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Purpose: 68 Ga-Trivehexin is an investigational PET radiopharmaceutical (NCT05799274) targeting αvβ6-integrin for PET imaging of carcinomas. 177 Lu-D0301 is a structurally related therapeutic peptide tetramer. However, it showed considerable kidney uptake in rodents, impeding clinical applicability. We therefore evaluated the impact of different kidney protection strategies on the biodistribution of both agents in normal and tumor-bearing mice., Methods: Ex-vivo biodistribution of 68 Ga-Trivehexin (90 min p.i.) and 177 Lu-D0301 (90 min and 24 h p.i.) was determined in healthy C57BL/6N and H2009 (human lung adenocarcinoma) xenografted CB17-SCID mice without and with co-infusion of 100 µL of solutions containing 2.5% arginine + 2.5% lysine (Arg/Lys), 4% succinylated gelatin (gelofusine, gelo), or combinations thereof. Arg/Lys was injected either i.p. 30 min before and after the radiopharmaceutical, or i.v. 2 min before the radiopharmaceutical. Gelo was administered either i.v. 2 min prior activity, or pre-mixed and injected together with the radiopharmaceutical (n = 5 per group). C57BL/6N mice were furthermore imaged by PET (90 min p.i.) and SPECT (24 h p.i.)., Results: Kidney uptake of 68 Ga-Trivehexin in C57BL/6N mice was reduced by 15% (Arg/Lys i.p.), 25% (Arg/Lys i.v.), and 70% (gelo i.v.), 90 min p.i., relative to control. 177 Lu-D0301 kidney uptake was reduced by 2% (Arg/Lys i.p.), 41% (Arg/Lys i.v.), 61% (gelo i.v.) and 66% (gelo + Arg/Lys i.v.) 24 h p.i., compared to control. Combination of Arg/Lys and gelo provided no substantial benefit. Gelo furthermore reduced kidney uptake of 177 Lu-D0301 by 76% (90 min p.i.) and 85% (24 h p.i.) in H2009 bearing SCID mice. Since tumor uptake was not (90 min p.i.) or only slightly reduced (15%, 24 h p.i.), the tumor/kidney ratio was improved by factors of 3.3 (90 min p.i.) and 2.6 (24 h p.i.). Reduction of kidney uptake was demonstrated by SPECT, which also showed that the remaining activity was located in the cortex., Conclusions: The kidney uptake of both investigated radiopharmaceuticals was more efficiently reduced by gelofusine (61-85%) than Arg/Lys (25-41%). Gelofusine appears particularly suitable for reducing renal uptake of αvβ6-integrin targeted 177 Lu-labeled peptide multimers because its application led to approximately three times higher tumor-to-kidney ratios. Since the incidence of severe adverse events (anaphylaxis) with succinylated gelatin products (reportedly 0.0062-0.038%) is comparable to that of gadolinium-based MRI or iodinated CT contrast agents (0.008% and 0.04%, respectively), clinical use of gelofusine during radioligand therapy appears feasible if similar risk management strategies as for contrast agents are applied., (© 2024. The Author(s).)

Chicoric acid (CA) is a natural nutrient found in plants, showcasing diverse biological activities, including anti-inflammatory and antioxidant properties. Despite its valuable properties, CA faces limitations in bioavailability and susceptibility to oxidative breakdown during utilization. Previous research introduced synthesized dihydrocaffeic acid grafted chitosan self-assembled nanomicelles (DA-g-CS), demonstrating its potential to enhance CA absorption. This study aims to investigate the pharmacokinetics, tissue distribution, and antioxidant activity of both CA and DA-g-CS loaded CA (DA-g-CS/CA) in broilers. An IPEC-J2 cell model was established and evaluated to delve deeper into the transport mechanism and antioxidant potential. The in vivo pharmacokinetic analysis in broilers highlighted a substantial difference: the maximum plasma concentration (Cmax) of DA-g-CS/CA exceeded CA by 2.6-fold, yielding a notable increased relative bioavailability to 214%. This evidence underscores the significant enhancement in CA's oral absorption, facilitated by DA-g-CS. The collective evaluation outcomes affirm the successful development of the cell model, indicating its suitability for drug transporter experiments. The findings from the intestinal transit analysis revealed that both CA and DA-g-CS/CA underwent passive entry into IPEC-J2 cells. Notably, the cellular uptake rate of DA-g-CS loaded with CA was significantly amplified, reaching 2.1 times higher than that of CA alone. Intracellular transport mechanisms involved microtubules, lysosomes, and the endoplasmic reticulum, with an additional pathway involving the endoplasmic reticulum observed specifically for DA-g-CS/CA, distinguishing it from CA. Moreover, the results from both in vivo and in vitro antioxidant assessments highlight the potent antioxidant activity of DA-g-CS/CA, showcasing its efficacy in preventing and treating cellular damage induced by oxidative stress. In summary, these findings underscore the significant enhancement of CA's efficacy facilitated by DA-g-CS, establishing a robust theoretical foundation for the prospective application of CA within livestock and poultry farming., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: To evaluate the efficacy of speech therapy in patients with acute ischemic stroke (AIS) who received comprehensive treatment, including speech therapy and Cytoflavin infusions., Material and Methods: 46 right-handed patients who were hospitalized during the acute phase of AIS in the left middle cerebral artery were included in the study. Patients received comprehensive speech therapy and were randomly assigned to one of two groups. The first group consisted of 25 patients whose treatment regimen included infusions of the Cytoflavin solution, while the second group ( n =21) received only basic therapy for the secondary prevention of AIS. To assess the patients' condition, the following scales were used: the National Institutes of Health Stroke Scale (NIHSS), the Modified Rankin Scale, a screening tool for aphasia, and the Goodglass-Kaplan Scale (GKS)., Results: After the completion of the treatment course, statistically significant improvements were noted in patients from both groups. However, the degree of disability and dependence on others for daily activities in patients receiving infusions of Cytoflavin solution was significantly lower in group 1 compared to group 2 ( p =0.015). After the treatment, there was a regression of aphasia to moderate compensation in patients from group 1 (mean score 3 [3-4] points) and group 2 (mean 2 [2-2] points), with p =0.007 significance. As a result, patients from group 1 were able to communicate verbally on everyday topics (mean GKS score 3), while patients from group 2 also improved their communication, but still required significant assistance from an interlocutor (mean GKS 2). A clinical example is provided., Conclusion: A positive result was observed from the inclusion of Cytoflavin in the treatment of patients with aphasic disorders in AIS. There was a significant decrease in disability levels, an improvement in speech communication abilities, and a regression of aphasia following the use of the combination of drug therapy, speech therapy, and physical rehabilitation methods. Additionally, patients who received drug support with Cytoflavin showed an increased tolerance to treatment loads during therapy.

Objective: To study was to evaluate the potential modulatory impact of succinate/SUCNR1 signaling on the non-genomic immunosuppressive and gene-mediated inflammatory-degenerative effects of glucocorticoid receptor (GR) activation in the cerebral cortex (CC) of aging rats., Material and Methods: Using Western blot analysis, we assessed the expression level of pro-inflammatory (TNF-α, IL-1β), anti-inflammatory cytokines (IL-10, TGF-β1), mitochondriogenesis markers (PGC-1α, NDUFV2, SDHA, cyt c1, COX2, ATP5A), angiogenesis marker VEGF, neurotrophin BDNF, GR, succinate receptor SUCNR1 in the CC of 18-month-old rats with isolated administration of the highly specific GR ligand dexamethasone (1 mg/kg, i.p., daily, 10 days) and its combined administration with the succinate-containing drug Mexidol (100 mg/kg, i.p., daily, 10 days)., Results: Dexamethasone caused a decrease in the content of all detectable parameters in the CC of 18-month-old rats, including anti-inflammatory IL-10, TGF-β1, PGC-1α, VEGF, BDNF, which progressed by 10 days, amounting to 40-60%, which is consistent with the literature data on transrepression by GR of key pro-inflammatory (NFkB, AP1, STAT1), anti-inflammatory (PPARγ, ERRα), pro-anabolic transcription factors (estrogen, androgen receptors). The administration of Mexidol daily an hour after the injection of dexamethasone did not affect the dexamethasone-induced suppression of pro-inflammatory cytokines, but increased the expression levels of anti-inflammatory cytokines, protein markers of mitochondrio-, angio- and synaptogenesis., Conclusion: The study demonstrates for the first time the prospect and pathogenetic foundation of the combined use of dexamethasone and Mexidol in an aging body in order to minimize the activity of GC aimed at suppressing pro-anabolic programs and mechanisms for resolving inflammation.

Objective: Evaluation of the effectiveness of Cytoflavin as a neuroprotective therapy for neurological complications in premature newborns with hypoxic-ischemic encephalopathy., Material and Methods: 56 premature newborns with low body weight were examined. Newborn children, depending on the therapy, were divided into 2 groups: Group I - 32 premature newborns with hypoxic-ischemic encephalopathy; received basic therapy and Cytoflavin; Group II - 24 premature newborns with hypoxic-ischemic encephalopathy; received only basic therapy. Moreover, the state of neurospecific enolase (NSE) and blood lactate were studied., Results: Patients of the first group who received cytoflavin, on days 5-6 after treatment there was a decrease in the severity of cerebral ischemia. Also, decreased levels of NSE and blood lactate., Conclusion: The revealed neuroprotective effect of cytoflavin in the treatment of premature newborns with hypoxic-ischemic encephalopathy, good tolerability of the drug and its compatibility with other drugs used in the standard treatment of perinatal lesions of the nervous system, which makes it possible to recommend Cytoflavin for the treatment of neurometabolic disorders in children in the first months of life in complex therapy perinatal lesions of the nervous system of premature newborns.

Objective: The present study aimed to investigate the impact of two Nrf2 agonists, tBHQ and 4-Octyl Itaconate, on nucleus pulposus (NP) degeneration and explore the underlying mechanism., Patients and Methods: We isolated the NP cells from the disc tissue of disc herniation patients. NP cells were pretreated with an adequate dose of tBHQ, Itaconate, or the mixture of them, and then subjected to the Lipopolysaccharides (LPS) stimulation to induce degeneration. Besides, the Nrf2 gene silenced NP cells were also used as a comparison. Moreover, the LPS-treated NP cells were also cultured in the mix of tBHQ and Itaconate to determine whether the agonists affected reverse degeneration., Results: LPS treatment suppressed Nrf2 expression and induced the NP cell degeneration with a decrease of cell viability and collagen II expression, an increase of reactive oxygen species (ROS) production, inflammatory cytokine accumulation (IL-1β, TNF-α), and apoptosis (Caspase3, Caspase8). However, tBHQ or Itaconate pretreated NP cells contained a higher level of Nrf2 protein and alleviated the negative effect caused by LPS, which was abolished with the silencing of Nrf2. Additionally, tBHQ showed a better ability to suppress ROS than Itaconate. Meanwhile, Itaconate inhibited a higher amount of IL-1β and TNF-α than tBHQ. Interestingly, when NP cells were pretreated with both tBHQ and Itaconate, the result indicated an excellent anti-ROS and anti-inflammatory peculiarity. Furthermore, when NP cells suffered from LPS first and then treated with the agonist, the anti-ROS and anti-inflammatory effects remained. However, the cell viability, collagen II, and apoptotic degree were not improved., Conclusions: Both tBHQ and Itaconate effectively prevent NP cells from degeneration through anti-ROS and anti-inflammation, and the combined use of them may have better effects. But in comparison, their impact on reversing NP cell degeneration has yet to be proven.

Oral iron supplementation constitutes the first line treatment for iron deficiency anemia (IDA), with daily doses between 80 mg and 200 mg of elemental iron. Ferrous salts, such as ferrous sulphate (FeSO 4 ), while efficacious, frequently give rise to gastrointestinal side effects. In the present paper we attempted to directly compare the efficacy of an alternative to the FeSO 4 formulation, which presents a better tolerability profile, iron protein succinylate (Ferplex ® ). In a diet-induced anemia model, rats were treated by oral gavage with vehicle, FeSO 4 , or Ferplex ® at a human-dose equivalent of 80 mg and 200 mg of elemental iron. We evaluated the change in anemia-related hematological and biochemical parameters, conducting a histological examination of the intestine at sacrifice. Results indicate that both types of iron supplementation are equally effective in the treatment of IDA, restoring hemoglobin, hematocrit, erythrocytes, free iron and transferrin levels in 15 days, with no statistical differences between treated groups and control. The impact of anemia on body weight was also attenuated following treatment with both iron supplements. Thrombocyte and reticulocyte levels, altered by the anemic condition, returned to homeostasis after 15 days of either FeSO 4 or Ferplex ® treatment. Importantly, the lower and higher doses of iron were equally effective, thus supporting the current school of thought which states that lower therapeutic doses are sufficient for management of IDA. In addition, the study shows for the first time that oral treatment with Ferplex ® does not increase serum hepcidin. Finally, Ferplex ® induced minimal iron depositions in the intestinal tissue compared to FeSO 4 .

Examination of the patterns of free-radical processes (FRP) and changes of the early screening markers to predict the course of hemorrhagic stroke (HS) and applied pathophysiologically based therapy can be of great practical importance. This study aimed to determine early changes in the parameters of oxidative stress and routine biochemistry blood tests in patients with HS and to assess their relationship with clinical outcome. The effects of early applied cytoflavin were also investigated. The prospective study included 151 patients with HS. Forty-eight percent of patients in the standard conservative therapy were given cytoflavin antioxidant energy therapy from the first day of hospitalization. The neurological status, neuroimaging, biochemical blood tests and FRP were assessed on days 1, 5, 10, and 20 of hospitalization. In patients with HS, an imbalance of all stages of FRP was detected proportionately to the severity of HS. The malondialdehyde concentration above 5.3 μmol/L, the number of leukocytes above 15 800, glucose above 11.9 mmol/L, lactate dehydrogenase above 574 IU/L, and lactate above 2.5 mmol/L, detected on the first day, predetermined a high risk of death. Additional cytoflavin treatment allowed stabilizing the clinical laboratory picture of HS, improved the treatment results, and reduced hospital mortality rate.

Mirtazapine (MTZ) is a noradrenergic and specific serotonergic antidepressant. MTZ is reportedly associated with an increased risk of bleeding. However, the underlying mechanism remains unclear. In this study, we investigated the antiplatelet effect of MTZ in mice via light transmission aggregometry to elucidate the mechanism of MTZ-induced bleeding. The results of the ex vivo study showed that the oral administration of MTZ (20 or 100 mg/kg) significantly suppressed platelet aggregation mediated by the synergic interaction of 5-hydroxytryptamine (5-HT) and adrenaline. Additionally, MTZ significantly suppressed platelet aggregation, mediated by the synergic interaction of ADP and 5-HT or adrenaline. Similar results were obtained in vitro, under the condition of 5-HT- and adrenaline-induced platelet aggregation. Overall, the results suggest that MTZ exerts antiplatelet effect by co-blocking 5-HT 2A and α 2 -adrenergic receptors on platelets and suppresses platelet aggregation mediated by ADP, increased by either 5-HT or adrenaline. Thus, a detailed monitoring of bleeding is recommended for patients taking MTZ.

Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease in which airway macrophages (AMs) play a key role. Itaconate has emerged as a mediator of macrophage function, but its role during fibrosis is unknown. Here, we reveal that itaconate is an endogenous antifibrotic factor in the lung. Itaconate levels are reduced in bronchoalveolar lavage, and itaconate-synthesizing cis-aconitate decarboxylase expression ( ACOD1 ) is reduced in AMs from patients with IPF compared with controls. In the murine bleomycin model of pulmonary fibrosis, Acod1 −/− mice develop persistent fibrosis, unlike wild-type (WT) littermates. Profibrotic gene expression is increased in Acod1 −/− tissue-resident AMs compared with WT, and adoptive transfer of WT monocyte-recruited AMs rescued mice from disease phenotype. Culture of lung fibroblasts with itaconate decreased proliferation and wound healing capacity, and inhaled itaconate was protective in mice in vivo. Collectively, these data identify itaconate as critical for controlling the severity of lung fibrosis, and targeting this pathway may be a viable therapeutic strategy.

Background & Aims: Blood volume expanding properties of colloids are superior to crystalloids. In addition to oncotic/osmotic properties, the electrolyte composition of infusions may have important effects on visceral perfusion, with infusions containing supraphysiological chloride causing hyperchloremic acidosis and decreased renal blood flow. In this non-inferiority study, a validated healthy human subject model was used to compare effects of colloid (4% succinylated gelatin) and crystalloid fluid regimens on blood volume, renal function, and cardiac output., Methods: Healthy male participants were given infusions over 60 min > 7 days apart in a randomized, crossover manner. Reference arm (A): 1.5 L of Sterofundin ISO, isoeffective arm (B): 0.5 L of 4% Gelaspan®, isovolumetric arm (C): 0.5 L of 4% Gelaspan® and 1 L of Sterofundin ISO (all B. Braun, Melsungen, Germany). Participants were studied over 240 min. Changes in blood volume were calculated from changes in weight and hematocrit. Renal volume, renal artery blood flow (RABF), renal cortex perfusion and diffusion, and cardiac index were measured with magnetic resonance imaging., Results: Ten of 12 males [mean (SE) age 23.9 (0.8) years] recruited, completed the study. Increase in body weight and extracellular fluid volume were significantly less after infusion B than infusions A and C, but changes in blood volume did not significantly differ between infusions. All infusions increased renal volume, with no significant differences between infusions. There was no significant difference in RABF across the infusion time course or between infusion types. Renal cortex perfusion decreased during the infusion (mean 18% decrease from baseline), with no significant difference between infusions. There was a trend for increased renal cortex diffusion (4.2% increase from baseline) for the crystalloid infusion. All infusions led to significant increases in cardiac index., Conclusions: A smaller volume of colloid (4% succinylated gelatin) was as effective as a larger volume of crystalloid at expanding blood volume, increasing cardiac output and changing renal function. Significantly less interstitial space expansion occurred with the colloid., Trial Registration: The protocol was registered with the European Union Drug Regulating Authorities Clinical Trials Database (https://eudract.ema.europa.eu) (EudraCT No. 2013-003260-32)., (Copyright © 2019 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objectives: Cerebral ischemia/reperfusion (IR) drives oxidative stress and injurious metabolic processes that lead to redox imbalance, inflammation, and tissue damage. However, the key mediators of reperfusion injury remain unclear, and therefore, there is considerable interest in therapeutically targeting metabolism and the cellular response to oxidative stress., Methods: The objective of this study was to investigate the molecular, metabolic, and physiological impact of itaconate treatment to mitigate reperfusion injuries in in vitro and in vivo model systems. We conducted metabolic flux and bioenergetic studies in response to exogenous itaconate treatment in cultures of primary rat cortical neurons and astrocytes. In addition, we administered itaconate to mouse models of cerebral reperfusion injury with ischemia or traumatic brain injury followed by hemorrhagic shock resuscitation. We quantitatively characterized the metabolite levels, neurological behavior, markers of redox stress, leukocyte adhesion, arterial blood flow, and arteriolar diameter in the brains of the treated/untreated mice., Results: We demonstrate that the "immunometabolite" itaconate slowed tricarboxylic acid (TCA) cycle metabolism and buffered redox imbalance via succinate dehydrogenase (SDH) inhibition and induction of anti-oxidative stress response in primary cultures of astrocytes and neurons. The addition of itaconate to reperfusion fluids after mouse cerebral IR injury increased glutathione levels and reduced reactive oxygen/nitrogen species (ROS/RNS) to improve neurological function. Plasma organic acids increased post-reperfusion injury, while administration of itaconate normalized these metabolites. In mouse cranial window models, itaconate significantly improved hemodynamics while reducing leukocyte adhesion. Further, itaconate supplementation increased survival in mice experiencing traumatic brain injury (TBI) and hemorrhagic shock., Conclusions: We hypothesize that itaconate transiently inhibits SDH to gradually "awaken" mitochondrial function upon reperfusion that minimizes ROS and tissue damage. Collectively, our data indicate that itaconate acts as a mitochondrial regulator that controls redox metabolism to improve physiological outcomes associated with IR injury., (Copyright © 2019 The Authors. Published by Elsevier GmbH.. All rights reserved.)

Aim: To evaluate the efficacy of including cytoflavin in rehabilitation measures in the early recovery period of patients with ischemic stroke., Material and Methods: Results of rehabilitation measures of 100 patients (50 women and 50 men, aged 18 to 85 years) in the early recovery period of ischemic stroke were analyzed. Psychological testing included NIHSS, MMSE, Rankin scale, Rivermead mobility index, exercise tolerance test. Depending on the rehabilitation scheme, patients were divided into the main group (n=50), who received a verticalization course and cytoflavin (intravenously, drip 20.0 ml in 250.0 ml 5% glucose for 14 days). The control group (n=50) included patients who received standard treatment., Results and Conclusion: Inclusion of cytoflavin in the rehabilitation scheme for patients with ischemic stroke increased the effectiveness of treatment, which was manifested by a decrease in the severity of neurological disorders assessed with NIHSS by 17.6% in the main group versus 10.8% in the control group (p<0.05) and recovery of cognitive functions assessed with MMSE by 5.8% versus 1.6%, respectively (p<0.05). In addition, there was a positive dynamics in the restoration of blood pressure (by 37.1% in the main group versus 30.6% in the control group (p<0.05)).

Objective: To evaluate the effectiveness of preparing a wound for plastic closure of autoskin using a negative pressure apparatus and Reamberin., Material and Methods: . The results of preoperative preparation of 24 patients with chronic wounds of various etiologies were analyzed. Depending on the treatment regimen, the patients were divided into groups: the main one ( n =18), the patients of which were divided into subgroups: in IA ( n =9) they used NPWT therapy for 5 days, in IB ( n =9) it was combined with Reamberin infusions (1.5% intravenously at a rate of 40-60 drops/min, 500 ml, once a day for 5 days). Patients of the comparison group (II, n =6) received standard preparation. In the dynamics of therapy, a morpho-histological study of wound biopsies was carried out with the determination of the area of fibroblasts, the area of the nucleus of fibroblasts, the number of vessels and the determination of their diameter. After autodermoplasty, the survival of the skin flap was determined., Results: It was found that the combined use of NPWT therapy and Reamberin significantly increases the effectiveness of therapy: the greatest effect on fibroblastogenesis was exerted by the inclusion of NPWT therapy in the regimen - an increase of 1.5 times compared with the results of the traditional regimen. The vascularization of the wound surface (increase in the area and diameter of blood vessels) was best influenced by the combined preparation (NPWT-therapy and Reamberin) preparations - an increase of 3.4 times in comparison with the comparison group, which affected the dynamics of the survival of the skin flap: it was 1.3 times higher than in the comparison group ( p <0.01)., Conclusions: The results obtained, along with good tolerability of the drug, allows us to recommend the inclusion of Reamberin in the scheme of preoperative preparation of patients with this pathology.

Objective: To substantiate the advisability of using cytoflavin to correct postoperative cognitive dysfunction (POCD) in patients undergoing video laparoscopic cholecystectomy (VLCE) under conditions of inhalation anesthesia with sevoflurane., Material and Methods: The data of two representative groups of patients ( n =60) who underwent video-laparoscopic cholecystectomy under the conditions of inhalation anesthesia with sevoflurane were analyzed. At the stages of the perioperative period, in order to monitor the state of higher mental functions, neuropsychological testing was performed: anxiety and depression scales (HADS), the Montreal scale of cognitive dysfunction (MoCA), and frontal dysfunction batteries (FAB). Patients of the first group ( n =19) were not corrected for POKD. For the correction of cognitive impairment, patients of the second group ( n =41) were treated with Cytoflavin according to the 20 ml regimen per 250 ml of 0.9% sodium chloride solution intravenously once before the operation, then within 4 days of the postoperative period., Results: Neuropsychological testing in group I patients revealed the development of moderate POCD. The inclusion of Cytoflavin in the treatment regimen in the II group of patients contributed to an improvement in the state of HMF, accompanied by a decrease in the level of anxiety and depression., Conclusion: The inclusion of Cytoflavin in treatment regimens helps prevent the development of POKD and is accompanied by an improvement in the state of higher mental functions, which is manifested by a decrease in the level of anxiety and depression, favorably affecting the emotional background of patients.

Background: Vasospastic angina (VSA) is characterized by coronary spasm, which can be aggravated by vasoactive substances such as serotonin. Hypothesis Sarpogrelate, a selective serotonin receptor antagonist, and high-dose statin have some effects on the reduction of coronary spasm in patients with VSA., Methods: We recruited 100 patients with angiographically confirmed VSA, and randomly assigned them into four groups: sarpogrelate with high-dose statin (Group A, n = 25), sarpogrelate with low-dose or no statin (Group B, n = 25), placebo with high-dose statin (Group C, n = 25), and placebo with low-dose or no statin (Group D, n = 25). The primary endpoint was the remission of coronary spasm on 1-year follow-up provocation test., Results: The most common site of coronary spasm was left anterior descending artery (42%). Most patients (96%) took calcium channel blockers, and 46% were treated with vasodilators. Overall, 40% of patients reported no chest pain at 1 year, and 23% showed complete remission of coronary spasm on 1-year follow-up provocation test. No difference was observed in symptomatic and angiographically complete remission rate between the sarpogrelate and the placebo group. Although the apolipoprotein B level at the 1-year follow-up was significantly lower in the high-dose statin group, symptomatic and angiographic outcomes were not different according to statin intensity. Distal thrombolysis in myocardial infarction (TIMI) flow on initial provocation test was independently associated with angiographically complete remission., Conclusions: Sarpogrelate or high-dose statin did not significantly improve the angiographic remission rate in patients with VSA. Distal TIMI flow on initial provocation test could predict the complete remission of coronary spasm at follow-up., (© 2019 The Authors. Clinical Cardiology published by Wiley Periodicals, Inc.)

Objective: To determine if low molecular weight synthetic colloid fluids administered to dogs interfere with refractometric estimates of total plasma protein (TPPr) and urine osmolality (UOsm)., Study Design: Experimental study., Animals: Eighteen healthy Greyhound dogs., Methods: Anaesthetized Greyhounds subjected to haemorrhage for 60 minutes were given 80 mL kg -1 of Plasma-Lyte 148 (CRYST), or 20 mL kg -1 of hydroxyethyl starch 130/0.4 (HES) or succinylated gelatine (GELO) (n = 6 per group) intravenously over 20 minutes. Refractometric (TPPr) and biuret total plasma protein (TPPb) were measured before haemorrhage (Baseline), at end of shock (Shock), immediately (T20), then 40 minutes (T60), 100 minutes (T120) and 160 minutes (T180) after fluid administration. Urine specific gravity (USG) and UOsm were measured at all time points except T20. Estimated UOsm (eUOsm) was calculated from USG. Bias and limits of agreement (LOA) for TPPr versus TPPb, and eUOsm versus UOsm were calculated at each time point., Results: For dogs given CRYST and GELO, median TPPr and TPPb decreased in parallel, with a small consistent TPP bias (CRYST range of bias, 0.38-0.67 g dL -1 ; GELO range of bias, 0.42-0.58 g dL -1 ). Dogs given HES showed divergence between median TPPr and TPPb after T20, with a peak bias at T20 of 1.62 g dL -1 (LOA 1.29-1.95). Dogs given HES and GELO had markedly increased USG [HES peak median USG at T180 of 1.119 (Q1-Q3 1.103-1.122); GELO peak median USG at T120 of 1.114 (Q1-Q3 1.082-1.119)], with large increases in bias between eUOsm and UOsm [HES peak bias at T60 of 2995 mOsm kg -1 (LOA 2032-3958 mOsm kg -1 ); GELO peak bias at T120 of 2465 mOsm kg -1 (LOA 940-3990 mOsm kg -1 )]., Conclusions and Clinical Relevance: Administration of HES and GELO to dogs with haemorrhagic shock interferes with refractometric measurements for at least 3 hours after administration., (Copyright © 2019 Association of Veterinary Anaesthetists and American College of Veterinary Anesthesia and Analgesia. Published by Elsevier Ltd. All rights reserved.)

Sarpogrelate is widely used to treat peripheral vascular disorders. However, it has been demonstrated to have a poor pharmacokinetic (PK) profile and marked within-subject variability. Here, the bioequivalence of 2 formulations of sarpogrelate (100-mg tablets) was assessed by using the reference-scaled average bioequivalence (RSABE) method, and the PK parameters were quantified in healthy Chinese subjects under fasting (n = 38) and fed (n = 35) conditions. In this open and randomized 4-way replicate study, a single dose of sarpogrelate was administered followed by a 3-day washout period. The sarpogrelate concentration in blood samples was measured by liquid chromatography-tandem mass spectrometry within 6 hours (fasting) or 10 hours (fed) of drug administration, and the PK parameters were determined by a noncompartmental model. The bioequivalence of the 2 formulations under both conditions was assessed using the ratios of ln(peak concentration [C max ]) and ln(area under the concentration-time curve [AUC]) within the limits based on the RSABE method. The 90% CIs for the ratios of lnC max , lnAUC 0-t , and lnAUC 0-∞ were 0.8531-1.1100, 0.9616-1.0737, and 0.9550-1.0684, respectively, under fasting conditions and 0.8918-1.1076, 0.9818-1.0694, and 0.9818-1.0686, respectively, under fed conditions, which were within the RSABE acceptance limits. Food intake decreased the systemic exposure and the C max of sarpogrelate by 0.9-fold and 0.5-fold, respectively., (© 2018, The American College of Clinical Pharmacology.)

Objective: To investigate the association between synthetic colloids and biomarkers of acute kidney injury (AKI) in dogs with hemorrhagic shock., Design: Experimental interventional study., Setting: University., Animals: Twenty-four healthy ex-racing Greyhounds., Interventions: Anesthetized Greyhounds subjected to hemorrhage for 60 min were resuscitated with 20 mL/kg of fresh whole blood (FWB), 6% hydroxyethyl starch (HES) 130/0.4, 4% succinylated gelatin (GELO), or 80 mL/kg of isotonic crystalloid (CRYST) over 20 min (n = 6 per treatment). Concentrations of biomarkers of AKI were measured at baseline, end of hemorrhage, and at 40 (T60), 100 (T120), and 160 (T180) min after fluid bolus. Biomarkers included neutrophil gelatinase-associated lipocalin in urine and serum (uNGAL; sNGAL), and urine cystatin C (uCYSC), kidney injury molecule-1 (uKIM), clusterin (uCLUST), osteopontin, gamma-glutamyl transferase, monocyte chemoattractant protein-1 (uMCP), interleukin-6, interleukin-8, protein (uPROT), hyaluronan, and F 2 -isoprostanes. Renal histology was scored for tubular injury and microvesiculation. Biomarker fold-change from baseline was compared between groups using mixed effects models (Bonferroni-Holm corrected P<0.05). Frequencies of histology scores were compared by Fisher's exact test., Measurements and Main Results: In dogs treated with GELO, uNGAL fold-change was markedly greater compared with all other groups at T60, T120, and T180 (all P<0.001), and uCYSC was greater at T60 compared with CRYST (P<0.001), and at T120 and T180 compared with all other groups (all P<0.001). Smaller, albeit significant, between-group differences in uKIM, uCLUST, uMCP, and urine protein concentration were observed across the FWB, GELO, and HES groups, compared with CRYST. The GELO group more frequently had marked tubular microvesiculation than the other groups (P = 0.015) although tubular injury scores were comparable., Conclusion: In dogs with hemorrhagic shock, GELO was associated with greater magnitude increases in urine biomarkers of AKI and more frequent marked tubular microvesiculation, compared with FWB, CRYST, and HES., (© Veterinary Emergency and Critical Care Society 2019.)

Background: The intense efforts made during 3-week stage races may reduce iron metabolism and hematological parameters. These efforts may increase the levels of circulating muscle damage markers and some hormones. All of these physiological changes may have negative consequences not only for the performance of athletes but also for their health. The main aim of this study was to evaluate the effects of supplementation with 80 mg/day of iron on haematological parameters, serum cortisol and biochemical muscle indicators on elite male cyclists during the 3-week stage race the Vuelta a España . Our secondary aim was to examine whether the hematological profile is associated with muscular damage parameters and cortisol., Methods: Eighteen elite male cyclists from two teams were randomly assigned to one of two groups: (1) control group (CG, n = 9; age: 26.1 ± 4.6 years; maximum oxygen uptake per kg: 78.0 ± 5.4 mL/kg/min) or (2) group treated with 80 mg/day iron (800 mg of iron protein succinylate, ITG, n = 9; age: 25.7 ± 6.4 years; maximum oxygen uptake per kg: 77.6 ± 6.5 mL/kg/min). The cyclists were subjected to blood tests one week before the start of the race (T1) and after 4 weeks of treatment, coinciding with the end of the competition (T2). Iron metabolism parameters, muscle damage indicators and serum cortisol were assessed. Repeated-measures ANOVA with group as a factor (GC and ITG) were used to examine the differences between groups throughout the study (time × group) after iron supplementation treatment., Results: Significant differences were observed between groups throughout the study in the group-by-time interaction and changes in serum iron (GC: -8.93 ± 10.35% vs. ITG: 0.60 ± 8.64%; p = 0.018), ferritin (GC: -13.88 ± 23.53% vs. ITG: 91.08 ± 118.30%; p = 0.004), haemoglobin (GC: 10.00 ± 3.32% vs. ITG: 13.04 ± 5.64%; p < 0.001), haematocrit (GC: -1.17 ± 3.78% vs. ITG: 7.32 ± 3.92%; p < 0.001) and cortisol (GC: 24.74 ± 25.84% vs. ITG: ⁻13.54 ± 13.61%; p = 0.005). However, no significant group-by-time interaction was observed for the circulating muscle biomarkers. Additionally, significant negative correlations of serum iron, haemoglobin and haematocrit with muscle circulating biomarkers and cortisol ( p < 0.05) were observed., Conclusions: Oral iron supplementation with 80 mg/day iron (800 mg of iron protein succinylate) effectively prevented a decline in haematological parameters (serum iron, ferritin, haemoglobin and haematocrit) and maintained optimal levels of recovery in elite cyclists during the Vuelta a España . Moreover, the hematological values were shown to have relationship with muscular recovery parameters.

Aim: To assess the effect of the modified infusion therapy regimen on the frequency of development of laboratory and clinical manifestations of fat embolism syndrome in patients after hip replacement., Material and Methods: The study was conducted in 80 patients (70 men and 10 women) who were admitted for planned revision hip arthroplasty. The criteria for not inclusion in the study were the presence of a traumatic brain injury, episodes of acute disturbance of blood supply (stroke) and diabetes mellitus in history. 40 patients of the main group during the operation were administered Gelofuzin and Sterofundin isotonic, and in the first day after the operation Remaxol and Sterofundin isotonic. Using the copy-steam method, a control group (n=40) out of 197 patients was selected by gender and age. In the control group, infusion therapy was carried out using a 0.9% NaCl solution. All patients underwent assessment of fat globulemia, water-electrolyte balance, acid-base status and oxygenation index - before surgery; 2, 24, 48, and 72 hours after the operation, on the third day, mental disorders were assessed using the Addenburg scale (ACE-R) for evaluating cognitive functions., Results: All patients underwent hip joint endoprosthetics. In the group receiving the modified infusion therapy regimen, the results were significantly better, there were no statistically significant changes in the level of electrolytes (p=0.14), episodes of a decrease in the oxygenation index and cognitive dysfunction. In contrast to patients in the control group, where the level of chlorine and sodium was significantly higher, the number of fat globules with a diameter of more than 8 μm, as well as in two patients, the development of postoperative delirium with a decrease in the oxygenation index below 300 was observed. The causal relationship between the number of fat globules with a diameter of more than 8 microns and clinical manifestations of cerebral and pulmonary forms of fat embolism (r-Pirsen = -0.87 and -0.80, respectively). There were no statistically significant changes in platelet count, potassium concentration with indicators of fat globulemia and a scale of cognitive impairment., Conclusion: A high correlation of fatty globulemia with the development of respiratory and pulmonary dysfunction after hip replacement was determined. The inclusion of Gelofuzin, Sterofundin isotonic and Remaxol in intensive therapy provides a pronounced emulsifying effect on fat globules appearing in the bloodstream in the first hours after hip replacement, and effective prevention of potentially dangerous fat embolism.

Although salinomycin sodium (SS) has shown in-vitro potential to inhibit cancer stem cell growth and development, its low water solubility makes it a poor candidate as an oral chemotherapeutic agent. To improve the bioavailability of SS, SS was encapsulated here using D-α-tocopherol polyethylene glycol succinate (TPGS)-emulsified poly(lactic-co-glycolic acid) (PLGA) nanoparticles and compared with its parent SS in terms of absorption, pharmacokinetics, and efficacy in suppressing nasopharyngeal carcinomas stem cells. The pharmacokinetics of SS and salinomycin sodium-loaded D-α-tocopherol polyethylene glycol succinate-emulsified poly(lactic-co-glycolic acid) nanoparticles (SLN) prepared by nanoprecipitation were analyzed in-vivo by timed-interval blood sampling and oral administration of SS and SLN to rats. Sensitive liquid chromatography-mass spectrometry (LC-MS) was developed to quantify plasma drug concentrations. SS and SLN transport in Caco-2 cells was also investigated. The therapeutic efficacy of SS and SLN against cancer stem cells was determined by orally administering the drugs to mice bearing CNE1 and CNE2 nasopharyngeal carcinoma xenografts and then evaluating CD133 cell proportions and tumorsphere formation. The in-vivo trial with rats showed that the Cmax, AUC(0-t), and Tmax for orally administered SLN were all significantly higher than those for SS (P<0.05). These findings were corroborated by a Caco-2 cell Transwell assay showing that relative SLN absorption was greater than that of SS on the basis of their apparent permeability coefficients (Papp). Significantly, therapeutic SLN efficacy against nasopharyngeal carcinoma stem cells was superior to that of SS. TPGS-emulsified PLGA nanoparticles effectively increase SS solubility and bioavailability. SLN is, therefore, promising as an oral chemotherapeutic agent against cancer stem cells.

A clinical case of successful combined use of NPWT-therapy and Reamberin infusion in the treatment of a non-healing (over 5 months) trophic ulcer of the lower limb in an elderly patient is presented. It was manifested that introduction of antioxidant/antihypoxant drug reamberin on the background of NPWT-therapy in patient with slow healing wounds has a positive effect on metabolic processes, resulting in more active and rapid cleansing of wound surface from opportunistic microflora by the 5th day of therapy. Absence of adverse effects to drug application allows to recommend its inclusion in the complex treatment scheme in patients with this pathology.

Aim: To study the efficacy of reamberin in treatment of epilepsy in children and to evaluate its effect on the antioxidant status., Material and Methods: The antioxidant activity of reamberin was investigated in children with epilepsy: 16 patients received intravenous reamberin once daily for 5 days in addition to carbamazepine. Patients of the control group (n=15) received only carbamazepine. The efficacy of the drug was evaluated by the levels of lipid hydroperoxides, conjugated dienes, and malondialdehyde and by the activity of the main components of the antioxidant system (ceruloplasmin, vitamin E, catalase) in the blood of patients., Results and Conclusion: Reamberin significantly reduces the plasma levels of lipid hydroperoxides by 16%, conjugated dienes by 12%, and malondialdehyde by 25% compared with the patients of the control group. An analysis of the effect of succinate-containing drugs on the activity of the antioxidant system components has shown that blood concentrations of ceruloplasmin, vitamin E and catalase are by 35, 14% and 15%, respectively, higher than those in the control group. Thus, the addition of reamberin into the treatment of children with epilepsy should be considered pathogenetically justified, clinically reasonable, and promising.

Aim: To study the effectiveness of intraoperative administration of Cytoflavine for the prevention of ischemic brain injury during cerebral aneurysm (CA) clipping with temporary occlusion of the leading artery under general anesthesia., Material and Methods: The prospective cohort single-center study included 40 patients with CA ( the main group - 27 patients with intraoperative administration of cytoflavine; the comparison group -13 patients without use of cytoflavine), who underwent aneurism clipping with temporary occlusion of the afferent artery. We assesed the intraoperative state of the brain, the time of awakening and extubation of patients after surgery, neurological deficit and local ischemic changes in the area of surgery according to the CT of the brain in the early postoperative period, resuscitation bed-day and the relationship of these indicators with the duration of temporary occlusion of the afferent artery in the selected groups of patients., Results: In intergroup comparison, patients of the main group treated with intraoperative cytoflavin showed a reduction in the time of awakening (p=0.013) and the time of extubation (p=0.01) both with temporary occlusion of the afferent artery and in patients without temporary occlusion (p<0.05). The duration of resuscitation bed-day decreased in the main group of patients receiving intraoperatively cytoflavine (p=0.01), as well as in patients in the comparison group without temporary occlusion (p<0.05)., Conclusion: Temporary occlusion of the afferent artery with short intervals of vessel occlusion in combination with intraoperative intravenous administration of cytoflavine expands the tolerability to artery occlusion in patients operated in the 'cold' period, reduces the possibility of neurological deficit, reduces the recovery period and resuscitation bed-day after surgical clipping CA.

Objective: The purpose of the study is to determine the correlation of changes in the humoral and tissue components of the hemostasis system with lipid metabolism in case of various urgent surgical diseases, on the basis of which the systemic coagulopathic distress syndrome can be used as the scientific basis for the definition of a new syndrome., Material and Methods: The work includes the results of experimental and clinical laboratory tests. Experiments on dogs: in the first group (n=18) destructive pancreatitis; in the second (n=18) - fecal peritonitis; in the third (n=15), acute obstructive intestinal obstruction; in the fourth (n=16) fecal peritonitis, in the postoperative period, Remaxol (15 ml/kg) was included in the therapy. The analysis of 55 patients with acute peritonitis, operated on for acute appendicitis, perforated gastric or duodenal ulcer, acute intestinal obstruction, acute destructive cholecystitis. In the study group (n=28), Remaxol is included in the postoperative therapy. The state of the humoral and tissue (in the experiment, the tissues of the liver, intestines, kidneys, heart, lungs, pancreas, in the clinic - tissues of the resected organs) components of the hemostasis system was evaluated, a number of lipid metabolism indicators were determined, etc., Results: In the early periods of all investigated urgent diseases of the abdomen, pronounced changes in the system of both humoral and tissue components of the hemostasis system were revealed. The modification of the coagulation system is registered not only in the tissues of the lesion organs, but also in the target organs (system tissue hemocoagulation modifications). The research established one of the most important processes - the trigger of the hemostatic cascade reaction - is membrane-destabilizing (the source of tissue thromboplastin), which is determined by changes in the phospholipid composition of various organs tissues (involved in the pathological process or not in it). Changes in lipid metabolism are due to the activation of phospholipases and membrane lipid peroxidation in tissues. The factual material was the scientific basis for the establishment of a new syndrome. Systemic coagulopathic distress syndrome is a set of pathological processes of the body, the most important component of which is a violation of the phospholipid bilayer of blood cell membranes and organ cells due to oxidative and phospholipase induced phenomena, leading to a coagulopathic condition. It changes understanding of the prevention of thrombohemorrhagic complications, proving the effectiveness of complex therapy, including not only anticoagulants, but also drugs with membrane-stabilizing activity, in particular, Remaxol.

The aim of the study was to assess the impact of cytoflavin and bioflavin therapy on the dynamics of clinical and psychophysiological status of patients with Osteochondrosis. 150 patients with osteochondrosis of a backbone were investigated. The patients were divided into two groups using method of randomization: the main group - 75 patients - and control group -75 patients. All patients received a standard treatment (non-steroidal anti-inflammatory drugs, myorelaxants, chondroprotectors, as well as physiotherapy). The main group in addition to standard treatment received biofeedback therapy and cytoflavin. The results showed that cytoflavin and biofeedback therapy significantly enhanced the positive effect of standard treatment and significantly increased the quality of life of patients. It is recommended to treat elderly patients with neurological complications of spinal osteochondrosis with Cytoflavin in combination with biofeedback therapy Before prescribing biofeedback therapy and Cytoflavin it is necessary to take into account a number of positive and negative predictors of their effectiveness in reducing severity of pain syndrome.

Chicoric acid (CA) is an active derivative of caffeic acid, which is naturally present in many medicinal plants and vegetables. In the present study, the metabolic profile of CA was determined in rat plasma, urine and feces and was subsequently used to propose the metabolic pathways of CA. CA (100 mg/kg) was orally administered to rats by gastric intubation. Then, the plasma, urine and feces samples were collected and treated with methanol and acetonitrile (1:1, V/V) to precipitate the proteins. The pretreated samples were separated by ultra performance liquid chromatography (UPLC) equipped with an HSS T3 column (2.1 mm × 100 mm I.D., 1.7 μm) and with quadrupole time-of-flight mass spectrometry (Q-TOF-MS) as the detection method. A total of nineteen metabolites were detected and identified based on the characteristics of their deprotonated ions in the plasma, urine and feces samples. The results revealed that the metabolism of CA followed a number of known in-vivo mammalian biotransformation pathways including hydrolysis, reduction, methylation, sulfation, glucuronidation, acetylation, isomerization and deoxygenation., (Copyright © 2018. Published by Elsevier B.V.)

Metabolic regulation has been recognized as a powerful principle guiding immune responses. Inflammatory macrophages undergo extensive metabolic rewiring 1 marked by the production of substantial amounts of itaconate, which has recently been described as an immunoregulatory metabolite 2 . Itaconate and its membrane-permeable derivative dimethyl itaconate (DI) selectively inhibit a subset of cytokines 2 , including IL-6 and IL-12 but not TNF. The major effects of itaconate on cellular metabolism during macrophage activation have been attributed to the inhibition of succinate dehydrogenase 2,3 , yet this inhibition alone is not sufficient to account for the pronounced immunoregulatory effects observed in the case of DI. Furthermore, the regulatory pathway responsible for such selective effects of itaconate and DI on the inflammatory program has not been defined. Here we show that itaconate and DI induce electrophilic stress, react with glutathione and subsequently induce both Nrf2 (also known as NFE2L2)-dependent and -independent responses. We find that electrophilic stress can selectively regulate secondary, but not primary, transcriptional responses to toll-like receptor stimulation via inhibition of IκBζ protein induction. The regulation of IκBζ is independent of Nrf2, and we identify ATF3 as its key mediator. The inhibitory effect is conserved across species and cell types, and the in vivo administration of DI can ameliorate IL-17-IκBζ-driven skin pathology in a mouse model of psoriasis, highlighting the therapeutic potential of this regulatory pathway. Our results demonstrate that targeting the DI-IκBζ regulatory axis could be an important new strategy for the treatment of IL-17-IκBζ-mediated autoimmune diseases.

Objectives: Carbapenemases such as MBLs are spreading among Gram-negative bacterial pathogens. Infections due to these MDR bacteria constitute a major global health challenge. Therapeutic strategies against carbapenemase-producing bacteria include β-lactamase inhibitor combinations. [S,S]-ethylenediamine-N,N'-disuccinic acid (EDDS) is a chelator and potential inhibitor of MBLs. We investigated the activity of EDDS in combination with imipenem against MBL-producing bacteria in vitro as well as in vivo., Methods: The inhibitory activity of EDDS was analysed by means of a fluorescence-based assay using purified recombinant MBLs, i.e. NDM-1, VIM-1, SIM-1 and IMP-1. The in vitro activity of imipenem ± EDDS against mutants as well as clinical isolates expressing MBLs was evaluated by broth microdilution assay. The in vivo activity of imipenem ± EDDS was analysed in a Galleria mellonella infection model., Results: EDDS revealed potent MBL inhibitory activity against purified NDM-1, weaker activity against VIM-1 and SIM-1, and marginal activity against IMP-1. EDDS did not exhibit any intrinsic antibacterial activity, but enabled a concentration-dependent potentiation of imipenem against mutants as well as clinical isolates expressing various MBLs. The in vivo model showed a significantly better survival rate for imipenem + EDDS-treated G. mellonella larvae infected with NDM-1-producing Klebsiella pneumoniae compared with monotherapy with imipenem., Conclusions: The bacterial natural zincophore EDDS is a potent MBL inhibitor and in combination with imipenem overcomes MBL-mediated carbapenem resistance in vitro and in vivo., (© The Author 2017. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

The aim of the study was to evaluate the impact of various variants of multimodal anesthesia on the cognitive functions of elderly patients after surgical interventions on pelvic organs, the development of preventive measures for POCD., Material and Methods: A study was conducted in 76 elderly patients aged 62 to 84 years with an increased risk of developing POCD. Of these, 46 women and 30 men. Patients were divided into two groups, depending on the type of anesthesia. The 1st group consisted of 37 patients who had low-flow anesthesia with sevoflurane combined with epidural analgesia. 2 nd - 39 patients who had anticipated multimodal analgesia on the basis of systemic administration of lidocaine, sulphate magnesia, verapamil. In each group, patients are divided into subgroups - the main (O) and control (K). In the main subgroups anesthetics were supplemented with 20 ml. Cytoflavin, administered 20-25 minutes before the end of surgery and on the 1-3 days of the perioperative period. Cognitive functions were assessed by standardized scales: Mini Mental State Examination (MMSE), Montreal Cognitive Evaluation Scale (MoCA), Frontal Assessment Batteries (FAB). The level of anxiety and depression was determined by the hospital scale of anxiety and depression (HADS)., Results: At oncological patients of advanced age in 52.5% of cases there is a moderate degree of cognitive impairment. In the perioperative period, in the study groups, when using different variants of multimodal anesthesia, there is an equivalent transient decrease in cognitive functions by 12.5 and 12.8%. The use of cytoflavin can reduce the manifestation of POCD from 1-day perioperative period, improve the cognitive status of patients., Conclusion: In cancer patients of advanced age, cognitive impairment is observed, aggravated after surgical treatment, regardless of the variant of multimodal anesthesia. Protection by Cytoflavin allows to restore the cognitive functions of elderly cancer patients, reduce the manifestations of POCD.

The aim of the study was to study the effectiveness of pathogenetic correction of the metabolism with the inclusion of reamberin (1.5% sodium meglumine succinate solution) in patients with lesions of large segments of the lower limbs. In connection with the task, the efficiency pathogenetic correction of metabolism in 211 patients with diaphyseal hip and shin bones fractures had been analyzed. Patients were divided into the main and control groups. In the main group (86 patients), intravenous infusions of reamberin were administered intravenously at a rate of 1 ml/min at a rate of 10 ml/kg of body weight 1 time per day, a course of 10 days. Patients in the comparison group (125 patients) received an infusion therapy with isotonic solution. The parameters of functional activity and peripheral blood dates had been analyzed. The analysis showed that the use of antihypoxants in the perioperative period provides an earlier recovery of the physical component of quality of life in patients with lesions of large segments of the lower limbs that have undergone stably - functional osteosynthesis according to the principles of Damage control.

The limited possibilities of determining myocardial morphological changes in the clinic make it necessary to investigate the effects of intermittent hypobaric hypoxia in an experiment setting., Objective: To reveal the peculiarities of changes in the markers of myocardial remodeling in experimental hypobaric hypoxia., Material and Methods: The investigation was conducted on 26 mature male Wistar rats weighing 220-310 g, which were divided into 3 groups: 1) 6 intact animals; 2) 10 rats that were exposed to 30-day simulated hypobaric hypoxia without correction; 3) 10 rats that were given once-daily intraperitoneal injections of cytoflavin solution at a rate of 0.5 ml/100 g of body weight for 30 days before immersion in a hypobaric chamber., Results: The early stages of myocardial remodeling in hypobaric hypoxia were found to be characterized by structural re-systematization of the components of the normal ventricular wall, which was manifested by cardiomyocyte hypertrophy and ischemia; circulatory disorders; fibroblast proliferation that dramatically enhances the extracellular expression of protein matrix, which can lead to the formation of fibrous tissue and irreversible myocardial dysfunction. Elevated matrix metalloproteinase levels are evidence for collagen degradation and cardiac remodeling. In the authors' opinion, the cyto- and angioprotective effects of cytoflavin in rats treated with the latter used in combination therapy are associated with the composition of the drug, the active components of which have mutually potentiating effects, are inducers of the major metabolic pathways in the cells and are also activators of key energy-generating processes., Conclusion: Identification of the molecular mechanisms of myocardial remodeling is of great practical importance. This enables remodeling markers to be considered as a potential therapeutic target in the treatment of hypoxia-induced myocardial injury.

Aim: The aim of this research was to study the effects of complex therapy with Remaxol inclusion on laparotomy wound tissue reparative process in patients with obstructive jaundice in early postoperative period., Material and Methods: Clinical and laboratory studies were carried out in 55 patients undergoing surgery of the biliary tract, including 35 patients with mechanical jaundice of non-tumor origin and 17 of them received Remaxol (for 5 days daily intravenous infusions of 400 ml each) in the early postoperative period., Results: It has been proved that mechanical jaundice is a significant complication in the reparative process of laparotomy wound tissue structures. A significant decrease in the reparative potential of tissues can occur due to a local deterioration of the tissue metabolism of regenerating structures, and on the organism level - endogenous intoxication syndrome, hypoxia, oxidative stress, hypoalbuminemia., Conclusion: Remaxol is a drug with hepatoprotective, antioxidant and antihypoxant effects and its use in patients with obstructive jaundice makes it possible to correct disease pathogenetic impact on organic and organism level, which leads to optimization of reparative regeneration. A noticeable decrease in the early postoperative period of wound complications has been established as well as a significant reduction in days patients spent in the hospital.

The purpose of this study was to determine the effect on the effectiveness of the correction of enteric insufficiency syndrome in patients with urgent surgical pathology included in the scheme of complex therapy Remaxol. The results of complex therapy of 227 patients (98 people with common peritonitis and 129 patients with acute intestinal obstruction) were analyzed. 128 patients of the main group in the postoperative period were included in the therapy scheme Remaxol: intravenously drip in a daily dose of 400 ml at a rate of 40 drops per minute, a course of -5 days. Patients of the control group (99 people) received standard treatment. The study is devoted to the role of postoperative hepatoprotective therapy in the treatment of patients with urgent surgical pathology. The main attention is paid to the hepatoenteric link of the pathogenesis of polyorganism insufficiency. This approach gives hope for a reduction in the risk of abdominal sepsis and a reduction in mortality among patients with acute abdominal pathology. The study found that in patients with acute abdominal pathology, an increase in the severity of enteric insufficiency syndrome due to toxic aggression and bacterial translocation can lead to hepatic dysfunction. Consequently, the implementation of hepatoprotective therapy is a pathogenetic link in the complex treatment of urgent surgical patients. The obtained results allowed to draw a number of conclusions. In particular, it has been established that the use of hepatoprotective therapy in the complex medical treatment of patients with acute abdominal pathology makes it possible to stop hepatorenal syndrome by the 5th day, and the syndrome of enteric insufficiency by the 7th day. Earlier relief of hepatic dysfunction and enteral insufficiency syndrome due to hepatoprotective therapy allowed to reduce the incidence of infectious complications to 9.7%, to reduce the lethality to 9.4% and to shorten hospitalization from 17.29 to 1.734 to 12.14±1.385 bed/day.

Currently cocrystals are considered as an established approach for making crystalline solids with overall improved physico-chemical properties. However, some otherwise well behaving cocrystals undergo rapid dissociation during dissolution, with ultimate conversion to parent drug and thus apparent loss of improved solubility. The polymeric carriers are long known to manipulate this conversion during dissolution to parent crystalline drug, which may hinder or accelerate the dissolution process if used in a dosage form. The goal of this study was to deliver in vivo a more soluble carbamazepine-succinic acid (CBZ-SUC) cocrystal in suspension formulation utilizing Hydroxypropyl methyl cellulose (HPMC-AS) as a crystallization inhibitor and Polyvinyl carpolactam-polyvinyl acetate-polyethylene glycol graft copolymer ® as solubilizer. The concentration of these polymers were systemically varied during in vitro dissolution studies, while selected formulations from dissolution studies were tested in vivo. Pharmacokinetic studies (PK) in rabbits demonstrated that formulation F7-X (1% cocrystal, 1% HPMC-AS and 2% Polyvinyl carpolactam-polyvinyl acetatepolyethylene glycol graft co-polymer®) caused almost 6fold improvement in AUC0-72 (***P k 0.05) as well as much higher C max of 4.73μ.mL-1 to that of 1.07μ.mL-1 of unformulated 'neat' cocrystal given orally. When reference formulation of CBZ (F5-X) with similar composition to F7-X were given to rabbits, cocrystal formulation gave 1.37fold (***P k 0.05) bioavailability than CBZ reference formulation. C max of reference formulation observed was 3.9μmL-1.

The aim of this study is to assess the effects of hypervolemic infusion with different solutions on microcirculation perfusion during laparoscopic colorectal surgery.Thirty-six patients were randomly divided into Ringer lactate solution [RL] group, succinylated gelatin injection [Gel] group, and hypertonic saline hydroxyethyl starch 40 injection [HS] group. Hypervolemic infusion was performed during the induction period of general anesthesia. Arterial blood-gas parameters, noninvasive hemodynamics, gastric tonometry values, and central venous pressure (CVP) were compared at baseline (T1); the end of hypervolemic infusion (T2); 5 min (T3), 15 min (T4), 30 min (T5), and 60 min (T6) during pneumoperitoneum; 5 min (T7), 15 min (T8), and 25 min (T9) after pneumoperitoneum. Patients were also grouped by age for further comparisons.The hematocrit levels of all groups after T2 decreased. The gastric mucosal-arterial carbon dioxide partial pressure (Pg-aCO2) started to decrease after T2 and rebounded after T5. There was no difference in the gastric mucosal perfusion when compared between 3 groups. The blood Na of HS group increased significantly after T2, then gradually restored and returned to baseline by T8. The plasma bicarbonate (HCO3) levels of RL and Gel groups elevated from T2 to T7, after which they started to decrease, but this phenomenon was not significant in HS group. In both RL and Gel groups, blood pressure has a significant fluctuation in elder patients.Hypervolemic infusion of these solutions during the induction of anesthesia can improve gastric mucosal perfusion. HS can maintain a more stable hemodynamic effect when used with caution in patients with preoperative hypernatremia.

Cichoric acid (CA), extracted from edible plants and vegetables, is a potential natural nutraceutical, with antioxidant and hypoglycaemic biological functions. The objective of this study was to explore the potential underlying molecular mechanisms involved in normalizing diabetes-related changes in hyperglycaemia via pancreas apoptosis and muscle injury induced by multiple low-dose STZ (MLD-STZ) injection in response to dietary supplementation with CA. To induce the MLD-STZ diabetic mice, the C57BL/6J mice were intraperitoneally injected with STZ (50 mg/kg body weight) for consecutive five days. CA (60 mg/kg/d) was supplemented in drinking water for 4 weeks. Compared with control, CA inhibited pancreas apoptosis and adjusted islet function in diabetic mice, leading to an increase in insulin generation and secretion. Moreover, CA regulated mitochondrial biogenesis, glycogen synthesis, and inhibited inflammation via activating antioxidant responses, which contributes to the improvement in athletic ability and diabetic myopathy. In general, CA is a natural food-derived compound with the potential application for regulating glucose homeostasis and improving diabetes and its complications., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

The aim of this study was to determine the role remaxol in complex intensive therapy of various jorms gipoergosis dur- ing the perioperative period in patients with hepatopancreatoduodenal zone malignancies. The treatment of 48 patients was analyzed. Immediately prior to surgery, at random, patients were divided into primary (n = 26) and control group (n = 22). In the study group for compensation the energy deficient states and organ hypoxia in the pancreas and the liver during the intra- and postoperative periods remaxol was included in the infusion therapy, the introduction ofwhich had been began before the start of anesthesia. In the control group antihypoxants weren't used. Integral assessment of prognosis and severity on a scale SAPS II and APACHE II. Status of energy and the type of energy deficit was estimated by the transport of oxygen and the concentration of lactate. In order to determine the level of stress exposure and the for- mation of adaptive reactions examined quantitative and qualitative composition of the peripheral blood. The study was conducted prior to surgery, on the 2nd and 5th day perioperative period. Inclusion in the scheme of metabolic remaxol program in the perioperative period in patients with malignant diseases of hepatopancreatoduodenal zone promotes the reduction of different types ofgipoergosis, efficient delivery and oxygen consumption, the adequacy of tissue oxygenation and restoration of adaptive physiological reactions such as.

Following traumatic brain injury, complex cerebral energy perturbations occur. Correlating with unfavourable outcome, high brain extracellular lactate/pyruvate ratio suggests hypoxic metabolism and/or mitochondrial dysfunction. We investigated whether focal administration of succinate, a tricarboxylic acid cycle intermediate interacting directly with the mitochondrial electron transport chain, could improve cerebral metabolism. Microdialysis perfused disodium 2,3- 13 C 2 succinate (12 mmol/L) for 24 h into nine sedated traumatic brain injury patients' brains, with simultaneous microdialysate collection for ISCUS analysis of energy metabolism biomarkers (nine patients) and nuclear magnetic resonance of 13 C-labelled metabolites (six patients). Metabolites 2,3- 13 C 2 malate and 2,3- 13 C 2 glutamine indicated tricarboxylic acid cycle metabolism, and 2,3- 13 C 2 lactate suggested tricarboxylic acid cycle spinout of pyruvate (by malic enzyme or phosphoenolpyruvate carboxykinase and pyruvate kinase), then lactate dehydrogenase-mediated conversion to lactate. Versus baseline, succinate perfusion significantly decreased lactate/pyruvate ratio (p = 0.015), mean difference -12%, due to increased pyruvate concentration (+17%); lactate changed little (-3%); concentrations decreased for glutamate (-43%) (p = 0.018) and glucose (-15%) (p = 0.038). Lower lactate/pyruvate ratio suggests better redox status: cytosolic NADH recycled to NAD + by mitochondrial shuttles (malate-aspartate and/or glycerol 3-phosphate), diminishing lactate dehydrogenase-mediated pyruvate-to-lactate conversion, and lowering glutamate. Glucose decrease suggests improved utilisation. Direct tricarboxylic acid cycle supplementation with 2,3- 13 C 2 succinate improved human traumatic brain injury brain chemistry, indicated by biomarkers and 13 C-labelling patterns in metabolites.

Mastocytosis comprises a heterogeneous group of disorders characterized by mast cell accumulation and proliferation in distinct organs. Kounis syndrome is defined as the concurrence of acute coronary syndromes with mast cell activation in a setting of allergic or hypersensitivity reactions. This is the first reported case of an intraoperative Kounis syndrome as the onset of an indolent systemic mastocytosis probably triggered by succinylated gelatin infusion during general anesthesia. The presentation of this case is intended to contribute to the knowledge of mastocytosis and Kounis syndrome at the time of diagnostic workup during intraoperative anaphylaxis or myocardial ischemia.

Inflammation plays a central role in the processes associated with neurodegeneration. The inflammatory response is mediated by activated microglia that release inflammatory mediators to the neuronal environment. Microglia-derived lysosomal cathepsins, including cathepsin X, are increasingly recognized as important mediators of the inflammation involved in lipopolysaccharide (LPS)-induced neuroinflammation. The current study was undertaken to investigate the role of cathepsin X and its molecular target, γ-enolase, in neuroinflammation and to elucidate the underlying mechanism. We determined that the exposure of activated BV2 and EOC 13.31 cells to LPS led to increased levels of cathepsin X protein and activity in the culture supernatants in a concentration- and time-dependent manner. In contrast, LPS stimulation of these two cells reduced the release of active γ-enolase in a manner regulated by the cathepsin X activity. Cathepsin X inhibitor AMS36 significantly reduced LPS-induced production of nitric oxide, reactive oxygen species and the pro-inflammatory cytokines interleukin-6 and tumor necrosis factor-α from BV2 cells. Inhibition of cathepsin X suppressed microglial activation through the reduced caspase-3 activity, together with diminished microglial cell death and apoptosis, and also through inhibition of the activity of the mitogen-activated protein kinases. Further, SH-SY5Y treatment with culture supernatants of activated microglial cells showed that cathepsin X inhibition reduces microglia-mediated neurotoxicity. These results indicate that up-regulated expression and increased release and activity of microglial cathepsin X leads to microglia activation-mediated neurodegeneration. Cathepsin X inhibitor caused neuroprotection via its inhibition of the activation of microglia. Cathepsin X could thus be a potential therapeutic target for neuroinflammatory disorders., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Aim: To improve the quality of anesthesia in school-age children by using intraoperative metabolic-mediated cerebroprotection to reduce the incidence of cognitive impairment after total intravenous anesthesia based on propofol., Material and Methods: A randomized, prospective, longitudinal clinical study was conducted, involving 60 school-age children operated under total intravenous anesthesia on the basis of propofol. Children were randomized into two equal groups. Patients of the 1st group did not receive intraoperative metabolic-mediated cerebroprotection, patients of the 2nd group were treated with cytoflavin. For Z-assessment of changes in cognitive potential, neuropsychological testing of 30 children of the same age who were not subjected to surgical intervention was performed., Results and Conclusion: On the 1st day of the postoperative period, 13.79% of patients of the 1st group had postoperative cognitive dysfunction (POCD), on the 7th day, POCD was observed in 26.67% of children. In the 2nd group, POCD was detected in 6.67% and 3.33% of patients on the 1st and 7th day, respectively (p=0,009). The results confirm the efficacy of cytoflavin in intraoperative prevention of POCD in school-age children.

5-Hydroxytryptamine (5-HT) modulates the cardiac parasympathetic neurotransmission, inhibiting the bradyarrhythmia by 5-HT2 receptor activation. We aimed to determine whether the chronic selective 5-HT2 blockade (sarpogrelate) could modify the serotonergic modulation on vagal cardiac outflow in pithed rat. Bradycardic responses in rats treated with sarpogrelate (30 mg·kg·d; orally) were obtained by electrical stimulation of the vagal fibers (3, 6, and 9 Hz) or intravenous (IV) injections of acetylcholine (1, 5, and 10 μg/kg). 5-HT7 receptor expression was quantified by Western blot in vagus nerve and right atrium. The IV administration of 5-HT (10-200 μg/kg) dose dependently decreased the vagally induced bradycardia, and agonists 5-CT (5-HT1/7), 8-OH-DPAT (5-HT1A), or AS-19 (5-HT7) (50 μg/kg each) mimicked the 5-HT-induced inhibitory effect. Neither agonists CGS-12066B (5-HT1B), L-694,247 (5-HT1D), nor 1-phenylbiguanide (5-HT3) modified the electrically-induced bradycardic responses. Moreover, SB-258719 (5-HT7 antagonist) abolished the 5-HT-, 5-CT-, 8-OH-DPAT-, and AS-19-induced bradycardia inhibition; 5-HT or AS-19 did not modify the bradycardia induced by IV acetylcholine; and 5-HT7 receptor was expressed in both the vagus nerve and the right atrium. Our outcomes suggest that blocking chronically 5-HT2 receptors modifies the serotonergic influence on cardiac vagal neurotransmission exhibiting 5-HT as an exclusively inhibitory agent via prejunctional 5-HT7 receptor.

A case of polyorganic insufficiency syndrome associated with coma, convulsive disorder, acute hepato-renal and respiratory dysfunction, hypovolemic shock, and hyperthermal syndrome in a 46 year-old participant ofa marathon competition is reported. The clinical picture was dominated by acute hepatic insufficiency treated with remaxol to activate substrate phosphorylation under effect of exogenous succinate for slowing down the development of energy deficit in mitochondria under condition of oxygen deficit. This case can be regarded as a variant of correction of mitochondrial dysfunction with the use of a mitochondria-targeted medication such as succinate-containing remaxol. This medication reduced AST and ALT activities and utilization of endogenous enzymes for succinate synthesis from alanine and aspartate under hypoxic conditions. Prescription of remaxol as a form of direct substitution therapy was dictated by pathogenetic considerations.

Aim: To compare the efficacy of cytoflavin in doses of 10 and 20 ml/day in the complex pharmacological therapy of patients with acute ischemic stroke., Material and Methods: Eighty-six patients, aged from 43 to 85 years, were examined. Patient's status was assessed using the NIHSS, the Rankin scale, the Barthel index and the Rivermead mobility index. Patients were stratified into 3 groups: patients of group 1 received standard treatment, patients of group 2 received cytoflavin in dose of 10 ml/day in addition to standard treatment and patients of group 3 were treated with cytoflavin in dose of 20 ml/day in addition to standard treatment., Results and Conclusion: Cytoflavin in doses of 10 and 20 ml/day significantly promotes the regression of neurological deficit, improves day-to-day activity, and therefore, improves functional independence in daily life. The dose-dependent effect of the drug was shown. The use of cytoflavin in dose of 20 ml/day resulted in the more rapid regress of neurological symptoms during inpatient treatment and higher indices of daily activities and functional independence of patients that was important for the further rehabilitation.

Aim: Studying influence of remaxol on reparative process of tissue reparation in a laparotomy wound., Material and Methods: 90 patients with the acute appendicitis complicated by local peritonitis in the early postoperative period are examined. 50 patients received traditional therapy. Therapy of other 40 patients included Remaxol (intravenous introduction, daily within 5 days, of 400 ml)., Results and Conclusion: It is established that Remaxol optimizes the course of reparative process in laparotomy wound that was confirmed with data of tenziomety and wound exudate cytological research. Efficiency of a Remaxol is based on its capability to improve microcirculation, antiedematous action and its capability to reduce excessive intensity peroxide oxidation of membrane lipids, phospholipase activity and the phenomena of a hypoxia.