Impact of vanadium complexes treatment on the oxidative stress factors in wistar rats plasma.

THE AIM OF THIS STUDY WAS TO INVESTIGATE THE CLINICAL EFFICACY OF VANADIUM COMPLEXES ON TRIGLYCERIDES (TG), TOTAL CHOLESTEROL (CHOL), URIC ACID (UA), UREA (U), AND ANTIOXIDANT PARAMETERS: nonenzymatic (FRAP-ferric reducing ability of plasma, and reduced glutathione-GSH) and enzymatic (glutathione peroxidase-GPx, catalase-CAT, and GPx/CAT ratio) activity in the plasma of healthy male Wistar rats. Three vanadium complexes: [VO(bpy)(2)]SO(4)·2H(2)O, [VO(4,4'Me(2)bpy)(2)]SO(4)·2H(2)O, and Na[VO(O(2))(2)(bpy)]·8H(2)O are administered by gavage during 5 weeks in two different diets such as control (C) and high fatty (F) diets. Changes of biochemical and antioxidants parameters are measured in plasma. All three vanadium complexes statistically decrease the body mass growth in comparison to the control and fatty diet. In plasma GSH was statistically increased in all vanadium complexes-treated rats from control and fatty group in comparison to only control group. Calculated GPX/CAT ratio was the highest in the control group in comparison to others.

A role of GABA analogues in the treatment of neurological diseases.

gamma-Amino butyric acid is an extremely important inhibitory neurotransmitter in the mammalian central nervous system and is essential for the overall balance between neuronal excitation and inhibition. It is well documented that GABA deficiency is associated with several important neurological disorders such as Huntington's chorea, Parkinson's and Alzheimer's disease and other psychiatric disorders, like anxiety, depression, pain, panic, or mania. Although, it is known that increasing the brain concentration of GABA prevents convulsions, the high polarity and flexible structure of this compound are probably responsible for its inefficiency as an anticonvulsant when administered orally or intravenously. To resolve this problem, GABA analogues are being designed. Over recent years, there has been increasing interest in the synthesis and pharmacological effect of new GABA derivatives, which can be considered as potent drugs in the treatment of neurodegenerative disorders.

Antidepressant-like activity of CGP 36742 and CGP 51176, selective GABAB receptor antagonists, in rodents.

BACKGROUND AND PURPOSE: A crucial role for the GABAB receptor in depression was proposed several years ago, but there are limited data to support this proposition. Therefore we decided to investigate the antidepressant-like activity of the selective GABAB receptor antagonists CGP 36742 and CGP 51176, and a selective agonist CGP 44532 in models of depression in rats and mice. EXPERIMENTAL APPROACH: Effects of CGP 36742 and CGP 51176 as well as the agonist CGP 44532 were assessed in the forced swim test in mice. Both antagonists were also investigated in an olfactory bulbectomy (OB) model of depression in rats, while CGP 51176 was also investigated in the chronic mild stress (CMS) rat model of depression. The density of GABAB receptors in the mouse hippocampus after chronic administration of CGP 51176 was also investigated. KEY RESULTS: The GABAB receptor antagonists CGP 36742 and CGP 51176 exhibited antidepressant-like activity in the forced swim test in mice. The GABAB receptor agonist CGP 44532 was not effective in this test, however, it counteracted the antidepressant-like effects of CGP 51176. The antagonists CGP 36742 and CGP 51176 were effective in an OB model of depression in rats. CGP 51176 was also effective in the CMS rat model of depression. Administration of CGP 51176 increased the density of GABAB receptors in the mouse hippocampus. CONCLUSIONS AND IMPLICATIONS: These data suggest that selective GABAB receptor antagonists may be useful in treatment of depression, and support an important role for GABA-ergic transmission in this disorder.

Central activity of new xanthone derivatives with chiral center in some pharmacological tests in mice.

The study was designed to investigate some central effects of chiral xanthone derivatives [(R,S)-2-N-(6-chloro-2-xanthonemethyl)-amino-1-propanol - MH-31, R enantiomer - MH-32 and S enantiomer - MH-33] in mice. The effects of these chiral compounds were examined in picrotoxin-induced seizures, spontaneous locomotor activity and chimney tests. The tested compounds demonstrated variable influence on the central nervous system in mice. The compound MH-32 exhibits anticonvulsant activity in picrotoxin-induced seizures, whereas MH-31 and its R enantiomer--compound MH-32 demonstrated antidepressant-like activity in the forced swimming test. Moreover, all tested xanthones reduced the locomotor activity in mice. The obtained results indicate the importance to examine pharmacologically enantiomers rather than only racemic mixtures of newly synthesized compounds.

Effects of a carane derivative local anesthetic on a phospholipid bilayer studied by molecular dynamics simulation.

Molecular dynamics (MD) simulations of two hydrated palmitoyloleoylphosphatidylcholine (POPC) bilayers each containing eight carane derivative (KP-23) local anesthetic (LA) molecules in neutral (POPC-LA) or protonated (POPC-LAH) forms were carried out to investigate the effect of KP-23 and its protonation on the bilayer. 3-ns trajectories were used for analyses. A pure POPC bilayer was employed as a reference system. In both POPC-LA and POPC-LAH systems a few KP-23 molecules intercalated into the bilayer and moved near the bilayer/water interface. They were located on the hydrophobic core side of the interface in the POPC-LA bilayer, but on the water phase side in the POPC-LAH bilayer. The order of the POPC chains was higher in the POPC-LA bilayer than in the pure POPC bilayer and was lower in the POPC-LAH bilayer. Interactions between polar groups of KP-23 and POPC or water were responsible for a lower hydration of POPC headgroups in POPC bilayers containing KP-23 than in the pure POPC bilayer. KP-23 molecules were found to form aggregates both in POPC-LA and POPC-LAH bilayers. Due to higher amphiphilicity of LAH, the LAH aggregate was more micelle-like and larger than the LA one. The results demonstrate the rapid timescales of the initial processes that take place at and near the bilayer interface as well as details of the atomic level interactions between local anesthetic and the lipid matrix of a cell membrane.

Influence of new gamma-aminobutyric acid amide derivatives and its phthalimide precursors on the central nervous system activity in mice.

The present study investigated the influence of BM-78, BM-121 (gamma-aminobutyric acid amide derivatives) and BM-42, BM-43 (phthalimide precursors of BM-78 and BM-121) on the spontaneous locomotor activity and on the picrotoxin-induced seizures. Results of pharmacological in vivo examination of the effects of new gamma-aminobutyric acid amide derivatives and its phthalimide precursors (compounds BM-78, BM-121, BM-42, BM-43), presented in this paper showed that all the compounds had different but clear influence on CNS in mice.

Antianaphylactic and antiasthmatic properties of new piperazinyl 7-(beta-hydroxypropyl)-theophylline derivatives in guinea pigs.

The present studies have demonstrated that new piperazinyl 7-(beta-hydroxypropyl)-theophylline derivatives (R3, R6, R7) possess antihistamine, antianaphylactic and antiasthmatic properties. The compound R6 exerted especially pronounced selective protective action in experimental histamine asthma and provided effective prevention against anaphylactic shock in guinea pigs. The evidence was also presented that compound R6 inhibited in vitro mast cell degranulation induced by the preparation 48/80 liberating endogenous histamine. It was shown that the compound R6, i.e. 7-beta-hydroxy-gamma-[N1-(N4-benzyl)-piperazinyl)-theophylline efficiently competed with histamine of both endo- and exogenous origin and inhibited the mediator release from the mast cells.

Comparative investigations of hydroxyamine carane derivative and its R,S-diastereoisomers with strong local anesthetic activity.

Our previously conducted pharmacological screening led as to the discovery of the strong local anesthetic activity of the compound designated as KP-23. Earlier crystallographic studies revealed that the compound KP-23 crystallized in diastereoisomeric form in lowest symmetry. The aim of these comparative investigations was to evaluate anesthetic activity of KP-23 and its R,S-diastereoisomers, which were synthesized at the Institute of Organic Chemistry, Biochemistry and Biotechnology, Wroclaw University of Technology.

Local anesthetic and antiarrhythmic effect of some imidazolidin-2-one derivatives.

A series of the new derivatives of imidazolidin-2-one was investigated in order to determine their local anesthetic and antiarrhythmic activity. All compounds tested showed strong local anesthetic properties and variable effects on adrenaline-, aconitine- and barium chloride- induced arrhythmia. The results suggest that the antiarrhythmic properties of these compounds is related to their local anesthetic properties.

Effect of monoterpene derivative KP-19 on the pressor activity of catecholamines in rats.

The present study investigated the influence of KP-19, the propranolol analogue, bearing natural monoterpene moiety in its structure, on the blood pressure and respiration, the effect on the isolated heart rhythm disturbances induced by occlusion and reperfusion and on the pressor activity of catecholamines in normotensive rats.

Influence of new monoterpene homologues of GABA on the central nervous system activity in mice.

This behavioral study in mice showed that the monoterpene homologues of GABA (SL-1, SL-2 and SL-3), characterized by low toxicity, induced an increase in spontaneous locomotor activity (SL-2 and SL-3). Moreover, SL-3 shortened hexobarbital-induced sleeping time, and SL-1 showed anticonvulsant activity in pentetrazole-induced seizures.

Propranolol analog with the natural monoterpene structure as a potent antiarrhythmic drug.

Antiarrhythmic effects and intracellular electrophysiological properties of a new antiarrhythmic compound (-)trans-4-[2-hydroxy-3(N-isopropylamino)-propoxyimino]-cis-car ane (9) were studied in several models of arrhythmia and in isolated guinea-pig myocardial preparations. Compound 9 prevented the aconitine-induced arrhythmia, reversed the ouabin-induced arrhythmia depressed the maximum rate depolarization (Vmax), and shortened the action potential duration (ADP) and the effective refractory period (ERP). The data indicate that compound 9 is an effective antiarrhythmic presumably with a class 1 B mechanism of action.

[Hepatoprotective effect of flower pollen lipid extract in paracetamol-induced hepatotoxicity in mice]. / Hepatoprotekcyjne dzialanie lipidowego ekstraktu pylku kwiatowego w toksycznym uszkodzeniu watroby paracetamolem u myszy.

Hepatoprotective effects of the lipid flower pollen extract (LEPK) in paracetamol intoxication in mice were shown. Normalisation of A1AT and LDH--biochemical indicators of necrotic changes in the hepatic cells, and high protection ultrastructural cell organelle such as mitochondrion substantially testifies to the hepatoprotective effect of investigated lipid flower pollen extract on the hepatic cells.

The effect of (-)-4-(2-hydroxy-3(N-isopropylamino)-propoxyimino)-cis-carane on basal and forskolin-stimulated accumulation of cyclic AMP in the cerebral cortical slices of the rat.

(-)-4-(2-Hydroxy-3(N-isopropylamino)-propoxyimino)-cis-carane++ +, a local anaesthetic and platelet aggregation inhibitor which is much more potent than lignocaine, facilitated forskolin-induced cyclic (c) AMP accumulation in cerebral cortical slices of the rat. Lignocaine was ineffective in this respect. It is hypothesized that a cAMP-related mechanism may be involved in increased efficacy of the compound.

Propranolol analogs containing natural monoterpene structures: synthesis and pharmacological properties.

A few derivatives of natural, bicyclic monoterpenes, which are propranolol analogs, were synthetized. Those compounds were studied pharmacologically in order to determine their toxicity, antiarrhythmic activity in selected experimental models of arrhythmia, the local anesthetic effect and influence on the cardiovascular system. The tested compounds showed a less potent or similar toxicity towards reference drugs, were devoid of an antiarrhythmic activity in the model of barium arrhythmia, yet some of them (compounds 9 and 12) increased the arrhythmogenic dose of strophanthin. All the compounds studied had a local anesthetic effect stronger than lidocaine in infiltration anesthesia, and compound 8--also in surface anesthesia.

Molecular structure and antiaggregating activity of the potent local anaesthetic (-)-4-[2-hydroxy-3-(N-isopropylamino)-propoxyimino]-cis-carane .

The molecular structure of (-)-4-[-2-hydroxy-3-(N-isopropylamino)- propoxyimino]-cis-carane (C16H30O2N2.HCl), a recently synthesized potent local anaesthetic, including the absolute configuration at 4 chirality centres was determined using X-ray diffraction method. The substance crystallizes in diastereoisomeric form in lowest symmetry (triclinic P1 space group). Determined intermolecular close contacts between chlorine atoms and nitrogen and hydroxyl oxygen are the main determinants of crystal packing. In the crystalline state nitrogen of the isopropylamine group has quaternary coordination. The influence of the title compound on blood platelets aggregation induced by adenosine diphosphate was studied. The results of parallel tests conducted for lidocaine and bupivacaine show that the antiaggregating activity of the title compound is much stronger. This property could be attributed to the monoterpene part of its molecule, in analogy to the observed cyclic adenosine monophosphate inhibitory action of forskolin (diterpene).

Interaction between ethanol and diltiazem in the model of barium arrhythmia in the rat.

The antiarrhythmic action of diltiazem in the model of barium arrhythmia was studied in rats non-dependent and dependent on ethanol. The results of our studies showed that single intragastric administration of ethanol jointly with diltiazem did not significantly attenuate the antiarrhythmic effect of diltiazem. Ethanol administered repeatedly and jointly with diltiazem influenced the antiarrhythmic action of diltiazem in different ways, depending on the used dose of diltiazem. After repeated joint administration of ethanol and diltiazem in a lower dose, attenuation of the antiarrhythmic effect of diltiazem was not observed. Repeated joint administration of ethanol and diltiazem in a higher dose attenuated the antiarrhythmic effect of diltiazem. Those experiments also showed that single administration of diltiazem did not significantly influence the ethanol level in the blood; however, when administered repeatedly, diltiazem reduced the concentration of ethanol in blood.

Influence of ethanol on the antiarrhythmic activity of verapamil.

The aim of this work was to determine the influence of ethanol on the antiarrhythmic activity of verapamil in the model of calcium arrhythmia in rats non-dependent and dependent on ethanol. The results of the experiment show that a combined, single administration of ethanol and verapamil attenuates in a statistically significant manner the antiarrhythmic effect of verapamil. Ethanol administered repeatedly together with verapamil does not diminish the antiarrhythmic activity of verapamil.

Synthesis and local anesthetic and circulatory actions of aminoesters and hydroxyamine monoterpene derivatives.

Esters of N,N-diethylaminoacetic acid and hydroxyamines, obtained from structurally different natural monoterpenes, were pharmacologically examined. It was proved that salts of the obtained compounds had local anesthetic properties in infiltration anesthesia, compounds 9, 6 and 8 having been more potent than lidocaine. Compounds 7-9 slightly increased the arrhythmogenic dose, and compound 12 - the lethal dose of strophanthin. All the examined compounds transiently decreased the arterial blood pressure and displayed a cardiopressive activity.