The cytotoxic and antiproliferative properties of ruthenium nitrosyl complexes and their modulation effect on cytochrome P450 in the HepG2 cell line.

Ruthenium nitrosyl complexes are actively investigated as antitumor agents. Evaluation of potential interactions between cytochromes P450 (CYPs) with new compounds is carried out regularly during early drug development. In this study we have investigated the cytotoxic and antiproliferative activities of ruthenium nitrosyl complexes with methyl/ethyl esters of nicotinic and isonicotinic acids and γ-picoline against 2D and 3D cultures of human hepatocellular carcinoma HepG2 and non-cancer human lung fibroblasts MRC-5, assessed their photoinduced activity at λrad = 445 nm, and also evaluated their modulating effect on CYP3A4, CYP2C9, and CYP2C19. The study of cytotoxic and antiproliferative activities against 2D and 3D cell models was performed using phenotypic-based high content screening (HCS). The expression of CYP3A4, CYP2C9, and CYP2C19 mRNAs and CYP3A4 protein was examined using target-based HCS. The results of CYP3A4 mRNA expression were confirmed by real-time reverse transcription-polymerase chain reaction (RT-PCR). The ruthenium nitrosyl complexes exhibited a dose-dependent cytotoxic effect against HepG2 and MRC-5 cells. The cytotoxic activity of complexes with ethyl isonicotinate (1) and nicotinate (3, 4) was significantly lower for MRC-5 than for HepG2, for a complex with methyl isonicotinate (2) it was higher for MRC-5 than for HepG2, for a complex with γ-picoline (5) it was comparable for both lines. The antiproliferative effect of complexes 2 and 5 was one order of magnitude higher for MRC-5; for complexes 1, 3, and 4 it was comparable for both lines. The cytotoxic activity of all compounds for 3D HepG2 was lower than for 2D HepG2, with the exception of 4. Photoactivation affected the activity of complex 1 only. Its cytotoxic activity decreased, while the antiproliferative activity increased. The ruthenium nitrosyl complexes 1-4 acted as inducers of CYP3A4 and CYP2C19, while the complex with γ-picoline (5) induced of CYP3A4. Among the studied ruthenium nitrosyl complexes, the most promising potential antitumor compound is the ruthenium compound with methyl nicotinate (4).

Organocatalyzed Amine-Free O-Phosphorylation of Alcohols with 4-Methylpyridine N-Oxide.

Amine-free phosphorylation of various alcohols was developed with 4-methylpyridine N-oxide in the presence of 4 Å molecular sieves at room temperature. This mild method gave various phosphorylated products in high yield and could be applied to acid- or base-sensitive substrates. Furthermore, this method was also effective for the chemoselective phosphorylation of diols or polyols.

[Efficacy of Mexidol in combination with cerebral revascularization in the treatment of ischemic stroke]. / Effektivnost' primeneniya Meksidola v kombinatsii s revaskulyarizatsiei golovnogo mozga v terapii ishemicheskogo insul'ta.

Stroke is an acute life-threatening condition; its outcome is determined by the degree of damage to brain tissue, the quality and speed of medical care in the first minutes and hours after its occurrence. The main mechanism of brain tissue damage during both ischemia and reperfusion is oxidative stress. The review covers adverse influence oxidative stress at the cerebral ischemia and reperfusion periodes of ischemic stroke. The results of preclinical studies demonstrating the ability of Mexidol to neutralize the effects of free radicals and activate antioxidant protection are presented. Data from clinical studies of the use of Mexidol in combination with thrombolysis in patients with ischemic stroke are reviewed.

[Possibilities of «therapeutic retargeting¼ of 3-hydroxypyridine and succinic acid derivatives due to their dopaminergic action]. / Vozmozhnosti «terapevticheskogo perenatselivaniya¼ proizvodnykh 3-oksipiridina i yantarnoi kisloty, obuslovlennye ikh dofaminergicheskim deistviem.

The review is devoted to a comparative analysis of the clinical efficacy of the original domestic derivatives of 3-hydroxypyridine and succinic acid (emoxipine, reamberin and mexidol) in comparison with the results of an experimental study of their dopaminergic action. The position that the dopaminomimetic activity of emoxipin, reamberin and mexidol largely determines their anti-ischemic, antihypoxic, insulin-potentiating neuroprotective, nootropic and antidepressant potential has been substantiated. A comparative analysis of the safety profile of emoxipine, reamberin and mexidol was carried out, taking into account potential and real side-effects caused by iatrogenic deviations from the eudopaminergic state. It has been shown that mexidol (2-ethyl-6-methyl-3-hydroxypyridine succinate), which is simultaneously a derivative of 3-hydroxypyridine and succinic acid, has the best balance of efficacy and safety. A generalized assessment of the available data on the successful use of off-label derivatives of 3-hydroxypyridine and succinic acid indicates the advisability of a significant expansion of indications for their clinical use. The authors resume that the «therapeutic retargeting¼ of emoxipin, reamberin and mexidol (i.e. their use for qualitatively new indications) will contribute to progress in the treatment of socially significant and most common diseases.

[Neurometabolic therapy of mild cognitive impairment in patients with chronic cerebral ischemia]. / Neirometabolicheskaya terapiya umerennykh kognitivnykh rasstroistv u patsientov s khronicheskoi ishemiei golovnogo mozga.

OBJECTIVE: To evaluate the effect of a sequential therapy regimen with Mexidol (500 mg injections intravenously for 14 days) and Mexidol FORTE 250 (250 mg tablets 3 times a day for 60 days) on higher cortical functions in patients with moderate cognitive disorders in chronic cerebral ischemia. MATERIAL AND METHODS: A comparative, prospective study included 63 patients with chronic cerebral ischemia with moderate cognitive impairment. All patients received basic therapy aimed at reducing risk factors (antihypertensive, antithrombotic drugs as indicated). Patients of the main group (30 people: 12 men, 18 women) received Mexidol intravenously 500 mg in 100 ml of 0.9% NaCl solution once a day for 14 days, then Mexidol FORTE 250 (film-coated tablets) 250 mg 3 times a day for the next 60 days. The comparison group consisted of 33 patients (14 men, 19 women) who received only basic therapy. The groups were comparable in terms of age, sex characteristics and severity of cognitive deficit. We examined cognitive status (MoCA scale, Frontal Dysfunction Battery, 10 Word Memorization tests), severity of asthenia (MFI-20 scale), anxiety and depression (HADS scale), patient's subjective assessment of the dynamics of the condition (CGI-improvement scale) in 1st, 14th and 74th±5 days of observation. On days 1 and 74±5 of observation, patients were examined using transcranial magnetic stimulation to study the neuronal activity of the cerebral cortex. RESULTS: In the main group, at the time of completion of taking Mexidol and Mexidol FORTE 250, a pronounced cognitive regression was noted (MoCA scale +3 points, difference with the comparison group 1 point (p<0.0001); Frontal Dysfunction Battery test +4 points, difference with comparison group 2 points (p<0.001); memory test «10 words¼ +2 points, difference with the comparison group 1 point (p<0.05), emotional (HADS anxiety scale -8 points, difference with the comparison group 3 points (p<0.001), depression -3.5 points, difference with the comparison group 1.5 points (p<0.01), asthenic disorders (MFI-20 scale -30 points, difference with the comparison group 15.5 points (p<0.01), improvement in the well-being of patients (CGI-improvement scale -2 points, difference with the comparison group 1 point (p<0.0001). According to the transcranial magnetic stimulation performed, a statistically significant decrease in the central motor conduction time at the level of 1 and 2 motor neurons of the pyramidal tract bilaterally from the start to the end of therapy with Mexidol and Mexidol FORTE 250 was determined (p<0.01). An inverse correlation was found between the time of central motor conduction and the results of the Frontal Dysfunction Battery test at the same time points with left-sided localization of 1 motor neuron (p<0.01). The results of a study of the use of sequential therapy with Mexidol 500 mg IV drip 1 time per day for 14 days followed by oral administration of Mexidol FORTE 250 1 tablet 3 times a day for 60 days indicate its clinical effectiveness and safety in patients with chronic cerebral ischemia with mild cognitive impairment, and also confirm its importance for preventing the progression of cognitive disorders.

[Treatment of patients with ishemic stroke in the vertebral-basilar system in acute period: experience of using the neuroprotective drug Mexidol]. / Lechenie bol'nykh ishemicheskim insul'tom v vertebral'no-bazilyarnoi sisteme v ostrom periode: opyt primeneniya neiroprotektivnogo preparata Meksidol.

OBJECTIVE: To assess the clinical efficacy and safety of Mexidol in patients in acute period of ishemic stroke in the vertebral-basilar system (iiVBS). MATERIAL AND METHODS: An open randomized comparative study involved 52 patients. 32 of them received Mexidol (mail group, MG) and 20 received therapy without neuroprotective drugs. Assessment of the severity of clinical manifestations of iiVBS was performed using the Hoffenberth scale, stroke severity was assessed using the NIHSS, the modified Rankin Scale was used to assess the degree of disability in patients after stroke, neuropsychological examination of patients was performed using the Montreal Cognitive Assessment (MoCA), dynamics were compared on the Hospital Anxiety and Depression Scale (HADS), Subjective assessment scale for asthenia (MFI-20), the patients' quality of life was assessed using the EQ-5D. RESULTS: The use of Mexidol in the form of long-term sequential therapy in the patients of the MG led to a 53.3% decrease in the severity of clinical manifestations of iiVBS and a 59.5% decrease in neurological deficit according to the NIHSS scale. By the end of Mexidol therapy, 96.9% of patients MG were able to manage their own affairs without assistance (modified Rankin Scale), which was accompanied by regression of emotional disturbances and improved quality of life of patients. CONCLUSION: Administration of Mexidol in therapy of patients with acute iiVBS can be considered the most justified, since it contributes to an earlier and more significant reduction of neurological deficit and improvement of patients' quality of life.

Crystal structure, intermolecular interactions, charge-density distribution and ADME properties of the acridinium 4-nitrobenzoate and 2-amino-3-methylpyridinium 4-nitrobenzoate salts: a combined experimental and theoretical study.

Acridines are a class of bioactive agents which exhibit high biological stability and the ability to intercalate with DNA; they have a wide range of applications. Pyridine derivatives have a wide range of biological activities. To enhance the properties of acridine and 2-amino-3-methylpyridine as the active pharmaceutical ingredient (API), 4-nitrobenzoic acid was chosen as a coformer. In the present study, a mixture of acridine and 4-nitrobenzoic acid forms the salt acridinium 4-nitrobenzoate, C13H10N+·C7H4NO4- (I), whereas a mixture of 2-amino-3-methylpyridine and 4-nitrobenzoic acid forms the salt 2-amino-3-methylpyridinium 4-nitrobenzoate, C6H9N2+·C7H4NO4- (II). In both salts, protonation takes place at the ring N atom. The crystal structure of both salts is predominantly governed by hydrogen-bond interactions. In salt I, C-H...O and N-H...O interactions form an infinite chain in the crystal, whereas in salt II, intermolecular N-H...O interactions form an eight-membered R22(8) ring motif. A theoretical charge-density analysis reveals the charge-density distribution of the inter- and intramolecular interactions of both salts. An in-silico ADME analysis predicts the druglikeness properties of both salts and the results confirm that both salts are potential drug candidates with good bioavailability scores and there is no violation of the Lipinski rules, which supports the druglikeness properties of both salts. However, although both salts exhibit drug-like properties, salt I has higher gastrointestinal absorption than salt II and hence it may be considered a potential drug candidate.

Comparison of the efficacy and tolerability of elobixibat plus sodium picosulfate with magnesium citrate and split-dose 2-L polyethylene glycol with ascorbic acid for bowel preparation before outpatient colonoscopy: a study protocol for the multicentre, randomised, controlled E-PLUS trial.

BACKGROUND: Sodium picosulfate (SP)/magnesium citrate (MC) and polyethylene glycol (PEG) plus ascorbic acid are recommended by Western guidelines as laxative solutions for bowel preparation. Clinically, SP/MC has a slower post-dose defaecation response than PEG and is perceived as less cleansing; therefore, it is not currently used for major bowel cancer screening preparation. The standard formulation for bowel preparation is PEG; however, a large dose is required, and it has a distinctive flavour that is considered unpleasant. SP/MC requires a small dose and ensures fluid intake because it is administered in another beverage. Therefore, clinical trials have shown that SP/MC is superior to PEG in terms of acceptability. We aim to compare the novel bowel cleansing method (test group) comprising SP/MC with elobixibat hydrate and the standard bowel cleansing method comprising PEG plus ascorbic acid (standard group) for patients preparing for outpatient colonoscopy. METHODS: This phase III, multicentre, single-blind, noninferiority, randomised, controlled, trial has not yet been completed. Patients aged 40-69 years will be included as participants. Patients with a history of abdominal or pelvic surgery, constipation, inflammatory bowel disease, or severe organ dysfunction will be excluded. The target number of research participants is 540 (standard group, 270 cases; test group, 270 cases). The primary endpoint is the degree of bowel cleansing (Boston Bowel Preparation Scale [BBPS] score ≥ 6). The secondary endpoints are patient acceptability, adverse events, polyp/adenoma detection rate, number of polyps/adenomas detected, degree of bowel cleansing according to the BBPS (BBPS score ≥ 8), degree of bowel cleansing according to the Aronchik scale, and bowel cleansing time. DISCUSSION: This trial aims to develop a "patient-first" colon cleansing regimen without the risk of inadequate bowel preparation by using both elobixibat hydrate and SP/MC. TRIAL REGISTRATION: Japan Registry of Clinical Trials (jRCT; no. s041210067; 9 September 2021; https://jrct.niph.go.jp/ ), protocol version 1.5 (May 1, 2023).

[The use of Mexidol in patients with mild (moderate) cognitive impairment: results of a meta-analysis]. / Primenenie Meksidola u patsientov s legkimi (umerennymi) kognitivnymi narusheniyami: rezul'taty metaanaliza.

OBJECTIVE: To conduct a meta-analysis of the effectiveness of Mexidol therapy in patients with chronic brain ischemia (CBI) and cognitive disorders (CD). MATERIAL AND METHODS: This meta-analysis included the results of studies on the effectiveness of Mexidol in patients with CD measured with Montreal Cognitive Assessment Scale (MoCA). The pooled effect assessment included all publications from independent clinical trials that provided efficacy data on the MoCA scale with a level of detail sufficient for further mathematical analysis. The main result of the meta-analysis was obtained for the final values of the effectiveness indicator in the Mexidol groups compared with the basic therapy groups. Data from 10 prospective randomized trials containing information on the final scores on the MoCA scale after therapy was analyzed. RESULTS: The meta-analysis of ten prospective clinical studies of the effectiveness of Mexidol against the background of basic therapy in patients with CCI and CD was carried out. The total number of patients taking Mexidol was 482; the comparison group consisted of 455 patients. According to the results of a statistical model of random effects, the effect size was 2.06; 95% confidence interval for the difference in effectiveness between the groups of the study drug and the control groups [0.98; 3.14] (p=0.0002). CONCLUSION: A statistically significant and clinically significant improvement in the cognitive functions of patients with CBI, was demonstrated after treatment with Mexidol.

[The impact of therapy with Mexidol on neurological deficit and functional outcome in patients with ischemic stroke: a systematic review and meta-analysis]. / Vliyanie terapii preparatom Meksidol na regress nevrologicheskogo defitsita i funktsional'nyi iskhod u patsientov s ishemicheskim insul'tom: sistematizirovannyi obzor i metaanaliz.

OBJECTIVE: To evaluate systematically the published peer-reviewed literature and estimate the effect of therapy with Mexidol on the course and outcomes of ischemic stroke (II) in adult patients. MATERIAL AND METHODS: The meta-analysis included 11 studies reported In Russian (2 randomized controlled studies, 9 non-randomized, unblinded cohort studies). RESULTS: The results obtained indicate a positive effect of Mexidol on the course of II in the treated adult patients: we found statistically significant decrease in NIHSS scores on days 7-10 and 21-24 and in modified Rankin scale scores on days 5-7 and days 10-14 compared with the control group. The cumulative effect of the drug was shown: the between-group difference of the NIHSS scores increases with the course of observation time. The effect of Mexidol on indicators on the NIHSS scale is more significant, the greater the initial severity of the patient's neurological deficit. CONCLUSION: Heterogeneity in study designs and patient characteristics has resulted in significant statistical heterogeneity, and the evidence presented at the time of writing requires further examination as new data become available.

[The possibilities of Mexidol usage in neuropediatrics]. / Vozmozhnosti primeneniya Meksidola v neiropediatrii.

Mexidol (ethylmethylhydroxypyridine succinate) is a modern neurometabolic medication increasingly being used in neuropediatrics. The results of recent studies confirming the positive effects of Mexidol pharmacotherapy in children with attention deficit hyperactivity disorder (ADHD), perinatal damages of the central nervous system (hypoxic-ischemic encephalopathy) and their consequences, neurological disorders and neurodevelopmental delay after surgery for congenital heart defects, neuroinfections (meningitis, encephalitis), posttraumatic epilepsy. Taking into account the unique multimodal action of Mexidol, it seems promising to expand the range of indications for its application in neuropediatrics, based on the results of new clinical trials organized in accordance with modern principles of evidence-based medicine.

[Improving the effectiveness of pharmacotherapy in comorbid patients with chronic cerebral ischemia on an outpatient basis]. / Povyshenie effektivnosti farmakoterapii u komorbidnykh patsientov s khronicheskoi ishemiei golovnogo mozga v ambulatornykh usloviyakh.

OBJECTIVE: To study the efficacy and safety of sequential therapy with Mexidol (500 mg 1 time/day for 14 days intravenously) and Mexidol FORTE 250 (Mexidol FORTE 250 for 250 mg 3 times/day, 60 days) in patients with chronic cerebral ischemia (CCI) on an outpatient basis. MATERIAL AND METHODS: The open comparative study included 56 patients aged 46-74 years, age - 60.5+7.9 years. In all patients, the diagnosis of CCI was confirmed by clinical and neuroimaging methods. Patients of group 1 (n=28) received basic therapy and Mexidol, group 2 (n=28) received only basic therapy. RESULTS: Against the background of therapy in patients of group 1, there was a statistically significant improvement in the state of cognitive functions, a decrease in the severity of symptoms of depression and anxiety, manifestations of asthenia. The treatment was characterized by good tolerability, absence of adverse events and cases of drug interactions. CONCLUSION: Sequential therapy with Mexidol and Mexidol FORTE 250 drugs provides relief of the main clinical manifestations of CCI, is characterized by good tolerability and safety.

Two New Picoline-Derived Meroterpenoids with Anti-Acetylcholinesterase Activity from Ascidian-Derived Fungus Amphichorda felina.

Amphichoterpenoids D (1) and E (2), two new picoline-derived meroterpenoids with a rare 6/6/6 tricyclic pyrano[3,2-c]pyridinyl-γ-pyranone scaffold, were isolated from the ascidian-derived fungus Amphichorda felina SYSU-MS7908. Their structures, including the absolute configurations, were established by extensive spectroscopic methods (1D and 2D NMR and high-resolution mass spectrometry) and ECD calculations. Compounds 1 and 2 showed anti-acetylcholinesterase (anti-AChE) activities with IC50 values of 12.5 µM and 11.6 µM, respectively. The binding interactions between 1, 2, and AChE were investigated using molecular docking analyses.

[The role of oxidative stress in hemorrhagic stroke and restorative effects of Mexidol]. / Rol' oksidativnogo stressa pri ostrom eksperimental'nom gemorragicheskom insul'te i terapevticheskie effekty Meksidola.

OBJECTIVE: Identification of the role of oxidative stress in the development of disorders that occur in hemorrhagic stroke (HS, post-traumatic intracerebral hematoma), and the study of the effects of Mexidol on neurological and cognitive deficits in HS with an analysis of the relationship between the therapeutic effects of the drug in HS with its antioxidant effect. MATERIAL AND METHODS: The study was carried out on mature outbred male rats weighing 260-280 g. HS was created by destruction of the brain tissue in the area of the capsula interna, with the introduction of blood into the site of injury. On the 1st, 7th, and 14th days after HS modeling, death, neurological deficits (McGrow scale, rotating rod), convulsive manifestations, and cognitive impairment were recorded in rats; blood plasma and homogenates of the cerebral cortex of rats. Mexidol was administered after the HS operation: first at a dose of 150 mg/kg, intraperitoneally, for 3 days and then 75 mg/kg, orally (from the 4th to the 14th day). RESULTS: Mexidol in rats with HS significantly increases the survival rate of animals, reduces the manifestations of neurological deficits according to the McGrow scale (playpen movements, paresis of 1-4 limbs, paralysis of the lower limbs, lateral position), eliminates individual motor convulsive manifestations, restores impaired coordination of movements (rotating rod test) and improves, impaired HS, learning and memory processes. Mexidol normalizes the concentration of TBA-active products in the blood of animals and homogenates of the cerebral cortex of rats, both a day and 7 days after HS modeling. CONCLUSION: The data obtained indicate the involvement of oxidative stress as a chain of pathogenesis in the development of disorders in HS and the ability of Mexidol to alleviate neurological deficits, convulsive manifestations and cognitive impairment in HS, which is accompanied by a decrease in oxidative stress. All this justifies the importance of the use of Mexidol in patients with hemorrhagic stroke, posttraumatic intracerebral hematoma and determines the features of its therapeutic effects.

The Effects of Quinone Imine, a New Potent Nitrification Inhibitor, Dicyandiamide, and Nitrapyrin on Target and Off-Target Soil Microbiota.

Dicyandiamide (DCD) and nitrapyrin (NP) are nitrification inhibitors (NIs) used in agriculture for over 40 years. Recently, ethoxyquin (EQ) was proposed as a novel potential NI, acting through its derivative quinone imine (QI). Still, the specific activity of these NIs on the different groups of ammonia-oxidizing microorganisms (AOM), and mostly their effects on other soil microbiota remain unknown. We determined the impact of QI, and comparatively of DCD and NP, applied at two doses (regular versus high), on the function, diversity, and dynamics of target (AOM), functionally associated (nitrite-oxidizing bacteria-NOB), and off-target prokaryotic and fungal communities in two soils mainly differing in pH (5.4 versus 7.9). QI was equally effective to DCD but more effective than NP in inhibiting nitrification in the acidic soil, while in the alkaline soil QI was less efficient than DCD and NP. This was attributed to the higher activity of QI toward AOA prevailing in the acidic soil. All NIs induced significant effects on the composition of the AOB community in both soils, unlike AOA, which were less responsive. Beyond on-target effects, we noted an inhibitory effect of all NIs on the abundance of NOB in the alkaline soil, with Nitrobacter being more sensitive than Nitrospira. QI, unlike the other NIs, induced significant changes in the composition of the bacterial and fungal communities in both soils. Our findings have serious implications for the efficiency and future use of NIs on agriculture and provide unprecedented evidence for the potential off-target effects of NIs on soil microbiota. IMPORTANCE NIs could improve N use efficiency and decelerate N cycling. Still, we know little about their activity on the distinct AOM groups and about their effects on off-target soil microorganisms. Here, we studied the behavior of a new potent NI, QI, compared to established NIs. We show that (i) the variable efficacy of NIs across soils with different pH reflects differences in the inherent specific activity of the NIs to AOA and AOB; (ii) beyond AOM, NIs exhibit negative effects on other nitrifiers, like NOB; (iii) QI was the sole NI that significantly affected prokaryotic and fungal diversity. Our findings (i) highlight the need for novel NI strategies that consider the variable sensitivity of AOM groups to the different NIs (ii) identify QI as a potent AOA inhibitor, and (iii) stress the need for monitoring NIs' impact on off-target soil microorganisms to ensure sustainable N fertilizers use and soil ecosystem functioning.

[Efficacy of Mexidol in patients with type 2 diabetes mellitus with neurological complications]. / Effektivnost' preparata Meksidol u patsientov s nevrologicheskimi oslozhneniyami sakharnogo diabeta 2-go tipa.

OBJECTIVE: Complications of Diabetes mellitus (DM), depends on the severity of hypoxic tissue damage. Amelioration of hypoxic injury may improve current therapy approaches and enhance the quality of life in patient's cohort suffered from DM. MATERIAL AND METHODS: 30 pts which DM were enrolled into the study. Mexidol forte, was given IV 500 mg/day for 14 days, follow up with oral administration 250 TID. Clinical impression, neuropsychological scales and biochemical blood tests were recorded. RESULTS: Mexidol administration improved cognitive functions, decreased the level of asthenia, depressia, improved sleep disturbances, and normalized biochemical landscape. CONCLUSIONS: Mexidol administration for the period 75 days may serve as important therapeutic supplementation and considered as adjunctive therapy in the treatment of patients with DM.

Comparative study between manitol and sodium picosulfate with magnesium oxide solutions in the preparation for colonoscopy.

This prospective, randomized and double-blind study aims to compare two different protocols used for bowel preparation in patients scheduled for colonoscopy. The protocols were composed by solutions of Mannitol or sodium picosulfate combined with magnesium oxide. Patients from the proctology outpatient clinic of the General Surgery Unit of the Regional Hospital of Asa Norte (HRAN) comprised the sample of this study. Both the patients and the colonoscopist had no prior knowledge of the substance used to prepare bowel, which was randomly distributed among the participants. Both protocols demonstrated good and similar results regarding the efficiency of colon preparation, although the review of literature shows a difference in favor of preparation made with Mannitol solution regarding the colon neatness during the exam. In line with the literature, patients who used Mannitol solution had more side effects, highlighting the significant difference found for vomiting and sleep impairment. The preparation with Sodium Picosulfate with Magnesium Oxide was significantly superior in relation to the ease of ingestion perceived by the patients.

[Results of a multicentre double-blind randomised placebo-controlled clinical trial evaluating the efficacy and safety of Mexidol in the treatment of Attention Deficit Hyperactivity Disorder in Children (MEGA)]. / Rezul'taty mnogotsentrovogo dvoinogo slepogo randomizirovannogo platsebo-kontroliruemogo klinicheskogo issledovaniya po otsenke effektivnosti i bezopasnosti preparata Meksidol v lechenii sindroma defitsita vnimaniya s giperaktivnost'yu u detei (MEGA).

OBJECTIVES: To evaluate the efficacy and safety of two dosing regimens of Mexidol film-coated tablets, 125 mg («RPC «PHARMASOFT¼ LLC Russia), compared with placebo in children with attention deficit hyperactivity disorder (ADHD) aged 6 to 12 years. MATERIAL AND METHODS: A multicenter randomized, double-blind, placebo-controlled study in 3 parallel groups was conducted in 14 clinical centres of the Russian Federation to assess efficacy and safety of Mexidol film-coated tablets, 125 mg («RPC «PHARMASOFT¼ LLC Russia) in the treatment of attention deficit hyperactivity disorder (ADHD) in children 6-12 years old with different dosing regimens. The study involved 333 boys and girls aged 6 to 12 years with a confirmed diagnosis of ADHD established in accordance with ICD-10 and DSM-5 criteria. After screening (up to 14 days) the patients were randomised into 3 treatment groups in a 1:1:1: Mexidol 125 mg 2 times daily, Mexidol 125 mg daily+placebo and the placebo group. The duration of treatment in all groups was 42 days. 332 children completed the study. ADHD and comorbid disorders assessment scales were used. RESULTS: There were statistically significant changes in the sum of the total scores on the SNAP-IV inattention and hyperactivity/impulsivity subscales after 6 weeks of therapy in all three study groups (p<0.05). There were statistically significant differences between the Mexidol 125 mg and placebo groups and between the Mexidol 125 mg 2 times daily and placebo groups (for the PP population: p=0.000308 and p=0.000024, respectively; for the FAS population: p=0.000198 and p=0.000024, respectively), indicating that Mexidol therapy is superior to placebo. Statistically significant differences (p<0.05) were also obtained for most of the secondary efficacy criteria (average change in SNAP-IV inattention subscale score, average change in SNAP-IV hyperactivity/impulsivity subscale score, average change in SNAP-IV subscale score - Conners index, average change in ADHD-RS-IV score, change in CGI-ADHD-S scores, change in CGI-I score - the Clinical Global Impressions Scale - Improvement) when comparing Mexidol therapy with placebo. The results of statistical analysis of the incidence of adverse events, laboratory values, physical examination show no significant differences between the compared groups in the main safety parameters. CONCLUSIONS: The regimen of Mexidol, 125 mg film-coated tablets twice daily has been shown to be superior to the regimen of Mexidol, 125 mg film-coated tablets once daily and placebo. The safety profiles of the studied dosing regimens of Mexidol and placebo were comparable.

[Neurological manifestations of postcovid syndrome]. / Nevrologicheskie proyavleniya postkovidnogo sindroma.

The problem of postcovid syndrome (PCS) attracts great interest due to the wide prevalence and variety of clinical manifestations. The main neurological manifestations of PCS are considered. The information about the proposed mechanisms of the formation of PCS is given. The possibility of using the drug Mexidol for the treatment of patients with PCS is discussed.

Nitrapyrin Addition Mitigated CO2 Emission from a Calcareous Soil Was Closely Associated with Its Effect on Decreasing Cellulolytic Fungal Community Diversity.

Application of nitrification inhibitors (NIs) has been widely used to inhibit nitrification and reduce N2O emissions. However, the impacts of NI addition on soil carbon transformation and carbon-degrading microbial communities have not been well explored. Here, a microcosm experiment was carried out, and four treatments were designed: (i) unfertilized control, (ii) urea alone, (iii) urea plus cattle manure, and (iv) urea plus cattle manure with nitrapyrin. The influence of nitrapyrin on soil CO2 emissions, carbon-degrading extracellular enzyme activities, and the abundance and diversity of the cbhI community was investigated. Compared to the treatment of urea plus cattle manure, nitrapyrin significantly decreased cumulative CO2 emissions by 51.8%. Moreover, cbhI community gene copies and their α-diversities (P < 0.05) were also significantly reduced by nitrapyrin application. A partial least squares path model showed that CO2 emission was positively associated with cbhI community α-diversity but negatively associated with nitrapyrin addition. We conclude that the mitigation of soil CO2 emissions by nitrapyrin can be ascribed to its effects on decreasing of cellulose-degrading gene community diversity. Our findings provide new insights into the side-effects of nitrapyrin on abating CO2 emission.