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Biomedical subjects

M Jokanović

Publications and source records attributed to M Jokanović.

At least 19 recordsLinked to original sources
PubMed2004

Transport of endogenous nucleosides in guinea pig heart.

The purpose of this study was to investigate the characteristics of transport of endogenous nucleosides into cardiac tissue from coronary circulation. The study was performed on the isolated perfused guinea pig heart, using the rapid paired tracers single-pass technique. The maximal cellular uptake (U(max)) and total cellular uptake (U(tot)) of adenosine, deoxyadenosine, thymidine, uridine, and cytidine were determined. The cellular uptake of adenosine was significantly higher than the cellular uptake of other studied nucleosides. To elucidate the mechanisms of nucleoside transport, competition studies were performed and the influence of S-(p-nitrobenzyl)-6-thioinosine (NBTI) and sodium ion absence on U(max) and U(tot) was investigated. Self- and cross-inhibition studies indicated the saturable mechanism of nucleosides transport into cardiac tissue and the involvement of different transport mechanisms for purine and pyrimidine nucleosides. The study also showed that both equilibrative-sensitive (es) and sodium-dependent transport were responsible for adenosine and thymidine cellular uptake.

Adenosine↗
PubMed2001

Biotransformation of organophosphorus compounds.

This study reviews current understanding of mechanisms of biotransformation of organophosphorus compounds (OPC). The first part of this article covers chemical aspects of biotransformation describing reactions that lead to activation or detoxication of OPC. The second part explains biochemical mechanisms of biotransformation describing the role of enzymes that are involved in this process. Among them are the enzymes that take part in metabolic activation of OPC such as cytochrome P450 system, NADPH-cytochrome P450 reductase and flavin-containing monooxygenases. Among enzymes participating in detoxication of OPC, the role of phosphoric triester hydrolases, carboxylesterases and glutathione redox system is explained. This article also deals with other aspects of detoxication of OPC such as protein binding and the role of tissue depots for these compounds.

Animals↗
PubMed2001

Effects of atropine, trimedoxime and methylprednisolone on the development of organophosphate-induced delayed polyneuropathy in the hen.

In this study we have examined the effects of atropine, trimedoxime (TMB-4) and methylprednisolone (MP) on the development of organophosphate-induced delayed polyneuropathy (OPIDP) in the hen. The birds were treated with standard neuropathic dose of diisopropylfluorophosphate (DFP) (1.1 mg/kg, sc), which produced OPIDP that could be graded as 5 on the 8-point scale, and the development of OPIDP was observed for the next 22 days. The results obtained have shown that atropine (20 mg/kg, ip), TMB-4 (15 mg/kg, im) and MP (2 or 10 mg/kg, ip) either alone or in different combinations are able to improve the condition of the birds. The most potent effect was obtained with atropine, TMB-4 (given 20 min before DFP) and MP (2 mg/kg, sc, given 20 min before and at 48 hour intrevals after poisoning) since the signs of OPIDP could hardly be seen (grade 1 at the 8-point scale). When TMB-4 and MP were given 15 or 40 min after DFP the protective/therapeutic effects of these drugs appeared to be diminished since walking disorders were more serious and graded as 2 or 4, respectively. The possible mechanisms of the action of the drugs in respect to OPIDP are discussed. In conclusion, the results of this study have shown that it is possible to prevent the development of DFP-induced OPIDP in the hen by treatment with atropine, trimedoxime and methylprednisolone when they were given before or soon after DFP.

Animals↗
PubMed2000

The treatment of delayed polyneuropathy induced by diisopropylfluorophosphate in hens.

This study was undertaken to examine the influence of atropine, oximes and benzodiazepine on organophosphate-induced delayed polyneuropathy (OPIDP) in hens, which were poisoned with diisopropylfluorophosphate (DFP). The birds were treated with a standard neuropathic dose of DFP (1.1 mg/kg, s.c.), which produced typical signs of OPIDP. The development of OPIDP was observed within the followings 22 days. All drugs were given subcutaneously (s.c.), intramuscularly (i.m.) or intraperitoneally (i.p.), 20 min before the poison. The results obtained have shown that atropine (20 mg/kg, i.p.) only in combination with oxime TMB-4 (15 mg/kg, i.m.) produced significant improvement of OPIDP symptoms in comparison with positive control. Clinical signs and symptoms of OPIDP in the group which was treated with atropine (20 mg/kg, i.p.), TMB-4 (15 mg/kg, i.m.) and midazolam (2.5 mg/kg, i.m.) were more improved than that in the presence of a combination of atropine and TMB-4. The results of these experiments have shown that it is possible to prevent the development of DFP-induced OPIDP in hens by treatment with atropine and TMB-4 or atropine, TMB-4 and midazolam when given before DFP.

Animals↗
PubMed2000

Influence of ribavirin on the micronucleus formation and in vitro proliferation of human lymphocytes.

Cytotoxic effects of the antiviremic drug ribavirin (1-beta-D-ribofuranosyl-1,2,4-triazole-3-carboxamide) were evaluated in vitro measuring micronucleus formation and cell proliferation kinetics in whole blood cultures employing cytokinesis block (CB) micronucleus test. The cells were exposed to ribavirin doses ranging from 0.05 0.65 micromol/ml at three different incubation times. The frequency of micronuclei in treated samples demonstrated relatively low ability of ribavirin to induce micronuclei. However, the lowest concentration ofribavirin markedly changed the frequency of mononucleated and multinucleated cells, particularly binucleated ones, which declined significantly. The decline in the frequency ofbinucleate cells was followed with accumulation of greater number of mononucleate cells. Decreased proliferation potential of lymphocytes treated with ribavirin indicates that cells are arrested prior to metaphase. The present investigation showed that ribavirin is capable to induce a delay in cellular proliferation at all the doses assayed. The study demonstrated that CB micronucleus assay is simple and rapid method that can be used to assess toxic effect of drugs in vitro.

Cell Division↗
PubMed1998

Modification of the rate of aging of diisopropylfluorophosphate-inhibited neuropathy target esterase of hen brain.

This study was aimed to investigate the possibility of modifying the rate of aging of diisopropylfluorophosphate-inhibited neuropathy target esterase (NTE) of hen brain. This reaction on NTE occurs with a half-time of 7.4 min. Atropine was effective in decreasing the rate of aging on DFP-inhibited NTE and this effect was time- and concentration-dependent. Atropine was also a weak but progressive inhibitor of NTE activity (I50 = 80 mM) and this reaction appears to be reversible at lower atropine concentrations. Among compounds containing oxime functional groups only OPAB, having longer methylene chain and being more lipophylic than other oximes usually used in acetylcholinesterase (AChE) reactivation studies, was effective in decreasing the rate of aging on DFP-inhibited NTE. However, when atropine and oximes were used together we have obtained a potentiating and/or synergistic effect which was most significant with combination of atropine and TMB-4 giving up to a 15-fold decrease in the rate of aging reaction. The efficacy of this particular combination was concentration-dependent. We have also discussed similarities and differences in aging reaction occurring on NTE and AChE.

Acetylcholinesterase↗
PubMed1998

Detection of apoptosis and phagocytosis in vitro in C6 rat glioma cells treated with tiazofurin.

Tiazofurin, an anticancer drug which inhibits IMP dehydrogenase activity and decreases GTP concentration in various malignant cells, induced inhibition of growth and apoptosis in C6 rat glioma in vitro. The effects of tiazofurin were significantly blocked by addition of exogenous guanosine, suggesting the role of decreased GTP in triggering specific signal transduction pathways involved in apoptosis of C6 cells. The most interesting result of this study was the evidence of phagocytosis of apoptotic cells in vitro by neighbouring cells, a phenomenon considered to occur only in apoptosis in vivo. The possibility of observing phagocytosis in C6 glioma cells suggests that this cell system could be a good model for studying mechanisms of phagocytosis in vitro.

Journal Article↗
PubMed1997

Abnormal cholinesterase activity: understanding and interpretation.

Abnormal acetylcholinesterase and cholinesterase activity may occur due to a) various physiological and pathological conditions, b) genetic factors or c) interaction with drugs and cholinesterase inhibitors. This paper reviews and discusses such conditions in which both cholinesterases show abnormal activity focusing on better understanding and interpretation of laboratory results. In particular, the mechanism of interaction of both cholinesterases with their inhibitors such as organophosphorus and carbamate compounds is discussed. Some practical recommendations concerning sampling and preparation of samples for enzyme assay are given in order to avoid errors that may affect laboratory findings.

Acetylcholinesterase↗
PubMed1996

Interaction of organophosphorus compounds with carboxylesterases in the rat.

Carboxylesterases (CarbE) are involved in detoxication of organophosphorus compounds (OPC) through two mechanisms: hydrolysis of ester bonds in OPC which contain them and binding of OPC at the active site of CarbE which reduces the amount of OPC available for acetylcholinesterase inhibition. This study of the interaction of rat plasma and liver CarbE with dichlorvos, soman and sarin in vitro and in vivo was undertaken in order to contribute to better understanding of the role of CarbE in detoxication of OPC. The results obtained have shown that inhibitory potency (I50) of dichlorvos, sarin and soman towards rat liver CarbE was 0.2 microM, 0.5 microM and 4.5 microM, respectively, for 20-min incubation at 25 degrees C. Second-order rate constants (k(a)) for liver CarbE inhibition were 2.3 x 10(5) M-1 min-1, 6.9 x 10(4) M-1 min-1 and 1.1 x 10(4) M-1 min-1 for dichlorvos, sarin and soman, respectively. The corresponding values for plasma CarbE could not be calculated because of dominant spontaneous reactivation of inhibited CarbE. CarbE inhibited with these OPC in vitro spontaneously reactivate with half-times of 18, 143 and 497 min for sarin, dichlorvos and soman in plasma and 111, 163 and 297 min for sarin, soman and dichlorvos in liver, respectively. These results were also confirmed in experiments in vivo in which rats were subcutaneously treated with 0.5 LD50 of these agents. The half-times of spontaneous reactivation of rat plasma CarbE in vivo were 1.2, 2.0 and 2.7 h for dichlorvos, sarin and soman, respectively. These findings have changed current understanding of the mechanism of interaction of CarbE with OPC and involvement of the enzymes in detoxication of OPC, suggesting an active and important role of the enzymes in metabolic conversions of OPC to their less toxic metabolites.

Animals↗
PubMed1996

Oxime-induced reactivation of acetylcholinesterase inhibited by phosphoramidates.

The reaction of human erythrocyte acetylcholinesterase (AChE) with a set of structurally related phosphoramidates was studied in order to investigate the properties of phosphorylated enzyme and the effects of 4 oximes PAM-2, TMB-4, HI-6 and BDB-106 on the reactivation of inhibited AChE. Second-order rate constant of the phosphorylation reaction of the compounds towards the active site of AChE range between 5.0 x 10(2) and 4.9 x 10(6) M-1min-1 and their inhibitory power (I50) was from 7.3 x 10(-5) to 5.7 x 10(-9) M for 20 min incubation at 37 degrees C. The oximes used were weak reactivators of inhibited AChE except for (C4H9O)(NH2)P(O)DCP (DCP, -O-2,5-dichlorphenyl group) and (C6H13O)(NH2)P(O)SCH3 where we have obtained good reactivation. Imidazole oxime BDB-106 proved to be a potent reactivator of tabun-inhibited AChE.

Acetylcholinesterase↗
PubMed1995

A comparison of trimedoxime, obidoxime, pralidoxime and HI-6 in the treatment of oral organophosphorus insecticide poisoning in the rat.

This study summarizes the results of examination of acute oral toxicity of 26 organophosphorus insecticides in rats. The effectiveness of trimedoxime, obidoxime, pralidoxime and HI-6, given with atropine and diazepam, was tested in the treatment of poisoning with 2 LD50 of the insecticides. It was shown that the oximes were potent antidotes in poisoning with phosphate insecticides. Obidoxime, pralidoxime and HI-6 had low effectiveness in the treatment of poisoning with phosphonates and phosphorothiolates. However, none of the oximes was an effective antidote in poisoning with dimethoate and pyridafenthion. Trimedoxime was the most effective oxime in the treatment of insecticide poisoning, being successful especially at the lowest tested doses.

Administration, Oral↗
PubMed1995

Interaction of phosphamidon with neuropathy target esterase and acetylcholinesterase of hen brain.

Phosphamidon (PSM) is an organophosphorus insecticide widely used in agriculture. This study was undertaken to examine the interaction of PSM with acetylcholinesterase (AChE) and neuropathy target esterase (NTE) of hen brain in vitro and in vivo. PSM was a potent inhibitor of AChE, with an I50 of 2.9 microM and second-order rate constant (ka) of 1.2 x 10(4) M-1 min-1 at 37 degrees C. PSM-inhibited AChE aged rapidly (t1/2 = 1.9 h). Pyridinium oximes pralidoxime, trimedoxime, obidoxime and HI-6 were effective reactivators of PSM-inhibited AChE, providing up to 75% reactivation. PSM was one of the weakest inhibitors of NTE among organophosphorus compounds, with an I50 of 19 mM and ka of 1.8 M-1 min-1 at 37 degrees C. Inhibited NTE did not reactivate spontaneously and KF-induced reactivation was not obtained even at the earliest tested moments, so it was not clear whether aging of PSM-inhibited NTE occurred very quickly or the KF molecule could not affect the stability of phosphoryl-NTE bond. From the ratio of kas for NTE and AChE (0.00015) it was predicted that delayed neuropathic effects of PSM in vivo would appear only at doses far above the acute LD50. The LD50 value of PSM p.o. for hens was 9 mg/kg. Hens were treated with a single oral dose of PSM, combined with standard antidotal treatment which included atropine, physostigmine, pralidoxime and anticonvulsant midazolam. Doses of 90 and 250 mg/kg caused up to 27% and 45% NTE inhibition 48 h after poisoning, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1993

Hydrolysis of some organophosphorus dichlorophenyl esters by hen brain homogenates and rabbit serum compared with hydrolysis of paraoxon.

The hydrolysis of four organophosphorus dichlorophenyl esters and of paraoxon was studied in hen brain homogenates and in rabbit serum. All compounds were hydrolysed by both preparations, but the rates were different in the two preparations. EDTA inhibited the hydrolysis almost completely in rabbit serum, but had only a small effect on the hydrolysis in hen brain homogenates.

Animals↗
PubMed1991

HI-6 in man: efficacy of the oxime in poisoning by organophosphorus insecticides.

The efficacy of the oxime HI-6 was studied as a treatment for organophosphorus poisoning. HI-6 was given four times daily as a single intramuscular injection of 500 mg accompanied by atropine and diazepam therapy. Oxime treatment was started on admission and continued for a minimum of 48 h and a maximum of 7 d. HI-6 rapidly reactivated human blood acetylcholinesterase inhibited by dimethoxy organophosphorus compounds, while the dimethoxy-inhibited enzyme was mainly resistant to the treatment by HI-6. Although both HI-6 and pralidoxime chloride reactivated the red blood cell cholinesterase in quinalphos-poisoned subjects, the return of enzyme activities was more rapid following the use of HI-6. The general improvement of poisoned patients, which was sometimes more rapid than the rise of acetylcholinesterase activity, pointed to direct pharmacological effects of HI-6. No undesirable side-effects were noted in patients when HI-6 plasma concentrations were maintained at levels far above the 'therapeutic' concentration for up to 7 d.

Adult↗
PubMed1989

Role of carboxylesterase in soman, sarin and tabun poisoning in rats.

TOCP (triorthocresyl phosphate) inhibits carboxylesterase (CarbE) activity in rat plasma and liver and significantly increases soman, sarin and tabun toxicity. Application of these agents after TOCP caused strong additional inhibition of CarbE and cholinesterases (ChE) in rat red blood cells, plasma, liver, brain, diaphragm and intercostal muscle. After phenobarbital pretreatment, which induced CarbE activity in plasma and liver by 80% and that of plasma ChE by 33%, acute toxicity of soman and tabun was greatly decreased, while that of sarin remained unaffected.

Animals↗
PubMed1987

Protective effects of oximes HI-6 and PAM-2 applied by osmotic minipumps in quinalphos-poisoned rats.

Protective and reactivating effects of oximes HI-6 and PAM-2, combined with atropine and diazepam, were investigated in quinalphos-poisoned rats. In protective experiments, atropine and diazepam decreased acute toxicity of the insecticide 3.3 times. Later administration of a single injection of oximes led to further improvement of protective indexes which were 1.45 (PAM-2) and 1.52 (HI-6) times larger. Plasma HI-6 concentrations below 1 microgram/ml, continuously maintained by osmotic minipumps and supported by a single administration of atropine and diazepam, protected animals from 18.6 LD50 of quinalphos, while its higher concentrations (ranging from 1 to 5.4 micrograms/ml) provided markedly better protection (up to 72 LD50). Corresponding plasma PAM-2 concentrations were even more effective in overcoming toxic effects of quinalphos. PAM-2 concentrations, continuously maintained in plasma, were distinctly better in protecting and reactivating peripheral cholinesterase activity than corresponding HI-6 concentrations in the case of quinalphos poisoning. On the basis of our findings we suggest that continuous maintenance of low oxime concentrations is preferred to single oxime administration in the therapy of organophosphate intoxications.

Animals↗