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PubMed2003

Effects of tetracaine and bupivacaine on chemiluminescence generated by formyl-methionyl-leucyl-phenylalanine-stimulated human leukocytes and cell-free systems.

We investigated the abilities of an ester-type local anesthetic tetracaine and an amide-type local anesthetic bupivacaine to inhibit reactive oxygen and/or nitrogen species generated by either human leukocytes or cell-free systems via luminol- and lucigenin-enhanced chemiluminescence (CL). Tetracaine (96+/-1%, n=6, 1 mM) and bupivacaine (97+/-0.4%, n=5, 1 mM) significantly inhibited FMLP-induced-CL in leukocyte assay. In cell-free experiments, CL due to superoxide production was significantly inhibited by tetracaine (23+/-2%, n=6) and bupivacaine (25+/-4%, n=6) at 1 mM. Although bupivacaine was ineffective on H(2)O(2)-induced CL, tetracaine activated H(2)O(2)-induced luminol CL. Additionally, tetracaine inhibited FeSO(4)-induced CL (42+/-2%, n=6, 1 mM). In hypochlorous acid (HOCl)-induced CL assay, 70+/-10% (n=5) and 57+/-4% (n=15) inhibitions were observed by tetracaine and bupivacaine, respectively. Peroxynitrite-induced luminol (54+/-7%, n=7, tetracaine, and 26+/-5%, n=8, bupivacaine, at 1 mM) and lucigenin CL (58+/-3%, n=6, tetracaine, and 22+/-14%, n=9, bupivacaine, at 1 mM) were markedly inhibited. Tetracaine interacted with superoxide, hydroxyl radical, HOCl and peroxynitrite, while bupivacaine scavenged superoxide, HOCl and peroxynitrite. These direct scavenging properties of these drugs might be involved in the inhibition observed in leukocyte free radical release. In general, a decrease in CL-response was seen with higher concentrations (0.1-1 mM) of the local anesthetics, it is likely that tetracine and bupivacaine at therapeutic concentrations do not suppress leukocyte function in vivo.

Acridines↗
PubMed2004

Synthesis and in vitro antioxidant activity of glycyrrhetinic acid derivatives tested with the cytochrome P450/NADPH system.

Five glycyrrhetinic acid (Ib) derivatives have been synthesized to try to improve the antioxidant activity. Their in vitro antioxidant activities were studied using a cytochrome P450/NADPH reductase system from rat liver microsomes. The generation of microsomal free radicals was followed by oxidation of the DCFH-DA probe, while evaluating the capacity to inhibit reactive oxygen species (ROS) formation. Two hydroxylated derivatives, 18beta-olean-12-ene-3beta,11alpha,30-triol (II) and 18beta-olean-12-ene-3beta,11beta,30-triol (IV), exhibited strong antioxidant activities. At a concentration of 1.0 mg/ml, these derivatives inhibited ROS formation by 50% and 51%, respectively. Moreover, two homo- and heterocyclic diene derivatives, 18beta-olean-11,13(18)-diene-3beta,30-diol (III) and 18beta-olean-9(11),12-diene-3beta,30-diol (V), were also effective in ROS-scavenging activity (inhibition of 41% and 44% of ROS activity, respectively). In the same conditions, the lead compound (Ib) and the reference vitamin E inhibited ROS activity by 31% and 32%, respectively. Our results suggest that the chemical reduction of the 11-keto and 30-carboxyl groups into hydroxyl function (example, II, IV) can increase the antioxidant activity of Ib significantly. In view of these results, our study represents a further approach to the development of potential therapeutic agents from Ib derivatives for use in pathologic events in which, free radical damage could be involved.

Animals↗
PubMed1999

Spectrophotometric and electrochemical study of protolytic equilibria of some oximes-acetylcholinesterase reactivators.

Newly synthesized oximes, mono and bis imidazole derivatives, which promise to be more effective acetylcholinesterase reactivators than standard antidotes used, were investigated by spectrophotometric and electrochemical methods. The electrochemical investigations confirmed the existence of overlapping equilibria, obtained by spectrophotometric methods. Dissociation constants of those oximes were also obtained by numerical treatment of overlapping equilibria, using the Lavendberg Marquardt least square method, and when compared with the same for some similar compounds, were found to be very effective acetylcholinesterase reactivators. The distribution of ionic forms of the investigated oximes, as a dependence of pH values, was calculated from the obtained values of dissociation constants. The results indicated that many oxime anions will be available at physiological pH 7.4 and a relative increased ability to reactivate inhibited acetylcholinesterase could be expected.

Cholinesterase Inhibitors↗
PubMed1989

The bispyridinium-dioxime HLö-7. A potent reactivator for acetylcholinesterase inhibited by the stereoisomers of tabun and soman.

Purification of (+)-tabun was accomplished by treatment with electric eel acetylcholinesterase (AChE) in order to bind contaminating (-)-tabun and with purified (+)-tabun shown similar properties in reactivation reactions with oximes (pH 7.5, 25 degrees). The bispyridinium-2,4-dioxime HLö-7 is a substantially active reactivator for these inhibited enzymes as well as for human erythrocyte AChE inhibited with (-)-tabun. In contrast, the corresponding bispyridinium-2-monooxime HI-6 does not show any activity at similar reaction conditions. HLö-7 is also much more active than HI-6 when used as a reactivator for electric eel AChE inhibited by some N-unsubstituted derivatives of tabun. Surprisingly, HLö-7 is highly active in reactivating human erythrocyte and rat diaphragm AChE inhibited by C(+)P(+/-)-and C(-)P(+/-)-soman, i.e. at least as active as HI-6, which is the most potent reactivator for soman-inhibited AChE reported so far. To our knowledge, HLö-7 is the first compound reported in literature that shows a potent reactivating activity towards both tabun-inhibited AChE and soman-inhibited AChE.

Acetylcholinesterase↗
PubMedDate not supplied

Bispyridinium oximes as antidotal treatment of cyclosarin poisoning-in vitro and in vivo testing.

The mechanism of intoxication with organophosphorus compounds, including highly toxic nerve agents and less toxic pesticides, is based on the formation of irreversibly inhibited acetylcholinesterase, which causes cumulation of neuromediator acetylcholine in synaptic clefts and subsequent overstimulation of cholinergic receptors, that is followed by a generalized cholinergic crisis. Nerve agent poisoning is conventionally treated using a combination of a cholinolytic (atropine mostly) to counteract the accumulation of acetylcholine and acetylcholinesterase reactivators (pralidoxime or obidoxime) to reactivate inhibited acetylcholinesterase. In this study of cyclosarin poisoning treatment, oximes of different chemical structures (obidoxime, HI-6, BI-6, and HS-6) were tested in vitro on rat brain acetylcholinesterase (enzyme source: rat brain homogenate), and afterwards, they were tested in vivo in equimolar doses, in mice and rats. The HI-6 oxime appeared to be the most effective oxime in vitro and in vivo.

Animals↗
PubMed2003

Scavenging of reactive oxygen species by a novel glucurinated flavonoid antioxidant isolated and purified from spinach.

NAO is a natural water soluble antioxidant that was isolated and purified from spinach leaves. Using HPLC, NMR, and CMR spectroscopy, the main components were identified as flavonoids and p-coumaric acid derivatives. The NAO was found to be a very effective antioxidant in several in vivo and in vitro biological systems. In the present study, the antioxidant activity of the novel antioxidant glucurinated flavonoid (GF) isolated and characterized from NAO, is compared to well-known antioxidants. In addition, the direct free radical scavenging properties of the purified component GF were studied using the electron spin resonance (ESR) technique. GF and NAO were found to be superior to EGCG and NAC and to the Vitamin E homologue Trolox in inhibiting reactive oxygen species (ROS) formation in the autooxidation system of linoleic acid and in fibroblasts exposed to metal oxidation. GF and NAO were found to inhibit the ESR signal intensity of DMPO-O(2) radical formation during the riboflavin photodynamic reaction. 10 mM GF caused approximately 90% inhibition in the intensity of the ESR signal, while NAO at a concentration of 60 microg/ml caused an inhibition of about 50%. Using the Fenton reaction, GF and NAO were found to inhibit DMPO-OH radical formation. A concentration of 2 mM GF caused a 70% inhibition in the intensity of the DMPO-OH radical ESR signal, while propyl gallate at the same concentration caused only 50% inhibition. Furthermore, both GF and NAO also inhibited the (1)O(2) dependent TEMPO radical generated in the photoradiation TPPS4 system. About 80% inhibition was obtained by 4 mM GF. The results obtained indicate that the natural antioxidants derived from spinach may directly affect the scavenging of ROS and, as a consequence, may be considered as effective sources for combating oxidative damage.

3T3 Cells↗
PubMed2004

Tachykinin NK2 receptor antagonists for the treatment of irritable bowel syndrome.

Tachykinin NK2 receptors are expressed in the gastrointestinal tract of both laboratory animals and humans. Experimental data indicate a role for these receptors in the regulation of intestinal motor functions (both excitatory and inhibitory), secretions, inflammation and visceral sensitivity. In particular, NK2 receptor stimulation inhibits intestinal motility by activating sympathetic extrinsic pathways or NANC intramural inhibitory components, whereas a modulatory effect on cholinergic nerves or a direct effect on smooth muscle account for the NK2 receptor-mediated increase in intestinal motility. Accordingly, selective NK2 receptor antagonists can reactivate inhibited motility or decrease inflammation- or stress-associated hypermotility. Intraluminal secretion of water is increased by NK2 receptor agonists via a direct effect on epithelial cells, and this mechanism is active in models of diarrhoea since selective antagonists reverse the increase in faecal water content in these models. Hyperalgesia in response to intraluminal volume signals is possibly mediated through the stimulation of NK2 receptors located on peripheral branches of primary afferent neurones. NK2 receptor antagonists reduce the hyper-responsiveness that occurs following intestinal inflammation or application of stressful stimuli to animals. Likewise, NK2 receptor antagonists reduce intestinal tissue damage induced by chemical irritation of the intestinal wall or lumen. In healthy volunteers, the selective NK2 antagonist nepadutant reduced the motility-stimulating effects and irritable bowel syndrome-like symptoms triggered by intravenous infusion of neurokinin A, and displayed other characteristics that could support its use in patients. It is concluded that blockade of peripheral tachykinin NK2 receptors should be considered as a viable mechanism for decreasing the painful symptoms and altered bowel habits of irritable bowel syndrome patients.

Animals↗
PubMedDate not supplied

[Thiamine phosphates and regulation of the pyruvate dehydrogenase complex activity in rat liver mitochondria].

The possibility of thiamine phosphates to participate in the regulation of pyruvate dehydrogenase complex activity on the level of isolated mitochondria is studied. It is shown that an increase in the thiamine diphosphate concentration in incubation medium produces no significant changes in the pyruvate dehydrogenase activity of mitochondria. The pyruvate dehydrogenase activity decreases when mitochondria are incubated with thiamine triphosphate or ATP under different conditions. Thiamine triphosphate is not able to replace ATP in kinase reaction of the isolated complex, but it inhibits reactivation of the complex with exogenase phosphatase; under the same conditions thiamine diphosphate activates phosphatase. Analysis of these data leads to conclusion that under native conditions an increase of the intramitochondrial thiamine triphosphate concentration can produce a drop in the pyruvate dehydrogenase complex activity by inhibition of the phosphatase reaction.

Animals↗
PubMed1998

A model of primary HIV-1 infection.

We construct a model based on biological principles of the interaction of HIV-1 with the CD4+ T cells at primary infection. Most of the parameters are obtained from the literature, the remainder from fitting the output of the model to data from seven patients. On the basis of the model we find that initial viral containment is due to an effective immune response. The viral level after the initial peak, a surrogate marker of disease progression, was determined by the rate of reactivation of memory cells. Differences in this rate may occur because of inter- or intra-individual differences in the capability of memory cells to recognise and dispose of variants of HIV, either due to immune escape mutations within the virus or because the virus directly inhibits reactivation. With no choice of parameters could direct and indirect killing produce the gradual loss in CD4+ T cells with the observed viral behaviour. The loss of CD4+ T cells is perhaps due to defective expansion of activated cells of both HIV specific and nonspecific cells. As less memory cells are produced as a result then this compartment decreases and hence so do naive numbers through less reversion of memory cells to the naive phenotype.

Adult↗
PubMed2005

[A comparison of the efficacy of the reactivators of acetylcholinesterase inhibited with tabun].

The nerve agent tabun inhibits acetylcholinesterase (AChE; EC 3.1.1.7) by the formation of a covalent bond with the enzyme. Afterwards, AChE is not able to fulfil its role in the organism and subsequently cholinergic crisis occurs. AChE reactivators (pralidoxime, obidoxime and HI-6) as causal antidotes are used for the cleavage of the bond between the enzyme and nerve agent. Unfortunately, their potency for reactivation of tabun-inhibited AChE is poor. The aim of the study was to choose the most potent reactivator of tabun-inhibited AChE. We have tested eight AChE reactivators--pralidoxime, obidoxime, trimedoxime, HI-6, methoxime, Hlö-7 and our newly synthesized oximes K027 and K048. All reactivators were tested using our standard in vitro reactivation test (pH 8, 25 degrees C, time of inhibition by the nerve agent 30 minutes, time of reactivation by AChE reactivator 10 minutes). According to our results, only trimedoxime was able to achieve 50% reactivation potency. However, this relatively high potency was achieved at high oxime concentration (10(-2) M). At a lower concentration of 10(-4) M (the probably attainable concentration in vivo), four AChE reactivators (trimedoxime, obidoxime, K027, and K048) were able to reactivate AChE inhibited by tabun reaching from 10 to 18%.

Acetylcholinesterase↗
PubMed2002

Different effects of genistein and resveratrol on oxidative DNA damage in vitro.

Previous studies have demonstrated that phenolic compounds, including genistein (4',5,7-trihydroxyisoflavone) and resveratrol (3,4',5-trihydroxystilbene), are able to protect against carcinogenesis in animal models. This study was undertaken to examine the ability of genistein and resveratrol to inhibit reactive oxygen species (ROS)-mediated strand breaks in phi X-174 plasmid DNA. H(2)O(2)/Cu(II) and hydroquinone/Cu(II) were used to cause oxidative DNA strand breaks in the plasmid DNA. We demonstrated that the presence of genistein at micromolar concentrations resulted in a marked inhibition of DNA strand breaks induced by either H(2)O(2)/Cu(II) or hydroquinone/Cu(II). Genistein neither affected the Cu(II)/Cu(I) redox cycle nor reacted with H(2)O(2) suggest that genistein may directly scavenge the ROS that participate in the induction of DNA strand breaks. In contrast to the inhibitory effects of genistein, the presence of resveratrol at similar concentrations led to increased DNA strand breaks induced by H(2)O(2)/Cu(II). Further studies showed that in the presence of Cu(II), resveratrol, but not genistein was able to cause DNA strand breaks. Moreover, both Cu(II)/Cu(I) redox cycle and H(2)O(2) were shown to be critically involved in resveratrol/copper-mediated DNA strand breaks. The above results indicate that despite their similar in vivo anticarcinogenic effects, genistein and resveratrol appear to exert different effects on oxidative DNA damage in vitro.

Anticarcinogenic Agents↗
PubMed1988

Human antiidiotypic antibody against opiate receptors.

Sera containing antibodies to beta-endorphin from 2 patients with major depressive disorder were shown to have antidiotypic antibodies that specifically inhibited reactivity between anti-beta-endorphin IgG and beta-endorphin. Autologous and homologous antiidiotypic anti-anti-beta-endorphin IgG antibodies were isolated by affinity chromatography. The purified antiidiotypic antibody did not bind beta-endorphin but competed with [125I]beta-endorphin for rat brain opiate receptors. Normal IgG that was similarly treated had negligible competitive effects. The antibody bound to the membrane preparation; such binding was inhibited by opiate receptor ligands. Binding of the antiidiotype to a 60,000-dalton protein from rat brain was detected by Western immunoblot analysis. This protein corresponds in molecular weight to proteins proposed to be components of opiate receptors. These findings imply that immune reactivity to neuropeptides could contribute to psychiatric impairment.

Animals↗
PubMed1989

Attenuation of reactive hyperemia caused by aspirin in canine coronary artery.

Effects of intracoronary aspirin on coronary blood flow and reactive hyperemia were evaluated in closed-chest, anesthetized dogs. In 18 dogs the left circumflex coronary artery was cannulated and perfused by arterial blood at a constant pressure. Coronary blood flow was measured by an electromagnetic flowmeter. Intracoronary aspirin at doses of 5, 10, and 20 mg reduced coronary blood flow in a dose-dependent manner. Injection of aspirin at doses of 10 to 25 mg also inhibited reactive hyperemia following the coronary occlusion for fifteen seconds. The mean peak flow ratio was reduced from 2.13 +/- 0.42 to 1.75 +/- 0.35 (p less than 0.005). The increment of coronary blood flow provoked by intracoronary arachidonic acid at doses of 150 to 300 micrograms was almost entirely inhibited by the pretreatment of the coronary artery with aspirin. The authors conclude that aspirin increases coronary arterial resistance in a dose-dependent manner and also restricts the maximal dilating capacity, possibly by inhibition of prostacyclin synthesis.

Animals↗
PubMed1983

Mitochondrial 2-oxoacid dehydrogenase complexes of animal tissues.

The pyruvate dehydrogenase and branched-chain 2-oxoacid dehydrogenase complexes of animal mitochondria are inactivated by phosphorylation of serine residues, and reactivated by dephosphorylation. In addition, phosphorylated branched-chain complex is reactivated, apparently without dephosphorylation, by a protein or protein-associated factor present in liver and kidney mitochondria but not in heart or skeletal muscle mitochondria. Interconversion of the branched-chain complex may adjust the degradation of branched-chain amino acids in different tissues in response to supply. Phosphorylation is inhibited by branched-chain ketoacids, ADP and TPP. The pyruvate dehydrogenase complex is almost totally inactivated (99%) by starvation or diabetes, the kinase reactions being accelerated by products of fatty acid oxidation and by a protein or protein-associated factor induced by starvation or diabetes. There are three sites of phosphorylation, but only sites 1 and 2 are inactivating. Site 1 phosphorylation accounts for 98% of inactivation except during dephosphorylation when its contribution falls to 93%. Sites 2 and 3 are only fully phosphorylated when the complex is fully inactivated (starvation, diabetes). Phosphorylation of sites 2 and 3 inhibits reactivation by phosphatase. The phosphatase reaction is activated by Ca2+ (which may mediate effects of muscle work) and possibly by uncharacterized factors mediating insulin action in adipocytes.

3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide)↗
PubMed1995

Nitric oxide synthase inhibitor and lipopolysaccharide effects on reactivity of guinea pig airways.

The in vivo and in vitro effects of nitric oxide (NO) synthase inhibitors and lipopolysaccharide (LPS) on reactivity of guinea pig airways were examined. In isolated, perfused tracheas from untreated animals, the NO synthase inhibitors, N omega-nitro-L-arginine methyl ester (L-NAME; 10(-4)M), NG-methyl-L-arginine (L-NMMA; 10(-4) M) and aminoguanidine (10(-4) M) had no effect or inhibited reactivity to extraluminally (EL) or intraluminally (IL) applied methacholine and histamine. L-NMMA (10(-4) M) did not appreciably contract resting or metacholine-contracted preparations (+/- 3 x 10(-4) M L-arginine) and L-arginine only weakly relaxed contracted tracheas (+/- L-NMMA). Sodium nitroprusside and S-nitroso-N-penicillamine elicited relaxant responses and were more potent extraluminally than intraluminally. Methylene blue (10(-5) M) antagonized relaxation to sodium nitroprusside. Incubation with Escherichia coli LPS (10 micrograms/ml; 30 min incubation) alone in the EL and IL baths depressed methacholine and histamine concentration-response curves. In the presence of LPS, L-NAME potentiated responses to intraluminally applied methacholine but did not affect responses to extraluminally added methacholine. Four days after i.p. injection of animals with LPS (4 mg/kg), L-NAME potentiated responses to IL methacholine, and L-arginine acquired greater relaxant activity. LPS injection increased sensitivity to intraluminally added but not extraluminally added isoproterenol. LPS given by i.p. injection or by inhalation did not affect basal specific airway resistance of conscious animals or reactivity to methacholine aerosol during a postexposure period of 6 to 72 h. NO seems to have little role in regulating reactivity of guinea pig airways to bronchoconstrictor agonists, except after in vitro or in vivo exposure to LPS. After LPS injection the in vitro changes suggestive of NO synthase induction are not associated with altered airway reactivity to inhaled methacholine.

Airway Resistance↗
PubMed1996

Role of cytochrome P450 3A4 in human metabolism of MK-639, a potent human immunodeficiency virus protease inhibitor.

MK-639 (L-735,524) is a potent human immunodeficiency virus protease inhibitor under investigation in the treatment of acquired immunodeficiency syndrome. Five in vitro approaches have been used to identify the cytochrome P450 isoform(s) responsible for the human microsomal oxidative metabolism of MK-639. These approaches are: 1) chemical inhibition; 2) immunochemical inhibition; 3) metabolism by cDNA-expressed human cytochrome P450 enzymes; 4) a correlation analysis; and 5) competitive inhibition of marker activities. Ketoconazole and troleandomycin, both selective inhibitors for cytochrome P450 3A4 (CYP3A4), markedly inhibited the formation of all oxidative metabolites of MK-639; whereas other inhibitors (furafylline, sulfaphenazole, quinidine, S-mephenytoin, and diethyldithiocarbamate) had little effect on MK-639 metabolism. This suggested the involvement of CYP3A4 in MK-639 metabolism. Consistent with this, an anti-rat CYP3A1 rabbit polyclonal antibody, which shows a cross-reactive inhibition of CYP3A4-dependent testosterone 6beta-hydroxylation in human liver microsomes, completely inhibited MK-639 metabolism. Human recombinant CYP3A4 showed a high metabolic activity to form all MK-639 metabolites found in native human liver microsomes. In addition, the formation of individual MK-639 metabolites correlated well with each other and with testosterone 6beta-hydroxylation in 12 different human liver microsomes, whereas no correlation was observed between MK-639 metabolite formation and bufuralol 1'-hydroxylation (or tolbutamide methyl hydroxylation). Furthermore, MK-639 strongly inhibited testosterone 6beta-hydroxylation in a concentration-dependent manner. Kinetic analysis showed that MK-639 is a very potent competitive inhibitor for testosterone 6beta-hydroxylation, with a Ki value of approximately 0.5 mu M. Collectively, these results consistently indicate that CYP3A4 is the isoform responsible for the oxidative metabolism of MK-639 in human liver microsomes.

Anti-Bacterial Agents↗
PubMed2005

Comparison of ability of some oximes to reactivate sarin-inhibited brain acetylcholinesterase from different species.

The aim of this work was the comparison of reactivation potency of four oxime acetylcholinesterase (AChE) reactivators (pralidoxime, HI-6, K027 and K033) on three resources of the enzyme (human, pig and rat brain homogenate) inhibited by nerve agent sarin. The results demonstrate remarkable differences in the reactivation of inhibited brain AChE, depending on the oxime and species

Acetylcholinesterase↗
PubMed1989

Sex differences in the lateralized processing of facial emotion.

Two reaction time tasks were administered to male and female normal subjects, involving judgments of facial emotion. In the Word-Face task, judgments of similarity or difference of a centrally presented emotion word and an emotional face presented in the left or right visual field were required, and in the Face-Face task, comparisons of a centrally presented and a laterally presented emotional face were required. Results were significant for the matching trials only. Reaction times to negative emotions were faster overall than to positive emotions, and an Emotional Valence by Visual Field interaction was found such that reaction times were faster for negative emotions in the left visual field and for positive emotions in the right visual field. This interaction was significant for the female but not the male subjects, although similar patterns were observed in both sexes. Further, an interaction of Gender, Task, and Emotional Valence was found, such that the two tasks had opposite effects for the two sexes. The Face-Face task appeared to inhibit the performance of the male subjects and facilitate the performance of the female subjects in terms of reaction time. It was suggested that specifying the target emotion by an emotional face elicits a greater emotional response on the part of the subject than specification by a word, and that this emotional elicitation may result in a reactive inhibition in the male subjects and in an elaboration of the emotional response in the female subjects.

Adult↗