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Biomedical subjects

M Maksimović

Publications and source records attributed to M Maksimović.

At least 19 recordsLinked to original sources
PubMed2002

Nitric oxide (NO) and convulsions induced by pentylenetetrazol.

Data about the role of nitric oxide (NO) in epileptogenesis are contradictory. It is found to exert both proconvulsant and anticonvulsant effects. In an attempt to elucidate the role of NO in seizures, male Wistar rats were treated intraperitoneally by pentylenetetrazol (PTZ) (60, 80, and 100 mg/kg) and by a nitric oxide synthase antagonist, N-omega-nitro-L-arginine-methyl-ester (L-NAME) (10, 40, and 70 mg/kg), applied before PTZ. The time to onset and incidence of forelimb dystonia (FLD), generalized clonic convulsions (GCC), clonic-tonic convulsions (CTC), and mortality were recorded. The most successful convulsive response and mortality prevention were found in PTZ (80 mg/kg)-treated groups, where L-NAME (70 mg/kg) decreased the incidence by 29, 50, 67 (p = 0.052), and 50%, respectively, and significantly prolonged the time to onset, except that for mortality. Unexpectedly, L-NAME (40 mg/kg) increased incidence of GCC and mortality by 16%, similar to L-NAME (10 mg/kg) in PTZ (60 mg/kg)-treated groups, where GCC, CTC, and mortality increased by 14, 14, and 28%, respectively. Convulsive latency was prolonged in some PTZ (100 mg/kg) + L-NAME (40 and 70 mg/kg)-treated groups. In the experimental model and protocol used, it is concluded that (1) the effects of NO are L-NAME- and PTZ-dose dependent; (2) clonic-tonic convulsions are more strongly influenced by NO than limbic, probably because of PTZ limbic structure overstimulation; (3) L-NAME decreases the incidence of CTC and prolongs FLD, GCC, and CTC times to onset, indicating that NO acts as a proconvulsant; and (3) increased GCC, CTC, and mortality that suggests an anticonvulsant effect of NO needs further investigation.

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↗
PubMed2001

A bioavailability/bioequivalence study of two oral lansoprazole formulations after single administration to healthy volunteers.

Two oral lansoprazole formulations, containing encapsulated microgranules, Lasoprol (test formulation) and Lanzor (reference), were administered to 12 healthy volunteers of both sexes in a single dose of 30 mg lansoprazole in order to investigate their comparative bioavailability. No statistically significant differences, at the probability level of 90%, were observed neither for the maximal serum concentrations (1.12:1.22 micrograms/ml) nor for the area under the concentration-time curves (5.01:5.77 micrograms/ml.h), the parameter to which the inhibition of acid secretion induced by lansoprazole is directly related. The similar holds true for the value of time to reach the maximal concentration of lansoprazole in serum, although this parameter was previously described as less sensitive in comparative bioavailability studies. The terminal elimination half-lives were 4.56 h for Lasoprol and 4.57 h for the reference formulation. The results indicate the bioequivalence and good tolerability of both lansoprazole formulations. The overall pharmacokinetic profile of the drug was comparable with the data previously reported by other investigators.

2-Pyridinylmethylsulfinylbenzimidazoles↗
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↗
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↗
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↗
PubMed1992

Pharmacokinetics of the oxime HI-6 from a mixture with atropine sulphate in dogs.

The pharmacokinetics of the oxime HI-6 from an aqueous solution and from a mixture containing HI-6 and atropine (in doses similar as proposed for their combination in an automatic injector) was studied in German shepherd dogs. A standard manual injection of mixed drugs was followed by enhanced resorption of HI-6 while the elimination curves were quite similar. A comparison of the parameters describing relative bioavailability at the 80% probability level did not reveal any significant differences between the formulations of HI-6. The increase in HI-6 level in blood of animals receiving a mixture is more likely to be attributed to the local vasodilatation than to the systemic cardiovascular effects of atropine.

Animals↗
PubMed1987

Oral kinetics and bioavailability of the cholinesterase reactivator HI-6 after administration of 2 different formulations of tablets to dogs.

A one-compartment open model with first-order absorption was used for comparing new oral formulations of the potent acetylcholinesterase reactivating oxime HI-6. Although mean peak plasma levels did not differ between retard and conventional tablets (21.38 and 20.74 mumol/l), the time for reaching peak levels was significantly longer (5.5 h) with retard than with conventional tablets (2.86 h). Among other pharmacokinetic estimates only absorption half-lives and areas under the concentration-time curve (AUC) were significantly different (P less than 0.05). The AUC with retard tablets was 8.07% and that of conventional tablets 5.42% of intravenous AUC, indicating low bioavailability of oral HI-6 formulations. Potential therapeutic use of HI-6 requires, therefore, further investigations in order to improve its gastrointestinal absorption.

Administration, Oral↗
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↗
PubMed1984

Reactivators of organophosphate-inhibited cholinesterase. 4-cycloalkylcarbonyl substituted bis-pyridinium monooximes.

Two isomeric cyclopentylcarbonyl and two cycloheptylcarbonyl derivatives of 2-hydroxyiminomethyl-1-[3-(1-pyridinio-2-oxapropyl]pyr idinium diiodide and 4-hydroxyiminomethyl-1-[3-(1-pyridinio-2-oxapropyl]pyr idinium diiodide were prepared and characterized by spectroscopic methods. The inhibitory power (I50) of the investigated oximes was determined using purified bovine erythrocyte AChE and human erythrocyte AChE. Percentage of reactivation after 30 min was estimated after inhibition of human erythrocyte AChE by sarin, VX, tabun, soman, and paraoxon. The in intro protective indices (p.i. and P50) against inhibition by soman have been calculated using bovine erythrocyte AChE for p.i. and human erythrocyte AChE for P50. Their I50 for human erythrocyte AChE varied from 1.4-9.8 (10(-4) mol . dm-3) and for bovine erythrocyte AChE in the range of 1.1-17 (10(-5) mol . dm-3). With 2 X 10(-5) mol . dm-3 oximes the percent of reactivation was: 0-17% for paraoxon-inhibited AChE, 9-49% for sarin-inhibited AChE, 16-65% for VX-inhibited AChE, 0-8% for tabun-inhibited AChE, and 0-4% for soman-inhibited AChE. The 2-hydroxyimino derivatives protect human erythrocyte AChE and purified bovine erythrocyte AChE from inhibition by soman.

Acetylcholinesterase↗
PubMed1982

Reactivators of organophosphate-inhibited cholinesterase. Phenylhydroxymethyl and cyclohexylhydroxymethyl substituted bis-pyridinium monooximes.

Eleven isomeric phenylhydroxymethyl and cyclohexylhydroxymethyl derivatives of 1-(2-hydroxyiminomethyl-1-pyridinio)-3-(1-pyridinio)-2-oxapropane diiodide and 1-(4-hydroxyiminomethyl-1-pyridinio)-3-(1-pyridinio)-2-oxapropane diiodide were prepared and characterized by spectroscopic methods and pKa values. The inhibitory power (I50) of the investigated oximes was determined on purified bovine erythrocyte AChE and human erythrocyte AChE. Percentage of reactivation after 30 min was estimated after inhibition of human erythrocyte AChE by sarin, VX, and paraoxon. The in vitro protective index against inhibition by soman has been calculated using bovine erythrocyte AChE. Their I50 for human erythrocyte AChE varied in the range of 9-61(10(-4) mol. dm-3) and for purified bovine erythrocyte AChE in the range of 11-57 (10(-5) mol . dm-3). With 2 X 10(-5) mol . dm-3 of oximes the percent of reactivation was: 0-63% for paraoxon inhibited AChE, 12-73% for sarin inhibited AChE and 11-80% for VX inhibited AChE. With the exception of 1-(2-hydroxyiminomethyl-1-pyridinio)-3-(4-phenylhydroxymethyl-1-pyridinio) -2-oxapropane diiodide (6) the derivatives of 4-hydroxyiminomethylpyridine are by far better reactivators. None of the compounds could protect purified bovine erythrocyte AChE from inhibition by soman.

Acetylcholinesterase↗