Synthesis of 1-[ω-(Bromophenoxy)alkyl]-3-naphthalenylmethyl Derivatives of Uracil and Their Analogues As Probable Inhibitors of Human Cytomegalovirus Replication.

The synthesis of a new series of 1-[ω-(bromophenoxy)alkyl]-uracil derivatives containing in position 3 naphthalen-1-yl-, naphthalen-2-yl-, 1-bromonaphthalen-2-ylmethyl, benzyl, and anthracene 9-methyl fragment was carried out. The antiviral properties of the synthesized compounds were studied against human cytomegalovirus. It was found that the compound that contained a bridge of five methylene groups has a high anti-cytomegalovirus activity in vitro.

Synthesis of 1-[ω-(Bromophenoxy)alkyl]-3-Naphthalenylmethyl Uracil Derivatives and Their Analogues as Probable Inhibitors of Human Cytomegalovirus Replication.

A new series of 1-[ω-(bromophenoxy)alkyl]-uracil derivatives containing naphthalen-1-yl, naphthalen-2-yl, 1-bromonaphthalen-2-ylmethyl, benzyl, and anthracene-9-ylmethyl fragments in position 3 of uracil residue was synthesized. The antiviral properties of the synthesized compounds against human cytomegalovirus were studied. It was found that the compound containing a bridge consisting of five methylene groups exhibits a high anti-cytomegalovirus activity in vitro.

Effects of Zoniporide and BMA-1321 Compound on the Rate of Oxygen Absorption by Cardiomyocyte Mitochondria in Rats with Experimental Chronic Heart Failure.

Uncoupling of respiration and ATP production by myocardial mitochondria was observed in rats with chronic isoproterenol intoxication (L-isoproterenol subcutaneously, 1 mg/kg, for 10 days) in comparison with controls (injected with the solvent). Inhibitors of NHE-1 zoniporide (1 mg/kg intraperitoneally, 13 days) and BMA-1321 compound (0.92 mg/kg intraperitoneally, 13 days) improved the mitochondrial function in rats with isoproterenol-induced cardiac failure: respiratory control coefficients increased, more so for the respiratory chain complex II, the main source of ROS in heart failure. The effect of BMA-1321 was more manifest (53%; p<0.05) in comparison with zoniporide (35%; p<0.05).

Synthesis and Antiviral Properties of 1-Substituted 3-[ω-(4-Oxoquinazolin-4(3H)-yl)alkyl]uracil Derivatives.

A series of uracil derivatives containing a 4-oxoquinazoline fragment bound to the nitrogen atom N3 of the pyrimidine ring by a short methylene bridge was synthesized to search for new antiviral agents. Some compounds in this series are shown to exhibit high inhibitory activity against human cytomegalovirus and the varicella zoster virus in a HEL cell culture.

The genus Toxoneura Macquart (Diptera, Pallopteridae) of the Oriental Region.

A new species of Toxoneura Macquart from Vietnam (Lai Châu province, Mt. Emei), T. gavryushini sp. n., is described and illustrated. This is the second species from the Oriental Region and the first species found in its continental part. The new species differs from other Oriental species, Toxoneura striata, in narrow gena and wing pattern. An identification key to the Oriental species is provided.

Contribution to the fauna of the genus Meroplius Rondani, 1874 (Diptera, Sepsidae) of the Australasian/Oceanian region.

Flies of the genus Meroplius Rondani, 1874 (Diptera: Sepsidae) of the Australasian and Oceanian regions, which includes 3 species, are reviewed. Generic and species descriptions and a key for the determination of species are given, and distribution data are summarized. One species, Meroplius timikana sp. nov. is described as new to science.

1-(4-Phenoxybenzyl) 5-Aminouracil Derivatives and Their Analogues - Novel Inhibitors of Human Adenovirus Replication.

Adenovirus infections are characterized by widespread distribution. The lack of causal therapy, which is effective in treating this group of diseases, explains the need for new therapeutic drugs. Notably, anti-adenoviral activity of [4-(phenoxy)benzyl]-5-(phenylamino)-6-azauracil, 1-[4-(phenoxy)benzyl]-5-(morpholino) uracil, 1-[4-(4-chlorophenoxy)benzyl]-5-(morpholino) uracil, and 1-[4-(4-fluorophenoxy)-benzyl]-5-(morpholino) uracil was observed.

[COMPARATIVE CEREBROPROTECTIVE EFFECT OF PREVENTIVE ADMINISTRATION OF MAGNESIUM HYDROXYBUTYRATE VERSUS MAGNESIUM SULFATE AND CAVINTON IN RATS WITH COMMON CAROTID ARTERY OCCLUSION].

Dose-dependent cerebroprotective effect of magnesium hydroxybutyrate (MHB) on common carotid artery occlusion model in rats was established. Administration of 150 mg/kg MHB led to significant decrease in animal mortality (up to 9.3 times) in comparison to control (p < 0.05). This MHB dose also produced significant decrease of neurological deficit on the McGraw scale in comparison to control and magnesium sulfate (50% and 20%, respectively). The MHB treated animals also showed improved locomotor and exploratory performance in the open-field test and retained memory performance in the passive avoidance test and extrapolation escape task test. The administration of 150 mg/kg MHB produced three-fold (p < 0.05) decrease of brain edema in animals with cerebral blood flow impairment in comparison to animals treated with magnesium sulfate and cavinton.

Comparison of the Efficiency of Adeprophen and Antidepressants of Various Groups on the Model of Reserpine-Induced Depression in Rats.

A new (aryloxyalkyl)adenine derivative Adeprophen (9-[2-(4-isopropylphenoxy)ethyl]adenine, VMA-99-82) has a strong antidepressant effect on the model of reserpine-induced depression in rats (single dose 4 mg/kg, intraperitoneally). This effect manifested in suppression of depression-like behavior in the Porsolt forced swimming test (shortening of immobility time and increase in immobility latency, number of jumping episodes, and time of active swimming) and sucrose consumption/preference test (increase in the consumption of 20% sucrose solution in g/100 g body weight and percentage of sucrose preference in relation to the total fluid preference). Adeprophen had a greater antidepressant effect than sertraline and fluoxetine, but was less potent than amitriptyline, imipramine, venlafaxine, and to a lesser extent to paroxetine.

Protective effect of magnesium acetyltaurate against endothelin-induced retinal and optic nerve injury.

Vascular dysregulation has long been recognized as an important pathophysiological factor underlying the development of glaucomatous neuropathy. Endothelin-1 (ET1) has been shown to be a key player due to its potent vasoconstrictive properties that result in retinal ischemia and oxidative stress leading to retinal ganglion cell (RGC) apoptosis and optic nerve (ON) damage. In this study we investigated the protective effects of magnesium acetyltaurate (MgAT) against retinal cell apoptosis and ON damage. MgAT was administered intravitreally prior to, along with or after administration of ET1. Seven days post-injection, animals were euthanized and retinae were subjected to morphometric analysis, TUNEL and caspase-3 staining. ON sections were stained with toluidine blue and were graded for neurodegenerative effects. Oxidative stress was also estimated in isolated retinae. Pre-treatment with MgAT significantly lowered ET1-induced retinal cell apoptosis as measured by retinal morphometry and TUNEL staining. This group of animals also showed significantly lesser caspase-3 activation and significantly reduced retinal oxidative stress compared to the animals that received intravitreal injection of only ET1. Additionally, the axonal degeneration in ON was markedly reduced in MgAT pretreated animals. The animals that received MgAT co- or post-treatment with ET1 also showed improvement in all parameters; however, the effects were not as significant as observed in MgAT pretreated animals. The current study showed that the intravitreal pre-treatment with MgAT reduces caspase-3 activation and prevents retinal cell apoptosis and axon loss in ON induced by ET1. This protective effect of ET1 was associated with reduced retinal oxidative stress.

A review of the genera Cleigastra Macquart, Gonarcticus Becker, Gonatherus Rondani, Hexamitocera Becker, Nanna Strobl, Orthacheta Becker and Spathephilus Becker (Diptera, Scathophagidae) of Russia.

Flies of the genera Cleigastra Macquart, 1835, Gonarcticus Becker, 1894, Gonatherus Rondani, 1856, Hexamitocera Becker, 1894, Nanna Strobl, 1894, Orthacheta Becker, 1894 and Spathephilus Becker, 1894 (all Scathophagidae) of the fauna of Russia are reviewed. Key to genera, generic descriptions and keys for determination of species are given, and data on geographical distribution are summarized. One species, Nanna cryophila sp. nov., is described as new to science. One new synonymy is proposed: Nanna kamtschatkense (Hendel, 1930) = Nanna tibiella (Zetterstedt, 1838). Orthacheta cornuta (Loew, 1863) is recorded from Europe for the first time. Gonarcticus arcticus (Becker, 1907) is newly recorded from the Palaearctic Region and Russia. Additionally, Nanna flavipes (Fallén, 1819) is newly recorded from China, and Spathephilus nigriventris (Loew, 1864) is newly recorded from Kazakhstan.

A new species of the shore-fly genus Notiphila Fallén, 1810 (Diptera: Ephydridae) from Indonesia.

A new shore-fly species, Notiphila oksanae sp.n. from Indonesia is described. The new species is similar to the Oriental species Notiphila thaica Krivosheina, 2010 in having many brown stripes on the thorax and in presurstyli broad in lateral view, but differs in 2 facial setae of subequal length, the absence of brown band on anepisternum and the presence of dark band on hind tibia. A key to the presently known Australasian/Oceanian species of the genus Notiphila Fallén, 1810 is given.

2-(2,4-Dioxy-1,2,3,4-Tetrahydropyrimidin-1-yl)-N-(4-Phenoxyphenyl)-Acetamides as a Novel Class of Cytomegalovirus Replication Inhibitors.

A series of novel uracil derivatives, bearing N-(4-phenoxyphenyl)acetamide moiety at N3 of a pyrimidine ring, has been synthesized. Their antiviral activity has been evaluated. It has been found that the novel compounds possess high inhibitory activity against replication of human cytomegalovirus (AD-169 and Davis strains) in HEL cell cultures. In addition, some of the derivatives proved to be inhibitory against varicella zoster virus.

[Study of some pharmacological properties of a new adenine derivative].

It is established that the new compound, 9-[2-(4-isopropylphenoxy)ethyl]adenine (9-IPE-adenine) in a dose of 10 mg/kg per day produces neuroprotective effect in rats with brain ischemia model. 9-IPE-adenine decreased the neurologic deficiency 1.2 times more effectively (p < 0.05) than the reference drug mexidol in analogous dose, and had equal effect with this drug at 25 mg/kg per day on the neurologic deficiency and survival of animals. Electrophysiological studies in hippocampal slices in rats showed that 9-IPE-adenine depressed orthodromic population spikes in CA1 area by 42 ± 4%. Non-competitive antagonist of NMDA receptor complex MK-801, in contrast to D-AP5 (competitive NMDA receptor antagonist) and CNQX (competitive AMPA receptor antagonist), enhanced the depressive effect of the new drug more than two times. These ese results are indicative of the ability of 9-IPE-adenine to modulate the ion channel of NMDA receptor complex.

[Absolute bioavailability of the adenine derivative VMA-99-82 possessing antiviral activity].

Investigation of the main pharmacokinetic parameters of adenine derivative VMA-99-82 in rats showed large values of the half-life (T1/2 = 11.03 h) and the mean retention time of drug molecules in the organism (MRT = 9.53 h). A high rate of the drug concentration decrease in the plasma determines a small value of the area under the pharmacokinetic curve (AUC = 74.96 mg h/ml). The total distribution volume (V(d) = 10.61 l/kg) is 15.8 times greater than the volume of extracellular fluid in the body of rat, which is indicative of a high ability of VMA-99-82 to be distributed and accumulated in the organs and tissues. The absolute bioavailability of VMA-99-82 is 66%.

Correction of furosemide-induced magnesium deficiency with different stereoisomers of organic magnesium salts: a comparative study.

We compared the efficiency of different stereoisomers of organic magnesium salts (Mg DL-, Mg D-, and Mg L-aspartate and Mg L- and Mg DL-glutamate) after oral administration under conditions of furosemide-induced magnesium deficiency. The time to complete compensation of erythrocyte magnesium level was 5 days for Mg L-aspartate, 10 and 8 days for Mg L-glutamate and Mg D-aspartate, respectively, and 11 days for Mg DL-aspartate and Mg DL-glutamate. These findings attest to better bioavailability of Mg complex with L-stereoisomer of aspartate in comparison with DL and D-stereoisomers and stereoisomers of Mg glutamate.

[Comparative study of magnesium salts bioavailability in rats fed a magnesium-deficient diet].

The purpose of this study was to compare efficiency of compensation of alimentary Mg deficiency after administration of 12 organic and 8 inorganic magnesium salts and to evaluate the ability of vitamin B6 to accelerate their effect. Two hundred eighty rats were placed on a Mg-deficient diet (Mg content (15 mg/kg) and demineralized water for 7 weeks. Twelve control rats were fed a basal diet (Mg content 500 mg/kg). Starting from day 49 of the Mg-deficient diet, the rats were given magnesium salts (50 mg magnesium and 5 mg pyridoxine per kg): Mg chloride, Mg sulphate, Mg oxide, M nitrate, Mg thiosulphate, Mg hydrophosphate, Mg carbonate, Mg trisilicate, Mg (L-, D- and DL-) aspartate, Mg (L- and DL-) pyroglutamate, Mg succinate, Mg glycinate, Mg orotate, Mg taurate, Mg lactate or their combination with vitamin B6 (5 mg/kg b.w.). Erythrocyte and plasma Mg levels were measured by spectrophotometry following the colour reaction between Mg and titanium yellow. Mg L-aspartate compensated for magnesium deficit more effectively and faster than all other salts. Mg chloride showed the highest efficiency among inorganic magnesium salts. Both Mg chloride and Mg L-aspartate in combination with vitamin B6 caused statistically significant compensation of magnesium deficit.

[Pharmacokinetics of benzimidazole derivatives]. / Farmakokinetika nekotorykh proizvodnykh benzimidazola.

Pharmacokinetic properties of benzimidazole derivatives drug possessing antipsychotic, actoprotector, antiarrhythmic, antiulcerogenic, antiallergic, uricosuric, anthelmintic activities have been summarized. Pharmacokinetics of benzimidazole derivatives used in veterinary practice as anthelmintic drugs is also considered. Benzimidazoles derivatives are characterised by multicompartment and ambiguous pharmacokinetic models. The derivatives of benzimidazoles are subjected to the first pass metabolism in the liver, and, therefore, they are converted to both active, and inactive metabolites. It is necessary to take into account for coadministration of benzimidazoles with other drugs. Hepatoduodenal circulation and repeated adsorption of unchanged drug and its metabolites in the gut is observed for benzimidazole. Many derivatives of benzimidazoles are characterised by rather low absolute bioavailability during peroral intake (from 2 up to 60%). Benzimidazsole derivative may bind to proteins and cell elements of blood. More often pharmacokinetic profile of benzimidazoles is linear for low doses, however, at high doses the linearity is lost. For animals and men pharmacokinetic models are always nearly identical.