Antihypoxic Activity Research Articles

Synthesis and Pharmacological Properties of 1-(6-Aminohexylamino)-1-Phenylcyclohexyl Dihydrochloride (IEM-2062) as Compared with Memantine

1-(6-Aminohexylamino)-1-phenylcyclohexyl dihydrochloride (IEM-2062) had significantly greater antihypoxic, anticonvulsant, antidepressant, and analgesic activity than memantine and similar antiparkinsonism activity as memantine; it had low toxicity and was safer for use. IEM-2062 produced significant pharmacological effects in the dose range 0.3 – 3 mg/kg.

Синтез и фармакологические свойства 1-(6-аминогексиламино)-1-фенилциклогексил дигидрохлорида (ИЭМ-2062) в сравнении с мемантином

Соединение 1(6-аминогексиламино)-1-фенилциклогексил дигидрохлорид (ИЭМ-2062) значительно превосходит мемантин по антигипоксической, противосудорожной, антидепрессивной и анальгезирующей активности, имеет равную с мемантином противопаркинсоническую активность, а также является малотоксичным и более безопасным для применения соединением. ИЭМ-2062 вызывает достоверные фармакологические эффекты в диапазоне доз 0,3 – 3 мг/кг.

Chemical constituents from rhizome of Menispermum dauricum and their anti-hypoxic activities

To study the chemical constituents from the rhizome of Menispermum dauricum,fifteen compounds,N-methylcorydaldine( 1),thalifoline( 2),stepholidine( 3),acutumine( 4),daurisoline( 5),acutumidine( 6),dauricicoline( 7),bianfugecine( 8),6-O-demethylmenisporphine( 9),bianfugedine( 10),dauricoside( 11),eleutheroside D( 12),aristolactone( 13),aristoloterpenateⅠ( 14) and aristolochic acid( 15) were isolated from 75% ethanol extract of Menispermi Rhizoma by using thin layer chromatography and column chromatography methods. Their structures were identified based on their physicochemical properties and spectral data. Among them,compounds 12-15 were obtained from the genus Menispermum for the first time. Six alkaloids with higher contents were subjected to evaluate the anti-hypoxic activities by using MTT method. As a result,six alkaloids exhibited significant anti-hypoxia activities.

Polysaccharides from the Edible Mushroom Agaricus bitorquis (Quél.) Sacc. Chaidam Show Anti-hypoxia Activities in Pulmonary Artery Smooth Muscle Cells.

Three kinds of new water-soluble polysaccharides (FA, FB and FC) were isolated from wild mushroom Agaricus bitorquis (Quél.) Sacc. Chaidam by the classical method “water extraction and alcohol precipitation” and purified by column chromatography. The Mw of FA, FB and FC ranged from 5690 Da to 38,340 Da. The three polysaccharide fractions in the fruiting body were mainly composed of 4 kinds of monosaccharides, including glucose, galactose, mannose, and arabinose, among which glucose and galactose were the major monosaccharides. The FTIR and NMR spectroscopy indicated that the skeleton of three fractions composed of a (1→4)-α-D-glycosidic backbone containing α-D-mannopyranose. In vitro anti-hypoxia activity data showed that three polysaccharide fractions possessed a significant effect on inhibiting PASM cells apoptosis under hypoxia. Among them, FC at the concentration of 200 µg/mL revealed a significant anti-hypoxia effect. These results revealed that the intracellular polysaccharides possessed potent anti-hypoxic activity, which might be related to inhibiting LDH and NADPH oxidase expression and promoting the formation of 5-hydroxytryptamine, dopamine, endothelins, acetylcholine. More importantly, FC showed good performance inducing KV1.5 expression and prohibiting KIR6.2 formation at protein level.

Synthesis, characterization and biological evaluation of Zn(II) and Co(II) complexes of N-allylimidazole as potential hypoxia-targeting agents

Zinc(II) and cobalt(II) complexes of N-allylimidazole, bis(N-allylimidazole)zinc diacetate (1) and bis(N-allylimidazole)cobalt dichloride (2), have been prepared and characterized by X-ray crystallography, NMR, FTIR spectroscopy, microanalysis and melting point. The single crystal X-ray diffraction analysis confirms that compounds 1 and 2 are monomeric with tetra-coordinate zinc and cobalt centers. Complexes 1 and 2 have been tested using four in vivo models of acute hypoxia of different genesis (hypobaric, hemic, histotoxic, hypoxia with hypercapnia). Complex 1 reveals a moderate effect against the hemic and histotoxic hypoxia, and a high effect against the hypobaric hypoxia and hypoxia with hypercapnia, while complex 2 demonstrates a high antihypoxic activity in all the studied models.

Antihypoxic and anti-ischemic properties of the North Caucasus flora plant extract

Nowdays it is established that ischemic brain damage like ischemic stroke is one of the leading cause of death and disability in the population that assumes relevance development of anti-ischemic drugs. The work studied the anti-hypoxic and anti-ischemic effect of 7 plant extracts. Antihypoxic activity was assessed on models of hypobaric, hypercapnic, histotoxic, hematotoxic hypoxia. Anti-ischemic activity of test-extracts was studied on the focal cerebral ischemia model. Administration of Tagetes patula, Gaillardia pulchella, Sorbaria sorbifolia, Grossularia reclinata, Ribes nigrum, Rubus caesius and Lysimachia punctata extracts contributed to the necrosis zone reduction by 56.6% (p<0.05); 37.3% (p<0.05); 73.2% (p<0.05); 49.4% (p<0.05); 42.5% (p<0.05); 85.5% (p<0.05); 44.2% (p<0.05) and also restored aerobic metabolism in brain tissue. Test - objects increased of the animal lifespan under hypoxia conditions. Based on the data obtained, it is assumed that further studies of North Caucasus flora plant extracts as cerebro-protective agents are promising.

The Effect of Mesedin on the Content of Oxidative Stress Biomarkers in the Brain Tissue in Ischemia

The effect of α2-adrenoblocker mesedin (2-(2-methylamino-4-thiazolyl)-1,4-benzodioxane hydrochloride) on the content of oxidative stress biomarkers in the brain tissue was well studied in ischemic disorders. The aim of this study is to reveal the possible mechanisms of the antihypoxic effect of mesedin. The quantitative changes of the final product of lipid peroxidation (LP)—malondialdehyde (MDA) and carbonyl derivatives of proteins — aldehyde-dinitrophenylhydrazones of neutral character (ADNPuv), ketone-dinitro-phenylhydrazones of neutral character (KDNPuv), aldehyde-dinitrophenylhydrazones of basic character (ADNPvs) and ketone-dinitrophenylhydrazones of basic character (KDNPvs) were studied in the brain tissue of rats (n = 56) under the condition of experimental ischemia caused by the ligation of the right common carotid artery. The study showed that one of the possible mechanisms of antihypoxic action of mesedin is its ability to prevent the accumulation of malondialdehyde and to limit protein carbonylation in brain ischemia. The data received demonstrates that mesedin could serve as a potential medicine for the correction of cerebrovascular ischemic disorders, for the reason that along with improving cerebral blood flow and preventing the development of morphological shifts and neurobehavioral disturbances in brain local ischemia, the medicine also mitigates the aggressive action of oxidative stress while protecting the brain tissue from the consequences of hypoxia.

MECHANISMS OF ANALEPTIC AND ANTIGIPOXIC EFFECTS OF HETEROSIDES – (DERIVATIVES FOR SULFUR AND NITROGEN CONTAINING HETEROCYCLES)

&#x0D; &#x0D; &#x0D; In order to expand the theoretical base of targeted search for analeptics, the awakening and antihypoxic properties of Heterosides-21, Heterosides-31 (derivatives of sulfur and nitrogen containing heterocycles) were studied and their mechanisms of action were established. Sodium thiopental (42 mg/kg) was used to simulate suppression of the respiratory and vasomotor centers of the brain. Comparative drugs were the combined analeptic sulfocamphocaine (SCC) (20 mg/kg) and antihypoxant Piracetam (300 mg/kg).The results were obtained on the models of thiopental anesthesia and normobaric hypoxia with hypercapnia, the analysis of which allowed: to qualitatively and quantitatively assess the awakening, antihypoxic activity of the studied substances and classical preparations; their effect on the respiratory center of the brain and the behavioral responses of animals; theoretically substantiate, experimentally confirm and establish aerobic, anaerobic and detoxification mechanisms for the realization of effects in various conditions; to formulate the theoretical foundations of a targeted search for universal analeptics and antihypoxic drugs, to offer an instrumental and methodological complex for their experimental reproduction.&#x0D; &#x0D; &#x0D;

Oxygen-ozone therapy in dentistry: current applications and future prospects

Starting from 2012, the dental research community began to assess the benefits of oxygen-ozone on human metabolism, for its immune-stimulant and anti-hypoxic action, the increase in protein biosynthesis and activation of angiogenesis. We report the case of a 69-year-old patient, for whom oxygenozone therapy was used as a treatment that could reduce the bone resorption of the alveolar ridges, considering the reduced state of hypoxia resulting therefrom, the improved neoangiogenesis and the positive effect on bone metabolism. The results exceeded our greatest expectations, given that the measurements even showed an increase in bone peaks.

Correction of hypoxic state by metabolic precursors of endogenous activator of mitochondrial ATP-dependent K+channels

Aim. The antihypoxic properties of uridine and uridine-5'-monophosphate (UMP), which are the metabolic precursors of the natural activator of mitochondrial ATP-dependent K+ channels (mitoKATP channels) uridine diphosphat were investigated on the models of hypoxic hypoxia with hypercapnia (HHH), hemic hypoxia and local circulatory hypoxia.&#x0D; Methods. HHH was created in males and females white mice weighing 28-30 g. The animals were placed one by one in hermetically closed container and the duration of their life was determined. The antihypoxic activity of the substances was compared with the reference anthypoxant amtizole (50 mg/kg). Hemic hypoxia was caused in Wistar rats weighing 350-370 g by the injection of sodium nitrite (intramuscularly, 100 mg/kg). Uridine or UMP 30 mg/kg was injected intraperitoneally 30 minutes before the onset of HHH and hemic hypoxia. Local circulatory hypoxia was modeled in male Wistar rats weighing 250-300 g. Acute coronary occlusion lasting 60 min was reproduced by legation of descending branch of the left coronary artery (LCA). Uridine or UMP (30 mg/kg) was administered intravenously 5 minutes prior to LCA occlusion. Selective blocker of mitoKATP channels 5-hydroxydecanoate (5 mg/kg, intravenously, 5 minutes prior uridine or UMP) was used to determine the role of these channels in the mechanism of antihypoxic action of the studied drugs. The volume of the damaged myocardium was used as the marker of antihypoxic activity of uridine and UMP.&#x0D; Results. Different resistance to hypoxia in female and male mice was observed in HHH. The female mice were more resistant, their life duration was 43% more than the males. Uridine and UMP displayed antihypoxic activity only in male mice, increasing their life duration by 25% and 20% respectively. This effect was 2 times less than that of amtisol. In similar conditions in females mice the preparations did not show a protective effect. In hemic hypoxia the life duration of rats treated with uridine and UMP did not differ from the control values. Circulatory hypoxia, caused by occlusion of the LCA, led to the formation of a local zone of myocardial damage. Uridine or UMP decreased the damage zone in 2 and 3,5 times respectively. The inhibitor of mitoKATP channels blocked the protective effect of these compounds.&#x0D; Conclusion. Uridine and UMP have a distinct antihypoxic effect in HHH and a marked protective effect in local circulatory hypoxia. The antihypoxic activity of druges in HHH is manifested differently in female and male mice. It may be due to sexual differences in the resistance to hypoxia. The maximum effect is observed in male who have initially low resistance to oxygen deficiency. The mechanism of the protective action of uridine and UMP in the circulatory hypoxia is associated with the activation of mitoKATP channels.

Comparative analysis of metal-complex and aminothiol antihypoxants efficiencies in the experiment

Aim. Comparative analysis of the efficiency of metal-complex (πQ1983, πQ2721) and aminothiol (Amtizole, Sunazole) antihypoxants in experiments on rats exposed to acute hypoxia with hypercapnia. Methods. Experiments performed on 182 male rats of Wistar line weighing 150-170 g. The study of antihypoxic activity of substances was carried out on the model the AH+Hc. The condition of acute hypoxia in rats was formed by placing them in glass airtight containers with a free volume of 1.0 L. Antihypoxic effect was evaluated by the life expectancy of animals in the described conditions. Substances πQ2721, πQ1983, Amtizole and Sunazole was administered once intraperitoneally at doses of 25, 50 and 100 mg/kg. Previously each substance was dissolved in 0.9% NaCl (1.0 ml). Testing the effectiveness of the substances on AH+Hc model was carried out after 1 h after administration of the substances and after 24 h. Animals of control groups were injected with 1.0 ml of 0.9% NaCl. In animals exposed to test AH+Hc in 1 h after administration were performed measurements of the rectal temperature before the experiment and through 1 h after administration, i.e. before AH+Hc. In animals selected for 24-hour observation, rectal temperature was measured before the experiment, and then after 1, 3, 6, 12, 18 and 24 h of observation, after which they were exposed to AH+Hc. Results. The antihypoxic effect of a selenium-containing substance πQ2721 based on Zn2+ was confirmed in experiments on rats. In a number of substances for comparison the πQ2721 proved himself not only as equally effective. It is found that after 1 h after administration at a dose of 50 mg/kg πQ2721 superior to all studied compounds, including antihypoxant with succinate Sunazole. An important advantage of the new promising antihypoxic agent was the preservation of its action for 24 hours after injection. (For citation: Evseev AV, Surmenev DV, Evseeva MA, et al. Comparative analysis of metal-complex and aminothiol antihypoxants efficiencies in the experiment. Reviews on Clinical Pharmacology and Drug Therapy. 2018;16(2):18-24. doi: 10.17816/RCF16218-24).

A REVIEW ON THE SYNTHETIC METHODOLOGIES OF CHROMONES

Chromones group of compounds and their derivatives form the essential component of pharmacophores in many biologically active molecules. They exhibit a wide range of biological activities such as antibiotic, antitumor, antiviral, antioxidant, antipsychotic, and antihypoxic activities. These applications have stimulated a continuous search for the synthesis of new compounds in this field and are being extensively investigated. The various methodologies so far reported for the synthesis of these compounds with the compounds biological applications are discussed in this communication

Protective effects of methanolic extract of Vicia cracca against hypoxia-induced lethality in mice

Vicia genus has 45 species in Iran. Many protective and biological activities have been reported from these species. In spite of many works, nothing is known about protective effect of V. cracca against hypoxia conditions. In this study, protective effects of V. cracca extract against hypoxia-induced lethality in mice were evaluated by three experimental models of hypoxia, asphyctic, haemic and circulatory. Statistically significant protective activities were observed in some doses of extract in three models. Antihypoxic activity was especially pronounced in asphyctic model. Extract at 200 mg/kg prolonged survival time (27.37 ± 4.0 min) but was not comparable with that of phenytoin (39.80 ± 1.92). At 100 mg/kg it also prolonged survival time (24.76 ± 3.7 min) which was so higher than control group. In haemic model, V. cracca extract significantly and dose dependently prolonged survival time as compared to control group. At 200 mg/kg, extract was being capable of keeping the mice alive for 15.38 ± 1.93 min. It was also effective in circulatory model. V. cracca extract at 200 mg/kg prolonged survival time (16.84 ± 1.47 min) that was statistically significant as compared to control group (13.14 ± 0.51 min). V. cracca extract showed a very good protective effect against the hypoxia in some models. Specifically, they produced significant and dose-dependent effect on the model of asphytic and haemic hypoxia. The presence of polyphenols in this plant may be a proposal mechanism for reported antihypoxic activities of this plant.

Rationale of method of analysis of evidence-based data on the pharmacological activity of succinic acid and its combinations drugs

Succinic acid as endogenous metabolite has a wide range of applications in medical practice in Ukraine and abroad. We research a new medicines, based on succinic acid, ascorbic acid and rutin for the prevention and treatment of influenza. Analysis of the data evidence-based medicine necessary for the implementation of quality assessment study feasibility of adding succinic acid in the various dosage forms and determine their pharmacological activity.&#x0D; It was studied international databases and registers of clinical trials MEDLINE®, EMBASE®, Scopus, Cochrane Library for the period from 1966 to June 2015. In the search for key phrases search engine electronic library «The Cochrane Library» found 872 913 publications, including 71 in the section «Trials». Of these, only 23 were devoted to review the results of clinical trials of medications that contain in their composition succinic acid.&#x0D; In the analysis of papers revealed that all 12 Trials of the search engine PubMed are present in search results «The Cochrane Library». Therefore, for further analysis we selected directory search results Trials «The Cochrane Library» and 3 Review of retrieval system PubMed.&#x0D; We analyzed Trials in terms of pharmacological activity and dynamics of publications. For pharmacological properties and relevance RCTs grouped as follows: antihypoxic action confirm 7 RCT (2003–2013 years), improve of iron absorption in the gastrointestinal tract – 6 RCT (1966–1974 years), hepatoprotective – 4 RCT (2013–2014 years). One RCT has effectiveness succinic acid for use in gastroenterology (in combination with omeprazole, 2012), depression (2013), the transplant (1993) during menopause (2008), renal failure (2013) for fever during surgery (2007). We can call such medicines containing succinic acid and have proven clinical efficacy: Remaksol, Tsytoflavin, Vecam (Omeprazole + succinic acid). We analyzed the Review of reviews of retrieval system PubMed. Analysis reviews MedLine (Review) opens new prospects for the use of succinic acid in the treatment of hypoxia and viral hepatitis. The results of clinical trials confirm the feasibility of developing new drugs with succinic acid.&#x0D; We conducted a review of evidence data about the inclusion of succinic acid in the various dosage forms. Succinic acid is the part of the drugs with different pharmacological effect. The results of clinical trials confirm the feasibility of developing of new drugs with succinic acid.

Structure–Activity (Antihypoxic) Relationship in a Series of Substituted Glyprolines

A series of C-substituted N-phenylacetylglycylprolines were synthesized. Their structure-activity (antihypoxic) relationship was studied in normobaric hypoxia tests at i.p. doses of 0.1 – 1 mg/kg as a function of the C-substitution. The amide and ethyl ester of N-phenylacetylglycyl-L-proline exhibited antihypoxic activity and could cyclize in biological fluids to form cycloprolylglycine that was identical to the endogenous peptide with antihypoxic, neuroprotective, and other types of neuropsychotropic activity. The antihypoxic effect was stereospecific because the D-enantiomers were inactive. These compounds at concentrations of 10–7 – 10–5 M also exhibited neuroprotective activity for SH-SY5Y human neuroblastoma cell culture with 6-hydroxydopamine neurotoxicity. The methylamide and analogous free acid of N-phenylacetylglycylproline could not be cyclized into cycloprolylglycine and were inactive. It was concluded that the activity of the substituted glyprolines was associated with their conversion into cycloprolylglycine.

Antihypoxic activities of Crataegus pentaegyn and Crataegus microphylla fruits-an in vivo assay

The aim of this study was to evaluate anti-hypoxia activity of polyphenolic extracts of Crataegus microphylla and Crataegus pentaegyn on mice. Three experimental models of hypoxia were considered, including asphyctic hypoxia, haemic hypoxia, and circulatory hypoxia. Polyphenolic extract of both plants exhibited significant anti-hypoxic activity and prolonged animal survival time. Anti-hypoia activity of C. pentaegyn was found to be superior to that of C. microphylla in circulatory and asphyctic hypoxia. Antihypoxic activity of these extracts may be attributed to their phenolic compounds.

Current realities and prospects for the arginine as a nitric oxide donor in purulent surgery

Recently, researchers have shown an increased interest in the use of L‑arginine for surgical practice. Positive effects of this powerful nitric oxide donor, which is used in the treatment of various nosology has already been experimentally and clinically proven. At the local level, the neo‑angiogenesis processes are stimulated significantly, mechanisms of mechanical and microbial cleansing of the wound are accelerated, pro‑inflammatory cytokines are indirectly inactivated due to the powerful antihypoxic action, allowing to obtain clinically and visually clean wounds in significantly shorter terms. Detailed mechanisms of the L‑arginine effect on the purulent wounds have not been thoroughly elucidated, so promising is the study of aimed activation on wound healing mechanisms at the various stages of the wound healing process.

Comparative Characteristics of Anti-depressant, Anti-hypoxic Action, and Effect on the Physical Endurance of Scutellaria baicalensis Drugs.

The influence of original drugs from Scutellaria baicalensis (SB) Georgi (dry extract, powder of rhizomes and roots, tablets "Scutex" on the basis of the dry extract and capsules "Scutella", which contain powder of rhizomes with roots) was studied on depressive behavior, physical endurance and anti-hypoxic activity in mice. The used dry extract SB (SBDE), powder of roots and rhizomes from SB (SBRP), tablets from dry extract of SB named "Scutex", and hard gelatin capsules from the crushed root of SB named "Scutella" were obtained from National University of Pharmacy, Department of Industrial Technology of Drugs. In the experiment, 94 random-breed white male mice weighing 20-29 g were used and kept in standard sanitary and laboratory conditions. The experiments revealed that SBDE had anti-depressant action. Powder from rhizomes and roots of SB and "Scutella" capsules had anti-hypoxic action. All test drugs showed no influence on the physical endurance of mice. These results suggest the possible use of SBDE as an anti-depressant drug, and rhizomes with roots and "Scutella" capsules as an anti-hypoxic remedy. SBDE at a dose 50 mg/kg shows anti-depressant activity that exceeds the activity of the comparison drug "Bilobil". SBDE, SBRP, "Scutex" tablets and "Scutella" capsules do not affect the physical endurance of mice. SBDE at a dose 50 mg/kg and SBRP at a dose of 173 mg/kg and 260 mg/kg exhibit anti-hypoxic activity. "Scutex" tablets show no anti-hypoxic action and "Scutella" capsules cause probable anti-hypoxic action that exceeds the effect of the reference drug "Bilobil".

Evaluation of efficiency and safety of Olatropil medication in complex treatment of discirculatory encephalopathy in patients with arterial hypertension

The article is devoted to the actual problem of modernity – chronic cerebrovascular pathology. The data on efficacy of therapy with combined nootropic Olatropyl are presented in comparison with piracetam in patients with chronic brain ischaemia due to arterial hypertension and cerebral atherosclerosis.The objective: study of effectiveness and safety of Olatropil in complex treatment of dyscirculatory encephalopathy in patients with arterial hypertension.Materials and methods. Sixty patients (men and women) with arterial hypertension (AH) and signs of discirculatory encephalopathy (DEP) of I and II degree aged from 46 to 65 years were examined. All patients were divided into two statistically homogeneous groups (main and control) of 30 people each. Patients of both groups received antihypertensive medications during diet therapy. Patients of the main group in addition to the basic therapy took Olatropil, and patients of control – piracetam.Results. Analysis of the results of the investigation showed that in patients of the main group who received Olatropil, compared with the control group, there was a significant decrease in clinical manifestations of AH, decrease in severity of asthenoneurotic syndrome, anxiety, improvement of cognitive functions, and increase of cerebral blood flow. During the investigation Olatropil demonstrated a favorable safety and tolerability profile.Conclusion. Inclusion combined medication Olatropil in complex therapy of dyscirculatory encephalopathy in patients with arterial hypertension provides more pronounced therapeutic effect due to its neurometabolic, nootropic, vasoconstrictive and antihypoxic action.

SOME INNOVATIVE APPROACHES TO MAINTAINING THE ADAPTIVE RESPONSE OF THE ORGANISM UNDER STRESS

The paper presents data on the development of complex means, which increase the power of the adaptive response of the organism under stress and pathological conditions. This complex includes dietary supplements based on natural metabolites with pronounced antihypoxic activity, perfluorocarbon drugs for improving the oxygen regime of tissues, and effective immunomodulators based on sodium aminodihydrophthalazinedione and the neurotransmitter oligopeptide with increased stability. Their application is promising in the healthcare and in the military medicine. They provide an increase in efficiency, acceleration of recovery processes, increasing the body’s resistance to extreme loads, intoxications, infections, various types of tissue damage.