvement was achieved by the 30th day of observation. By the 180th day of observation, 5% of patients had returned to their original cognitive status, which is probably due to the need for a repeated course of therapy to maintain the clinical effect. The antiamnestic effect of Ampasse was also manifested in patients with a multifunctional amnestic phenotype of MCI, which may indicate a comorbidity with a neurodegenerative disease. A total of 84% of patients experienced a decrease in pain intensity during treatment (decrease by 2.3 points on VAS, decrease in consumption of analgesics by 1.5 tablets per day, p<0.05). This effect persisted throughout the observation period and was associated with improved sleep quality. In the course of treatment, no cases of anxiety or depression were detected. All patients showed an improvement in their quality of life according to the scale SF-36. The use of Ampasse showed a good level of tolerability and safety. CONCLUSION: The use of Ampasse is effective and safe in the treatment of MCI in CCI and helps to reduce the clinical manifestations of pain syndromes of various origins. The mechanism of the analgesic action of Ampasse, as well as the need for and optimal timing of repeated courses of therapy, require further study.

[The effect of the start date of cognitive rehabilitation after ischemic stroke on the level of recovery]. / Vliyanie sroka nachala kognitivnoi reabilitatsii posle perenesennogo ishemicheskogo insul'ta na uroven' vosstanovleniya.

OBJECTIVE: The dependence of result of cognitive training in patients who have suffered an ischemic stroke (IS) on the timing of their onset continues to be discussed. The aim was to study the results of cognitive rehabilitation of patients after IS during various periods after it. MATERIAL AND METHODS: 140 patients were examined during complex rehabilitation in terms up to 1, 2-3, 4-6 and 7-12 months after IS, 78 of them received drug support (DS) of rehabilitation with intravenous injections of ampasse. The Montreal Cognitive Assessment (MoCA) and Hospital Anxiety and Depression Scale (HADS) were used to monitor the effectiveness of rehabilitation. RESULTS: In all subgroups, there was a statistically significant increase in the MoCA score after the course, but number of people with an increase in the score by 1 or more points was highest among those who started the course 3 or more months after the development of IS (p=0.015). Among those who received DS, an increase in the MoCA was noted in 87.2%, in those who did not receive it - 38.7% (p<0.001). There was no statistically significant increase in the severity of anxiety and depression after the course of treatment in any of the subgroups. CONCLUSION: The used approach of a combination of cognitive, physical rehabilitation and DS proved to be justified for achieving results during a two-week course of inpatient rehabilitation of patients both in the early and late recovery period after IS.

[Ampakines - a promising approach to neuroprotection]. / Ampakiny ­ novyi podkhod k neiroprotektsii.

Increased interest in glutamatergic neurotransmission emerged in the second half of the twentieth century. Later, the role of glutamate neurotransmission in learning and memory processes became clear. AMPA receptors (AMPR) and NMDA receptors (NMDAR) turned out to be important links in the mechanism of long-term potentiation (LTP) involved in memory processes, which was expressed in an increase in the excitatory postsynaptic potential in response to repeated stimuli. The data obtained in recent decades indicate that AMPR is the main regulators of synaptic plasticity, learning and memory. In clinical terms, the greatest interest is not the formation of memory traces in various parts of the brain, but its restoration in various pathological processes, including reactivation of connections between neurons activated by learning in various areas of the brain. AMPAR synaptic plasticity disorder has been detected in several neurodegenerative diseases accompanied by cognitive disorders. Ampakines, a heterogeneous class of numerous small molecules that bind to the allosteric site on the AMPAR receptor, which slows down the kinetics of AMPAR deactivation, enhances excitatory synaptic current and enhances LTP, have become increasingly attracting the attention of researchers.

Identification of specific gene methylation patterns during motor neuron differentiation from spinal muscular atrophy patient-derived iPSC.

Spinal muscular atrophy is a progressive motor neuron disorder caused by deletions or point mutations in the SMN1 gene. It is not known why motor neurons are particularly sensitive to a decrease in SMN protein levels and what factors besides SMN2 underlie the high clinical heterogeneity of the disease. Here we studied the methylation patterns of genes on sequential stages of motor neuron differentiation from induced pluripotent stem cells derived from the patients with SMA type I and II. The genes involved in the regulation of pluripotency, neural differentiation as well as those associated with spinal muscular atrophy development were included. The results show that the PAX6, HB9, CHAT, ARHGAP22, and SMN2 genes are differently methylated in cells derived from SMA patients compared to the cells of healthy individuals. This study clarifies the specificities of the disease pathogenesis and extends the knowledge of pathways involved in the SMA progression.

[Dynamics of recovery of cognitive deficit in patients in the early recovery period of ischemic stroke]. / Dinamika vosstanovleniya kognitivnogo defitsita u patsientov v rannem vosstanovitel'nom periode ishemicheskogo insul'ta.

OBJECTIVE: Study of the effectiveness of the use of the drug Ampasse in the process of complex rehabilitation in patients in the early recovery period of ischemic stroke at the second (stationary) stage. MATERIAL AND METHODS: The study included 60 patients, 28 women and 32 men, aged 43 to 76 years (mean - 58.4±9.1 years), in the recovery period after suffering a stroke in the period from 1 to 12 months (on average - 4.7±3.5 months). All patients received complex rehabilitation, patients of the 1st group received additional intravenous injections of the drug Ampasse 25 mg (5.0 ml), 15 injections. Patients of the 2nd group (n 0) did not receive Ampasse. To assess cognitive functions, the following tests were used: the Montreal Cognitive Assessment Scale (MoCA), Stroop's test, subtest 9 of the Wechsler test, Koos cubes (CC), the severity of anxiety and depression was assessed, and motor recovery was assessed by the hand motor activity test (ARAT). The assessment was carried out before the start of treatment and on the 21st day. RESULTS: There was a statistically significant increase in the score on the MoCA scale, in patients of the 1st group by an average of 2 points, in the 2nd group there was no significant dynamics, a statistically significant difference was found in the proportion of patients who had an increase in the MoCA index after the course of treatment in the 1st group. compared with the 2nd (χ2 - 22.528, p<0.001). Decreased the level of rigidity according to the Stroop test in patients of the 1st group compared with the 2nd (χ2 - 8.297, p=0.004). The number of patients who showed positive dynamics in the Koos cubes test in the 1st group was statistically significantly higher (χ2- 4.344, p=0.038). A statistically significant decrease in the level of depression was revealed in patients of the 1st group. The number of patients with improved motor function of the hand was greater in the 1st group of MG (χ2 - 4.286, p<0.039). CONCLUSION: In patients in complex therapy receiving intravenous administration of the drug Ampasse at a dose of 25 mg (5.0 ml) 15 administrations, a statistically significant improvement in cognitive functions was revealed according to MoCA tests, Stroop test, Koos Cubes, when compared with the comparison group. The use of Ampasse increased the effectiveness of cognitive and motor rehabilitation in patients with post-stroke disorders.

[Efficacy and safety of treatment with ampasse: the results of a randomized, double-blind, placebo-controlled trial in patients with chronic cerebrovascular disorders]. / Effektivnost' i bezopasnost' terapii preparatom ampasse: rezul'taty randomizirovannogo dvoinogo slepogo platsebo-kontroliruemogo issledovaniya u patsientov s khronicheskim narusheniem mozgovogo krovoobrashcheniya.

OBJECTIVE: To assess the efficacy and safety of the drug ampasse in the treatment of patients with chronic cerebrovascular disorders (CCVD). MATERIALS AND METHODS: A multicenter, randomized, double-blind, placebo-controlled, confirmatory study of the efficacy and safety of ampasse (phase III) was conducted in 124 patients aged 50 to 75 years. The main group (MG) - 62 patients, received the test drug ampasse, solution for intravenous administration, 5 mg/ml, at a dose of 5 ml (25 mg), intravenously bolus slowly, the duration of treatment was 15 days. Control group (CG) - 62 patients, received comparison drug: placebo (0.9% sodium chloride-5 ml). RESULTS: All 124 patients fully completed the procedures and visits, there were no dropouts from the study. The proportion of patients who reached the primary endpoint (an increase in the score by 2 or more points on the MoCA scale) was 83.87% in MG and 22.58% in CG, that is, the efficacy of therapy in MG was 61.29% higher than in CG (p<0.001), and good tolerability of the drug was proved. The secondary endpoint is an increase in quality of life (QOL) on the SF-36 V2 scale on Day 31. In MG, there was a statistically significant improvement in all indicators of QOL compared to the baseline. When assessing the safety spectrum, the proportion of patients who had adverse events was 14.52% in MG and 8.06% in CG (p=0.395). CONCLUSION: Ampasse has a positive effect on cognitive functions and QOL, does not increase the frequency of adverse events in patients with CCVD compared to placebo, does not cause significant side effects, and is well tolerated by patients.

Generation of a spinal muscular atrophy type III patient-specific induced pluripotent stem cell line ICGi003-A.

Spinal muscular atrophy (SMA) is a genetic disease, which characterized by the degeneration of motor neurons in the spinal cord and further striated muscle atrophy. The research of the processes in diseased neurons is complicated due to the impossibility of obtaining them safely from patients. Thus, we generated SMA type III induced pluripotent stem cell lines via using non-integrated episomal plasmid vectors. The resulting cell line expresses the major pluripotency markers and can differentiate in vitro into derivatives of three germ layers. The iPSC line can be used for further studies by providing in vitro the relevant cell types.

Generation of three Duchenne muscular dystrophy patient-derived induced pluripotent stem cell (iPSC) lines ICGi002-A, ICGi002-B and ICGi002-C.

Duchenne muscular dystrophy (DMD) is a severe and rapidly progressive hereditary muscular disease with X-linked recessive inheritance, occurring mainly in males. A complete loss of dystrophin resulted from out-of-frame deletion mutations in the DMD gene leads to Duchenne muscular dystrophy. DMD induced pluripotent stem cells (iPSCs) are a suitable cell model to study muscle development and disease mechanisms underlying muscular dystrophy and to screen novel compounds with potential therapeutic effects. We generated iPSCs from a DMD patient using non-integrating episomal plasmid vectors. The obtained iPSC lines showed ESC-like morphology, expression pluripotency markers, displayed a normal karyotype and possessed trilineage differentiation potential.

[Cys-Flanked Cationic Peptides For Cell Delivery of the Herpes Simplex Virus Thymidine Kinase Gene for Suicide Gene Therapy of Uterine Leiomyoma].

Uterine leiomyoma (UL) is the most common benign tumor in women of reproductive age. Gene therapy using suicidal genes appears to be a promising approach for UL treatment. One of key factors for success of gene therapy is the right choice of genetic construct carrier. A promising group of non-viral carriers for cell delivery of expression vectors is cationic Cys-flanked peptides which form tight complexes with DNA due to electrostatic interactions and the presence of interpeptide disulfide bonds. The paper reports a comparative study of the physico-chemical, toxic, and transfectional properties of the DNA-peptide complexes obtained by matrix polymerization or oxidative polycondensation of Cys-flanked peptides using the chain growth terminator 2-amino ethanethiol. We have demonstrated the therapeutic effect of the delivery of the pPTK-1 plasmid carrying the herpes simplex virus type 1 (HSV-1) thymidine kinase gene into PANC-1, and HEK-293T cell culture as well as into primary UL cells. It has been shown that the carriers obtained by oxidative polycondensation transform primary UL cells more efficiently than those produced by matrix polymerization. Treatment with ganciclovir resulted in the death of up to 40% of UL cells transfected with the pPTK-1 plasmid. The perspectives of use of the polyR6 carrier produced by oxidative polycondensation as a tool for the development of modular peptide carriers for the purposes of UL gene therapy were discussed.

Calcium Salt of N-(5-Hydroxynicotinoyl)-L-Glutamic Acid Weakens Depressive-Like Behavior and Parkinsonian Syndrome in Experiment on Rodents.

We studied antidepressant and antiparkinsonian properties of N-(5-hydroxynicotinoyl)-Lglutamic acid calcium salt (Ampasse) in rodents. It was found that Ampasse in a dose of 30 mg/kg exhibited antidepressant activity in the forced swimming test in mice and in a dose of 0.1 mg/kg maximally alleviates the symptoms of parkinsonian syndrome induced by systemic administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in C57Bl/6 mice, and haloperidol-induced catalepsy in rats.

[A randomized, double-blind, placebo-controlled study of the efficacy and safety of ampasse in the treatment of chronic cerebral ischemia]. / Randomizirovannoe dvoinoe slepoe platsebo-kontroliruemoe issledovanie éffektivnosti i bezopasnosti preparata ampasse v terapii khronicheskoi ishemii mozga.

AIM: To study the efficacy and safety of ampasse in the treatment of chronic cerebral ischemia. MATERIAL AND METHODS: A randomized, double-blind, placebo-controlled study of the efficacy and safety of the 5-hydroxy-3-carboxypyridine-L-glutamine acid monocalcium salt (ampasse) was performed in 80 patients, aged from 50 to 75 years, with chronic cerebrovascular accident due to arterial hypertension and/or atherosclerosis of the main arteries of the head. The drug was used in daily doses of 5, 10, or 25 mg intravenously once a day for 15 days. Sodium chloride 0.9% was used as a placebo. RESULTS AND CONCLUSION: It has been established that ampasse improves the state of patients with chronic cerebral ischemia in relation to depression, sleep quality and cognitive functions.

Generation of two spinal muscular atrophy (SMA) type I patient-derived induced pluripotent stem cell (iPSC) lines and two SMA type II patient-derived iPSC lines.

Spinal muscular atrophy (SMA) is a neuromuscular disease caused by deletion or mutation in SMN1 gene. SMA human induced pluripotent stem cells (iPSCs) represent a useful and valid model for the study of the disorder, as they provide in vitro the target cells. We generated iPSCs from a SMA type I patient and SMA type II patient by using non-integrating episomal plasmid vectors. The resulting iPSCs are episomal-free, express pluripotency markers, display a normal karyotype, retain the mutation (homozygous deletion of SMN1) and are able to differentiate into the three germ layers.

N-(5-Hydroxynicotinoil)-L-Glutamic Acid Calcium Salt Modifies Responses of Rat Hippocampal CA1 Pyramidal Neurons during Orthodromic Stimulation.

The study examined the effect of calcium salt of N-(5-hydroxynicotinoil)-L-glutamic acid (Ampasse preparation) on neuronal activity in hippocampal CA1 area evoked by stimulation of Schaffer collaterals at a rate of 1 Hz (30 impulses during 30 sec) in the surviving hippocampal slices of Wistar rats. The records of 1st and 30th orthodromic population spikes showed that Ampasse in concentrations of 500 µM, 1, 2, and 10 mM facilitated the synaptic transmission in Schaffer collaterals - hippocampal CA1 pyramidal neurons axis; the maximum effect was observed at 2 mM Ampasse. When used in a concentration of 10 mM, Ampasse provoked epileptiform activity, which could be prevented by MK-801, a specific noncompetitive antagonist of the NMDA-receptor complex.

[Pathogenesis of cognitive disorders in patients with Duchenne muscular dystrophy]. / Patogenez kognitivnykh rasstroistv pri myshechnoi distrofii Diushenna.

AIM: Clarification of the pathogenesis of cognitive disorders in patients with Duchenne muscular dystrophy in the clinical laboratory and molecular genetic study. MATERIAL AND METHODS: Thirty-six male patients with Duchenne muscular dystrophy (DMD), aged from 5 to 22 years (mean age 13.7 years), were examined. The control group consisted of 30 healthy people (7-22 years old, mean age 13.8). The clinical, molecular-genetic and laboratory study was conducted. The search for mutations in the dystrophin gene was carried out using multiplex PCR and multiplex ligation-dependent probe amplification. The laboratory study included determination of neurotrophins: brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF) and ciliary neurotrophic factor (CNTF) using immunoenzyme method in serum. RESULTS AND CONCLUSION: Severe cognitive impairment was found in 33% of patients with DMD. The distribution of mutations in the DMD gene was not uniform, most often the mutations were found in the region from exon 43 to exon 50. Serum concentration of NGF in patients with DMD was higher than in the control group (2391 pg/ml [1587; 4136] and 553 pg / ml [314; 864], respectively (p<0.001)). In the group of patients with cognitive disorders, there was a decreased concentration of BGF (23 670 [21 700; 30 720] pg/ml (p<0.001)). In patients with BGF concentration less than 31 000 pg/ml, the chances of cognitive disorders were more than 10 times higher (p<0.001, odds ratio OR=12.0, 95% CI [1.9-76.4]). Thus, biochemical mechanisms, such as NGF overexpression and BGF deficiency, are involved in the development of cognitive disorders in patients with DMD.

[Evaluating the effectiveness of Solanum tuberosum shoots extract in experimental ocular herpes].

UNLABELLED: Ocular herpes (OH) is an infectious disease caused by the herpes simplex virus (HSV) characterized by a variable clinical presentation and often accompanied by complications that may lead to deterioration of visual functions, cataract development, or even blindness. Its treatment is arduous. The aim of this work was to evaluate the effectiveness, tolerability, and safety of Panavir eye drops in a rabbit model of OH. MATERIAL AND METHODS: Ocular infection was induced with HSV-1 (EU strain) in grey rabbits (all males, 2.5-3.0 kg) according to the standard technique. The treatment included Panavir-GLA (Panavir-gamma-linolenic acid) and Panavir medications. RESULTS: Panavir eye drops instilled 6 times daily for 8 days showed a pronounced therapeutic effect and prevented the development of severe corneal opacities. The most rapid and significant results were seen in rabbits with epithelial keratitis and those with short-term persistence of the virus. Generally, the effectiveness of Panavir eye drops was comparable with that of the reference drug (Oftalmoferon). Panavir instillations caused no irritation, toxic and/or allergic effects and were well tolerated by the rabbits. CONCLUSION: The data obtained suggest that Panavir eye drops may be included in OH treatment schemes.

[Results of using Solanum tuberosum sprouts extract for the treatment of ophthalmoherpes].

The efficacy, tolerability and safety of the extract of Solanum tuberosum sprouts (Panavir eyedrops) have been studied on the model of ophthalmic disorder in rabbits caused by herpes simplex virus (HSV) type 1. It is established that Panavir applied via 6 instillations per day for a period of days has potent therapeutic efficacy and prevents the development of gross corneal opacity in rabbits. Instillation of Panavir eyedrops does not cause irritation, toxic and allergic effects and are well tolerated by rabbits. The fastest and most pronounced effect of Panavir eyedrops was observed in the treatment of epithelial keratitis, as well as for not prolonged persistence of HSV. The effectiveness of Panavir eyedrops is comparable with that of the reference preparation OphthalmoferonR.

Wide-aperture TeO2 AOTF at low temperatures: operation and survival.

The effect of temperature on the performance in a wide-angle paratellurite acousto-optic tunable filter (AOTF) is analyzed on the example of two different AOTF configurations. The present study is a by-product of the AOTF characterization for space-borne applications. The two AOTFs serve as dispersion elements in spectrometers for Moon and Mars space missions. The operation of the AO filters was tested in the range of -50° to+40°C; we have also demonstrated the survival of an AOTF device at -130°C. The phase matching ultrasound frequency varies with temperature within 2.5×10(-5) K(-1) and 6.6×10(-5) K(-1). We link this temperature shift to elastic characteristics of the TeO2, and demonstrate that it is mostly explained by the temperature modification of the slow acoustic wave velocity. We point out the best reference describing experimental results (Silvestrova et al., 1987). A generalization is made for all wide-angle acousto-optic tunable filters based on tellurium dioxide crystal.

[Experience of the implementation of the method of the integral assessment of drinking water on indicators of chemical harmlessness in St. Petersburg].

Providing population with quality drinking water--one of the priority tasks of the state policy aimed at maintaining the health of citizens. Hygienic rating of the drinking water quality envisages requirements to assurance its safety in the epidemiological and radiation relations, harmlessness of chemical composition and good organoleptic properties. There are numerous data proving the relationship between the chemical composition of drinking water and human health, and therefore the issue of taking a hygienically sound measures to improve the efficiency of water treatment has more and more priority. High water quality--the result of complex solution of tasks, including an integral approach to assessment of the quality of drinking water the use of hygienically sound decisions in the modernization of water treatment systems. The results of the integral assessment of drinking water on the properties of harmlessness have shown its actuality in the development and implementation of management decisions. The use of the spatial characteristics of integrated indices permits to visualize changes in the quality of drinking water in all stages of production and transportation from the position of health risks, evaluate the effectiveness of technological solutions and set priorities for investing.

Effects of physicochemical forms of phenazepam and Panavir on their action at ultra-low doses.

A concept of physicochemical forms of biologically active substances introduced in investigation of the action mechanism of ultra-low doses allows qualitative explanation of the main effects of ultra-low doses, chemical diversity of biologically active substances, and physical boundaries for these effects. Phenazepam was shown to possess activity in ultra-low doses only in disperse state, in the form of nanoparticles with a diameter <100-300 nm; these nanoparticles appear as micelles of surface active substances and solvated. Panavir possesses pharmacological activity in ultra-low doses and appears as nanoparticles with a diameter of 200-300 nm, which have uncompensated negative surface charge and polymer nature.

[The influence of calcium N-(5-hydroxynicotinoyl)-L-glutamate on reproductive function, prenatal and postnatal development of rats].

The safety of a new nootrope and neuroprotector--calcium N-(5-hydroxynicotinoyl)-L-glutamate (ampasse)--has been evaluated. It is shown that ampasse at a dose of 6.7 mg/kg (10 times the maximum therapeutic dose for humans) did not affect the reproductive function in experimental animals and did not produced any embryotoxic and teratogenic effects.