Focally administered succinate improves cerebral metabolism in traumatic brain injury patients with mitochondrial dysfunction.

Following traumatic brain injury (TBI), raised cerebral lactate/pyruvate ratio (LPR) reflects impaired energy metabolism. Raised LPR correlates with poor outcome and mortality following TBI. We prospectively recruited patients with TBI requiring neurocritical care and multimodal monitoring, and utilised a tiered management protocol targeting LPR. We identified patients with persistent raised LPR despite adequate cerebral glucose and oxygen provision, which we clinically classified as cerebral 'mitochondrial dysfunction' (MD). In patients with TBI and MD, we administered disodium 2,3-13C2 succinate (12 mmol/L) by retrodialysis into the monitored region of the brain. We recovered 13C-labelled metabolites by microdialysis and utilised nuclear magnetic resonance spectroscopy (NMR) for identification and quantification.Of 33 patients with complete monitoring, 73% had MD at some point during monitoring. In 5 patients with multimodality-defined MD, succinate administration resulted in reduced LPR(-12%) and raised brain glucose(+17%). NMR of microdialysates demonstrated that the exogenous 13C-labelled succinate was metabolised intracellularly via the tricarboxylic acid cycle. By targeting LPR using a tiered clinical algorithm incorporating intracranial pressure, brain tissue oxygenation and microdialysis parameters, we identified MD in TBI patients requiring neurointensive care. In these, focal succinate administration improved energy metabolism, evidenced by reduction in LPR. Succinate merits further investigation for TBI therapy.

Dietary succinate supplementation to maternal mice improves fetal brown adipose tissue development and thermogenesis of female offspring.

Succinic acid widely exists in foods and is used as a food additive. Succinate not only serves as an energy substrate, but also induces protein succinylation. Histone succinylation activates gene transcription. The brown adipose tissue (BAT) is critical for prevention of obesity and metabolic dysfunction, and the fetal stage is pivotal for BAT development. Up to now, the role of maternal succinate supplementation on fetal BAT development and offspring BAT function remains unexamined. To test, female C57BL/6J mice (2-month-old) were separated into 2 groups, received with or without 0.5% succinic acid in drinking water during gestation and lactation. After weaning, female offspring were challenged with high fat diet (HFD) for 12 weeks. Newborn, female weanling, and HFD female offspring mice were analyzed. For neonatal and weaning mice, the BAT weight relative to the whole body weight was significantly increased in the succinate group. The expression of PGC-1α, a key transcription co-activator promoting mitochondrial biogenesis, was elevated in BAT of female neonatal and offspring born to succinate-fed dams. Consistently, maternal succinate supplementation enhanced thermogenesis and the expression of thermogenic genes in offspring BAT. Additionally, maternal succinate supplementation protected female offspring against HFD-induced obesity. Furthermore, in C3H10T1/2 cells, succinate supplementation promoted PGC-1α expression and brown adipogenesis. Mechanistically, succinate supplementation increased permissive histone succinylation and H3K4me3 modification in the Ppargc1a promoter, which correlated with the higher expression of Ppargc1a. In conclusion, maternal succinate supplementation during pregnancy and lactation enhanced fetal BAT development and offspring BAT thermogenesis, which prevented HFD-induced obesity and metabolism dysfunction in offspring.

Succinate Injection Rescues Vasculature and Improves Functional Recovery Following Acute Peripheral Ischemia in Rodents: A Multimodal Imaging Study.

Succinate influences angiogenesis and neovascularization via a hormonelike effect on G-protein-coupled receptor 91 (GPR91). This effect has been demonstrated in the pathophysiology of diabetic retinopathy and rheumatoid arthritis. To evaluate whether succinate can play a role in acute peripheral ischemia, a preclinical study was conducted with ischemic mice treated with succinate or PBS and evaluated by imaging. Acute ischemia was followed by an increased in GPR91 expression in the ischemic muscle. As assessed with LASER-Doppler, succinate treatment resulted in an earlier and more intense reperfusion of the ischemic hindlimb compared to the control group (* p = 0.0189). A microPET study using a radiolabeled integrin ligand ([68Ga]Ga-RGD2) showed an earlier angiogenic activation in the succinate arm compared to control mice (* p = 0.020) with a prolonged effect. Additionally, clinical recovery following ischemia was better in the succinate group. In conclusion, succinate injection promotes earlier angiogenesis after ischemia, resulting in a more effective revascularization and subsequently a better functional recovery.

Ex vivo use of cell-permeable succinate prodrug attenuates mitochondrial dysfunction in blood cells obtained from carbon monoxide-poisoned individuals.

The purpose of this study was to evaluate a new pharmacological strategy using a first-generation succinate prodrug, NV118, in peripheral blood mononuclear cells (PBMCs) obtained from subjects with carbon monoxide (CO) poisoning and healthy controls. We obtained human blood cells from subjects with CO poisoning and healthy control subjects. Intact PBMCs from subjects in the CO and Control group were analyzed with high-resolution respirometry measured in pmol O2 per second per 10-6 PBMCs. In addition to obtaining baseline respiration, NV118 (100 µM) was injected, and the same parameters of respiration were obtained for comparison in PBMCs. We measured mitochondrial dynamics with microscopy with the same conditions. We enrolled 37 patients (17 in the CO group and 20 in the Control group for comparison) in the study. PMBCs obtained from subjects in the CO group had overall significantly lower respiration compared with the Control group (P < 0.0001). There was a significant increase in respiration with NV118, specifically with an increase in maximum respiration and respiration from complex II and complex IV (P < 0.0001). The mitochondria in PBMCs demonstrated an overall increase in net movement compared with the Control group. Our results of this study suggest that the therapeutic compound, NV118, increases respiration at complex II and IV as well as restoration of mitochondrial movement in PBMCs obtained from subjects with CO poisoning. Mitochondrial-directed therapy offers a potential future strategy with further exploration in vivo.

RNA-seq revealed the signatures of immunity and metabolism in the Litopenaeus vannamei intestine in response to dietary succinate.

The intestine is important for nutrition, metabolism and immunity. Succinate (SA) plays a vital role in the physiological homeostasis of animal intestines. However, the effects of dietary SA on the intestinal immunity and metabolism in shrimp are not clear. In this study, we investigated the immune and metabolic responses in the intestine of Litopenaeus vannamei that were fed diets consisting of different levels of SA: 0 g/kg (Con) and 10 g/kg (SA) for 56 days. The results from a RNA-seq analysis identified 6005 differentially expressed genes (DEGs), including 2728 upregulated genes and 3277 downregulated genes, which were grouped into 312 pathways. The DEGs were most enriched in pathways related to protein synthesis and amino acid metabolism, including "ribosome", "aminoacyl-tRNA biosynthesis", "pyrimidine metabolism", and "arginine and proline metabolism"; additionally, carbohydrate and lipid metabolism pathways were also activated. A large number of immune-related genes were associated with mucus barrier modification, antimicrobial activity, pathogen attachment and recognition, antioxidant activity, and apoptosis. The expression patterns of several candidate genes involved in the immune response and nutrition metabolism were detected by qPCR. This study provides insight into the transcriptomic modulating mechanisms associated with intestinal immunity and the metabolism of L. vannamei in response to the intake of dietary SA.

Parenteral Succinate Reduces Systemic ROS Production in Septic Rats, but It Does Not Reduce Creatinine Levels.

In sepsis, reactive oxygen species (ROS) production is increased. This process takes place mainly within the electron transport chain. ROS production is part of the pathophysiology of multiple organ failure in sepsis. Succinate yields Dihydroflavine-Adenine Dinucleotide (FADH2), which enters the chain through complex II, avoiding complex I, through which electrons are lost. The aim of this work is to determine if parenteral succinate reduces systemic ROS production and improves kidney function. Rats with cecal ligation and puncture were used as model of sepsis, and 4 groups were made: Control group; Succinate group, which only received parenteral succinate; Sepsis group; and Sepsis which received parenteral succinate. Systemic ROS are measured 24 hours after the procedure. Rats subjected to cecal puncture treated with succinate had less systemic ROS than Septic untreated rats (p = 0.007), while there were no differences in creatinine levels (p = 0.07). There was no correlation between creatinine and systemic ROS levels (p = 0.3). We concluded that parenteral succinate reduces ROS levels, but it does not reduce creatinine levels. Since there is no correlation between both levels, the processes would not be related.

The effect of succinate on brain NADH/NAD+ redox state and high energy phosphate metabolism in acute traumatic brain injury.

A key pathophysiological process and therapeutic target in the critical early post-injury period of traumatic brain injury (TBI) is cell mitochondrial dysfunction; characterised by elevation of brain lactate/pyruvate (L/P) ratio in the absence of hypoxia. We previously showed that succinate can improve brain extracellular chemistry in acute TBI, but it was not clear if this translates to a change in downstream energy metabolism. We studied the effect of microdialysis-delivered succinate on brain energy state (phosphocreatine/ATP ratio (PCr/ATP)) with 31P MRS at 3T, and tissue NADH/NAD+ redox state using microdialysis (L/P ratio) in eight patients with acute major TBI (mean 7 days). Succinate perfusion was associated with increased extracellular pyruvate (+26%, p < 0.0001) and decreased L/P ratio (-13%, p < 0.0001) in patients overall (baseline-vs-supplementation over time), but no clear-cut change in 31P MRS PCr/ATP existed in our cohort (p > 0.4, supplemented-voxel-vs-contralateral voxel). However, the percentage decrease in L/P ratio for each patient following succinate perfusion correlated significantly with their percentage increase in PCr/ATP ratio (Spearman's rank correlation, r = -0.86, p = 0.024). Our findings support the interpretation that L/P ratio is linked to brain energy state, and that succinate may support brain energy metabolism in select TBI patients suffering from mitochondrial dysfunction.

Activation of intestinal tuft cell-expressed Sucnr1 triggers type 2 immunity in the mouse small intestine.

The hallmark features of type 2 mucosal immunity include intestinal tuft and goblet cell expansion initiated by tuft cell activation. How infectious agents that induce type 2 mucosal immunity are detected by tuft cells is unknown. Published microarray analysis suggested that succinate receptor 1 (Sucnr1) is specifically expressed in tuft cells. Thus, we hypothesized that the succinate-Sucnr1 axis may be utilized by tuft cells to detect certain infectious agents. Here we confirmed that Sucnr1 is specifically expressed in intestinal tuft cells but not in other types of intestinal epithelial cells, and demonstrated that dietary succinate induces tuft and goblet cell hyperplasia via Sucnr1 and the tuft cell-expressed chemosensory signaling elements gustducin and Trpm5. Conventional mice with a genetic Sucnr1 deficiency (Sucnr1-/-) showed diminished immune responses to treatment with polyethylene glycol and streptomycin, which are known to enhance microbiota-derived succinate, but responded normally to inoculation with the parasitic worm Nippostrongylus brasiliensis that also produces succinate. Thus, Sucnr1 is required for microbiota-induced but not for a generalized worm-induced type 2 immunity.

Cation instructed steroidal prodrug supramolecular hydrogel.

In the present study, we propose an ionic coordination strategy for the design of a steroidal prodrug supramolecular hydrogel. The hydrogel composed of nanofibril networks formed spontaneously by the introduction of divalent cations (e.g., Mg2+, Ca2+, Zn2+ and Fe2+) and NH4+ to a succinated dexamethasone (Dex-SA) aqueous solution at room temperature. The formation of the nanofibril structure was dominantly driven by the ionic coordination with the assistance of a delicate balance of multiple noncovalent interactions. A rheological analysis indicated that the formed Ca2+/Dex-SA supramolecular hydrogel exhibits dominant elastic and thixotropic properties. The formed Ca2+/Dex-SA supramolecular hydrogel allowed the gradual release of Dex and Dex-SA in vitro, and the drug release behaviour can be finely tuned by changing the Ca2+ concentration. Storage stability studies showed that Dex-SA in hydrogel underwent an apparent chemical decomposition at 4 °C and 37 °C. In contrast, the Dex-SA xerogel was quite stable without any obvious chemical decomposition of Dex-SA in storage at -20 °C for 35 days, and it was able to turn into a hydrogel again within one minute after rehydration. The formed Ca2+/Dex-SA supramolecular hydrogel caused negligible cytotoxicity against HCEC and L-929 cells at drug concentrations up to 2 mM, as indicated by the in vitro cytotoxicity tests. Additionally, the proposed Ca2+/Dex-SA supramolecular hydrogel displayed a comparable anti-inflammatory efficacy with Dexp via the downregulation of NO, TNF-α and IL-6 expression in lipopolysaccharide (LPS)-activated RAW264.7 macrophage. Overall, the cation instructed steroidal prodrug supramolecular hydrogel might be a promising ophthalmic drug delivery system for anti-inflammatory therapy.

Glycosylation-enhanced biocompatibility of the supramolecular hydrogel of an anti-inflammatory drug for topical suppression of inflammation.

Intravitreal/periocular injection of triamcinolone acetonide (TA) suspension is a common uveitis treatment, but it displays a high risk for serious side effects (e.g., high intraocular pressure, retinal toxicity). We report here an intravitreally injectable thermosensitive glycosylated TA (TA-SA-Glu) hydrogel, formed by covalently conjugating glucosamine (Glu) with succinate TA (TA-SA), for treating uveitis. The TA-SA-Glu hydrogelator forms a supramolecular hydrogel spontaneously in aqueous solution with a minimal gelation concentration of 0.25 wt%. Structural analysis revealed that hydrogen bonds assisted by hydrophobic interaction resulted in self-assembled nanofibers. Rheology analysis demonstrated that this TA-SA-Glu hydrogel exhibited a typical thixotropic property. Sustained release of both TA-SA-Glu and TA from the hydrogel occurred throughout the 3-day in vitro release study. The obtained TA-SA-Glu hardly caused cytotoxicity against ARPE-19 and RAW264.7 cells after 24 h of incubation at drug concentration up to 600 µM. In particular, TA-SA-Glu exhibited a comparable anti-inflammatory efficacy to TA in terms of inhibiting the production of nitric oxide, tumor necrosis factor-α, and interleukin-6 in activated RAW264.7 macrophages. Following a single intravitreal injection, 69 nmol TA-SA-Glu hydrogel caused minimal apparent retinal toxicity, whereas the TA suspension displayed significant effects in terms of localized retinal toxicity. A single intravitreal injection of TA-SA-Glu hydrogel was more effective in controlling inflammatory response than that of the TA suspension treatment, particularly in down-regulating the pro-inflammatory Th1 and Th17 effector responses for treating experimental autoimmune uveitis. This study strongly indicates that supramolecular TA-SA-Glu hydrogels may represent a new option for posterior uveitis management. STATEMENT OF SIGNIFICANCE: Intravitreal/periocular injection of triamcinolone acetonide (TA) suspension is a common uveitis treatment, but suffers a high risk for serious side effects (e.g., high intraocular pressure, retinal toxicity). We generated an injectable glycosylated triamcinolone acetonide hydrogelator (TA-SA-Glu) hydrogel for treating uveitis. Following a single intravitreal injection, the proposed TA-SA-Glu hydrogel hardly caused apparent retinal toxicity at a dosage of 69 nmol per eye. Furthermore, TA-SA-Glu hydrogel was more effective in controlling non-infectious uveitis over than a TA suspension, particularly in terms of down-regulating the pro-inflammatory Th1 and Th17 effector responses for treating experimental autoimmune uveitis (EAU). This study strongly indicates that TA-SA-Glu supramolecular hydrogels may represent a new option for the management of various intraocular inflammations.

Dietary effects of succinic acid on the growth, digestive enzymes, immune response and resistance to ammonia stress of Litopenaeus vannamei.

Organic acids acts as an growth promoter and antimicrobial agent in aquaculture. The present study investigated the effects of a natural organic acid - succinic acid (SA) on the growth, digestive enzymes, immune response and resistance to ammonia stress of Litopenaeus vannamei. The shrimps were firstly fed with diets containing different levels of SA: 0% (Control), 0.25% (SA1), 0.50% (SA2), and 1.0% (SA3) (w/w) for 56 days, followed by an acute ammonia stress for 48 h. The results indicated that dietary of SA improved the growth of shrimp, and increased the survival rate of shrimp after ammonia stress for 48 h. The amylase, lipase and pepsin activity increased in hepatopancreas in three SA group, while trypsin activity was only increased in the SA1 and SA2 groups. At 56 d, T-NOS activity, proPO and HSP70 gene expression level increased in the three SA group, PO activity increased in the SA1 and SA2 groups, T-AOC content and Toll gene expression level increased in the SA2 and SA3 groups, Trx and SOD gene expression level increased in the SA2 group, while Imd, GS and GDH gene expression level was no changes. After exposure to ammonia stress for 48 h, immune biochemical parameters (T-AOC and PO) and genes (proPO, HSP70, Trx and GDH) expression level increased in the three SA group, T-NOS activity, Toll, Imd and GS gene expression level increased in the SA2 and SA3 groups, while SOD gene expression level increased in the SA1 and SA2 groups. These results indicated that SA improved growth, enhanced digestive and immune capacities of L. vannamei against ammonia stress, and may be a potential feed additive for shrimp. The optimal dietary supplementation dosage is 0.50% (w/w) in diet.

Short-term succinic acid treatment mitigates cerebellar mitochondrial OXPHOS dysfunction, neurodegeneration and ataxia in a Purkinje-specific spinocerebellar ataxia type 1 (SCA1) mouse model.

Mitochondrial dysfunction plays a significant role in neurodegenerative disease including ataxias and other movement disorders, particularly those marked by progressive degeneration in the cerebellum. In this study, we investigate the role of mitochondrial oxidative phosphorylation (OXPHOS) deficits in cerebellar tissue of a Purkinje cell-driven spinocerebellar ataxia type 1 (SCA1) mouse. Using RNA sequencing transcriptomics, OXPHOS complex assembly analysis and oxygen consumption assays, we report that in the presence of mutant polyglutamine-expanded ataxin-1, SCA1 mice display deficits in cerebellar OXPHOS complex I (NADH-coenzyme Q oxidoreductase). Complex I genes are upregulated at the time of symptom onset and upregulation persists into late stage disease; yet, functional assembly of complex I macromolecules are diminished and oxygen respiration through complex I is reduced. Acute treatment of postsymptomatic SCA1 mice with succinic acid, a complex II (succinate dehydrogenase) electron donor to bypass complex I dysfunction, ameliorated cerebellar OXPHOS dysfunction, reduced cerebellar pathology and improved motor behavior. Thus, exploration of mitochondrial dysfunction and its role in neurodegenerative ataxias, and warrants further investigation.

Dual 7-ethyl-10-hydroxycamptothecin conjugated phospholipid prodrug assembled liposomes with in vitro anticancer effects.

7-Ethyl-10-hydroxycamptothecin (SN38), as a highly active topoisomerase I inhibitor, is 200-2000-fold more cytotoxic than irinotecan (CPT-11) commercially available as Camptosar®. However, poor solubility and low stability extensively restricted its clinical utility. In this report, dual SN38 phospholipid conjugate (Di-SN38-PC) prodrug based liposomes were developed in order to compact these drawbacks. Di-SN38-PC prodrug was first synthesized by inhomogeneous conjugation of two SN38-20-O-succinic acid molecules with L-α-glycerophosphorylcholine (GPC). The assembly of the prodrug was carried out without any excipient by using thin film method. Dynamic light scattering (DLS), transmission electron microscope (TEM) and cryogenic transmission electron microscopy (cyro-TEM) characterization indicated that Di-SN38-PC can form spherical liposomes with narrow particle size (<200nm) and negatively charged surface (-21.6±3.5mV). The loading efficiency of SN38 is 65.2 wt.% after a simple calculation. In vitro release test was further performed in detail. The results demonstrated that Di-SN38-PC liposomes were stable in neutral environment but degraded in a weakly acidic condition thereby released parent drug SN38 effectively. Cellular uptake studies reflected that the liposomes could be internalized into cells more significantly than SN38. In vitro antitumor activities were finally evaluated by MTT assay, colony formation assay, flow cytometry, RT-PCR analysis and Western Blot. The results showed that Di-SN38-PC liposomes had a comparable cytotoxicity with SN38 against MCF-7 and HBL-100, and a selective promotion of apoptosis of tumor cells. Furthermore, a pharmacokinetics test showed that Di-SN38-PC liposomes had a longer circulating time in blood compared with the parent drug. All the results indicate that Di-SN38-PC liposomes are an effective delivery system of SN38.

Treatment of climacteric symptoms with an ammonium succinate-based dietary supplement: a randomized, double-blind, placebo-controlled trial.

Peri- and postmenopausal women commonly suffer from climacteric symptoms. We evaluated the effectiveness and safety of dietary supplement Amberen to relieve vasomotor and psychosomatic symptoms during the course of a 3-month, randomized, double-blind, placebo-controlled study. General clinical assessment, evaluation using the Greene climacteric test and Spielberger-Hanin test, determination of plasma levels of gonadotropins, estradiol, leptin and apolipoproteins were used to evaluate 42-60-year-old women with vasomotor and psychosomatic menopausal symptoms. One hundred and twenty-five women were enrolled in the study and randomized between two groups. Based on the Greene test results, there was a statistically significant improvement (р < 0.05) in 13 out of 21 menopausal symptoms in women who took Amberen. During the course and by the end of the study, patients showed statistically significant changes in the levels of estradiol, gonadotropins and leptin, and decreases in body weight and waist circumference. Spielberger-Hanin test showed that Amberen stabilizes patients' psychological state with a statistically significant decrease in anxiety, increased stress resistance and improved adaptability. Comparative analysis of the vital signs measurements, blood tests and urinalysis did not show any negative effects of Amberen on the patients. Our findings indicate that Amberen can be considered a method of choice to relief mild/moderate climacteric symptoms.

RELATIVE BIOAVAILABILITY STUDY OF SUCCINIC ACID COCRYSTAL TABLET AND MARKETED CONVENTIONAL IMMEDIATE RELEASE TABLET FORMULATION OF CARBAMAZEPINE 200 MG IN RABBITS.

A single-dose study was performed to observe the bioequivalence of the newly formulated carbamazepine-succinic cocrystal (CBZ-SUC) immediate release tablet (F(1)) with marketed immediate release formulation Epitoll 200 mg tablet (F(0)). In this study on albino rabbits, the plasma levels resulting from 250 mg cocrystal equivalent to 200 mg of carbamazepine and conventional tablets 200 mg immediate release tablets were compared. An open-label, randomized 2 x 2 crossover study design, with a 1-week washout period, was used. Carbamazapine (CBZ) plasma concentrations were determined by a high-performance liquid chromatography validated method using ultraviolet detection. CBZ plasma levels were measured at predose and various postdose time points up to 72 h and the following pharmacokinetic parameters were used for evaluation: area under the curve (AUC), maximum plasma drug concentration (C(max)), time to achieve C(max), and elimination rate constant. (K(e)). By applying paired t-test to AUC2(0-72) (calculated by linear trapezoidal rule), the experimental formulation F(1), was found to have statistically significant (***p < 0.05) improvement in bioavailability of CBZ. However, these statistical differences do not have practical implications and the two formulations (F(0) and F(1)) were found to be bioequivalent as the relative bioavailability of both formulations (106.9%) falls with- in the acceptable FDA set range of two bioequivalent products 80-125%.

Animal Models of Depression and Drug Delivery with Food as an Effective Dosing Method: Evidences from Studies with Celecoxib and Dicholine Succinate.

Multiple models of human neuropsychiatric pathologies have been generated during the last decades which frequently use chronic dosing. Unfortunately, some drug administration methods may result in undesirable effects creating analysis confounds hampering model validity and preclinical assay outcomes. Here, automated analysis of floating behaviour, a sign of a depressive-like state, revealed that mice, subjected to a three-week intraperitoneal injection regimen, had increased floating. In order to probe an alternative dosing design that would preclude this effect, we studied the efficacy of a low dose of the antidepressant imipramine (7 mg/kg/day) delivered via food pellets. Antidepressant action for this treatment was found while no other behavioural effects were observed. We further investigated the potential efficacy of chronic dosing via food pellets by testing the antidepressant activity of new drug candidates, celecoxib (30 mg/kg/day) and dicholine succinate (50 mg/kg/day), against standard antidepressants, imipramine (7 mg/kg/day) and citalopram (15 mg/kg/day), utilizing the forced swim and tail suspension tests. Antidepressant effects of these compounds were found in both assays. Thus, chronic dosing via food pellets is efficacious in small rodents, even with a low drug dose design, and can prevail against potential confounds in translational research within depression models applicable to adverse chronic invasive pharmacotherapies.

[Anxiolytic and antidepressant effects of 3-oxypiridine and succinic acid derivatives in alloxan diabetes].

The effects of 3-oxypyridine and succinic acid derivatives (emoxipine, reamberin and mexidol) on affective disorders in rats with alloxan diabetes were studied. The efficiency of emoxipine, reamberin and mexidol was compared to alpha-lipoic acid, which is considered a "golden standard" in treatment of diabetic neuropathies. Emoxipine, reamberin and mexidol after seven administrations in single doses, that are equivalent to therapeutic range in humans, corrected the anxiety-depressive disorders in rats with alloxan diabetes. Unlike reamberin and alpha-lipoic acid, emoxipine and mexidol corrected the affective status concurrently with the decrease in hyperglycemia. At the same time, emoxipine outperformed mexidol in tranquilizing action (in maximal doses) but yielded mexidol in the antidepressant effect (in minimal doses).

Potassium dehydroandrographolide succinate injection for treat- ment of infantile pneumonia: a systematic review and Meta-analysis.

OBJECTIVE: To evaluate systematically the clinical efficacy and safety of potassium dehydroandrographolide succinate injection (PDS) in treatment of infantile pneumonia. METHODS: Randomized controlled trials (RCTs) of infantile pneumonia treated by PDS were searched in China National Knowledge Infrastructure Database, China Science and Technology Journal Database, Wanfang Database, Chinese Biomedical Literature Database, PubMed, and Cochrane Library, from January 1979 to July 2013. Two reviewers independently retrieved the RCTs and extracted the information. The quality of included studies was assessed by the Cochrane risk of bias, and a Meta-analysis was conducted with Review Manager 5.2 software. RESULTS: A total of 9 studies with 1056 participants were included. The quality of the studies was generally no high, only one study mentioned the random method. The Meta-analysis indicated that PDS was significantly superior to the conventional therapy in the total effective rate [relative risk (RR) = 1.21, 95% CI (1.14, 1.27), P < 0.000 01], the time of temperature recovery [mean difference (MD) = -1.43, 95% CI (-1.75, -1.11), P < 0.000 01], rale disappeared and cough relieving [MD = -1.44, 95% CI (-1.93, -0.90), P < 0.000 01]. Six adverse drug reactions from five studies mainly represented rash and diarrhea, and no serious ADRs were reported. CONCLUSION: Based on this systematic review, PDS was proved effective and relatively safe in treatment of infantile pneumonia. However the articles enrolled in the study were not high in quality, studies with higher quality should be conducted for assessment of efficacy and safety of PDS in treatment of infantile pneumonia.

[Correction of neurotrophic disorders in patients, suffering consequences of a spinal cord and peripheral nerves trauma].

On clinical base of cathedra of the disasters medicine, military medicine, anesthesiology and reanimatology in 2010 - 2013 yrs 62 patients were treated for neurotrophic disorders, in 12 of them the method was applied, elaborated in the clinic. For neurotrophic ulcers in 5 patients autodermoplasty was performed, using splitted cutaneous flap, in 1 for the wound defect on a forearm--plasty, using rotational cutaneo-adipose flap, based on axial blood supply. In 44 patients after a spinal cord trauma a neurotrophic defects degree III - IV have formed. The kind of operative intervention was selected depending on size of the defect, the wound depth and functional peculiarities of the injured area. Introduction of a new method of treatment of neurotrophic ulcers of the lower extremities, using preparation of hyaluronic acid with sodium succinate, expands the perspectives of treatment in patients, suffering defects of cover tissues. Differentiated approach to choice of the wound closure method, caused by damage of central and peripheral neural system, have permitted to achieve positive results in 98.1% of patients.

[Experience of treatment of diabetic foot syndrome].

In The Clinic of Cathedra of The Catastrophes Medicine, Military Medicine, Anesthesiology and Reanimatology in 2010 - 2013 yrs 53 patients, ageing 23-65 yrs, were treated for diabetic foot syndrome (DFS) of neuropathic and mixed forms. Diagnostic-treatment algorithm was proposed for determination of level and degree of a circulation and neuropathic disorders, introduction of which have promoted optimization of surgical and local treatment, improvement of the complex treatment results in patients, suffering DFS. A new method of treatment application, using combined preparation of hyaluronic acid with the sodium succinic, have permitted to achieve a complete healing of the ulcer defect.