Search PubMed for references concerning: Ro-2-0683
16 moreTitle: An explanation for the different inhibitory characteristics of human serum butyrylcholinesterase phenotypes deriving from inhibition of atypical heterozygotes Simeon-Rudolf V, Kovarik Z, Skrinjaric-Spoljar M, Evans RT Ref: Chemico-Biological Interactions, 119-120:159, 1999 : PubMed
The time course of inhibition of butyrylcholinesterase (EC 3.1.1.8) by the dimethylcarbamate Ro 02-0683 in sera taken from patients heterozygous for the usual (U), atypical (A), K or J variants was followed using propionylthiocholine as substrate. Data obtained were used to determine rate constants of inhibition together with the contribution made by each variant to total enzyme activity. The findings substantiate earlier reports that J and K mutations lead to quantitative changes in the concentration of usual enzyme in contrast to the qualitative changes of the atypical variant. The contribution of the atypical enzyme to the total activity in serum from UA, AK and AJ heterozygotes was respectively 17-20, 24-31 and 34-53%. The altered ratios of atypical to usual, K or J enzyme in UA, AK and AJ together with the constants on the usual enzyme alone, explain the differences in observed inhibitor numbers which enable these heterozygotes to be identified.
        
Title: Differential inhibition of plasma cholinesterase variants using the dibutyrate analogue of pancuronium bromide Whittaker M, Britten JJ Ref: Hum Hered, 31:242, 1981 : PubMed
A steroid, the dibutyrate analogue of pancuronium bromide (9.8 X 10(-8)M), has been used as differential inhibitor in the study of the plasma cholinesterase variants. Pancuronium dibutyrate numbers have been measured for 190 individuals, and the mean values for six of the known genotypes, E1uE1u, E1uE1f, E1uE1a, E1fE1a, E1aE1a, and E1fE1f, have been calculated. Evidence is presented that a combination of the pancuronium dibutyrate number and the fluoride number give better resolution of the six genotypes than the combination of the pancuronium dibutyrate and the dibucaine number. This new differential inhibitor has real potential for revealing the probable existence of new genotypes.
        
Title: The activity of various esterase inhibitors towards atypical human serum cholinesterase Kalow W, Davies R0 Ref: Biochemical Pharmacology, 1:183, 1958 : PubMed
16 lessTitle: An improvement in segregation of human butyrylcholinesterase phenotypes having the fluoride-resistant variants Kovarik Z, Simeon-Rudolf V Ref: Arh Hig Rada Toksikol, 54:239, 2003 : PubMed
Correct recognition of butyrylcholinesterase (BChE; EC 3.1.1.8) variants in human serum is essential if patients susceptible to a prolonged reaction following treatment with short acting muscle relaxants, like suxamethonium, are to be reliably identified. The dimethylcarbamate Ro 02-0683 is used in standard procedures for identification of BChE variant by measuring residual activity after two hours of inhibition. Such a long inhibition time distinguishes well between the usual (U) and atypical (A), but less successfully the fluoride-resistant (F) variant. In this paper, inhibition rate constants were determined from the initial time course of inhibition of homozygous (FF) and heterozygous (UF and AF) BChE phenotypes by Ro 02-0683; 1.6 x 10(6), 2.7 x 10(6) and 6.2 x 10(6) dm3 mol-1 min-1 for AF, FF and UF, respectively. After only 30 min of inhibition the resolution between the phenotypes was even better than after two hours. Hence, determination of the residual activity after 30 min inhibition is recommended for the segregation of the suxamethonium sensitive fluoride-resistant variants.
Human butyrylcholinesterase (EC 3.1.1.8) (BChE) is present in serum mainly as "usual UU" form, but it has also been found in variant forms known as "atypical" BChE. The most important predictive value of BChE phenotype is for anesthetist to prevent prolonged apnea. BChE has an important role in the hydrolysis of neuromuscular relaxant succinylcholine (suxamethonium, scoline) used during anesthesia. In order to detect atypical variants of BChE and give these findings to the anesthetists-surgeons before an operation to avoid the prolonged apnea, we phenotyped 542 sera of children before tonsillectomies. Total BChE activity was measured using butyrylthiocholine as substrate and dibucaine, fluoride, urea and dimethylcarbamate Ro 02-0683 were used as inhibitors. The frequencies of phenotypes in 542 children were: UU, UA, US, SS, AS and AA--92.25%, 7.01%, 0.18%, 0.18%, 0.18%, 0.18% respectively. Once established phenotype of BChE does not change during the lifetime. Therefore the carriers of atypical phenotype of BChE received a "Warning card", which is a permanent warning for succinylcholine application, as well as a sign to the members of the families to test their own phenotype of BChE. In our study three "Warning cards" were given: two to the carriers of atypical phenotype and third to a child presented as SS phenotype with low total activity of BChE. The present study is the first clinical evaluation of this genetic abnormality in the Republic of Croatia.
The objective of this study was to evaluate the efficacy of thienyl phencyclidine (tenocyclidine, TCP) and its newly synthesized adamantyl derivatives containing piperidine (TAPIP), pyrolidine (TAPIR) and morpholine (TAMORF) groups, which were tested with or without standard therapy in mice poisoned with organophosphates (OPs) and carbamates. These compounds with potential activity at the N-methyl- D-aspartate and muscarinic receptors showed low acute toxicity, having LD50 values varying from 106.00 mg/kg (TCP) to >504.00 mg/kg body weight (TAMORF). TCP and its adamantyl derivatives were administered intraperitoneally (2.5 mg/kg body weight) together with atropine (10.0 mg/kg body weight) and with or without 1/4 LD50 of the oxime HI-6. Each compound administered with atropine had a therapeutic effect against poisoning with carbamates propoxur, aldicarb and Ro 02-0683 (protective ratio of tenocyclidines was from 3.99 LD50 of aldicarb to >16.00 LD50 for propoxur). However, the efficacy of those compounds in combination with atropine was lower against poisoning with the OP insecticide dichlorvos (DDVP) and chemical warfare agents soman and tabun. In soman-poisoned mice, the best therapeutic effects were obtained with the combination of HI-6 plus atropine and test compounds, with protective ratios being from 5.40 to 7.12 LD50 of soman. The results suggest that TCP and adamantyl tenocyclidines could be used in combination with atropine as antidotes in carbamate poisoning and as adjuvant therapy to HI-6 and atropine in soman poisoning.
        
Title: Amino acid residues involved in the interaction of acetylcholinesterase and butyrylcholinesterase with the carbamates Ro 02-0683 and bambuterol, and with terbutaline Kovarik Z, Radic Z, Grgas B, Skrinjaric-Spoljar M, Reiner E, Simeon-Rudolf V Ref: Biochimica & Biophysica Acta, 1433:261, 1999 : PubMed
In order to identify amino acids involved in the interaction of acetylcholinesterase (AChE; EC 3.1.1.7) and butyrylcholinesterase (BChE; EC 3.1.1.8) with carbamates, the time course of inhibition of the recombinant mouse enzymes BChE wild-type (w.t.), AChE w.t. and of 11 site-directed AChE mutants by Ro 02-0683 and bambuterol was studied. In addition, the reversible inhibition of cholinesterases by terbutaline, the leaving group of bambuterol, was studied. The bimolecular rate constant of AChE w.t. inhibition was 6.8 times smaller by Ro 02-0683 and 16000 times smaller by bambuterol than that of BChE w.t. The two carbamates were equipotent BChE inhibitors. Replacement of tyrosine-337 in AChE with alanine (resembling the choline binding site of BChE) resulted in 630 times faster inhibition by bambuterol. The same replacement decreased the inhibition by Ro 02-0683 ten times. The difference in size of the choline binding site in the two w.t. enzymes appeared critical for the selectivity of bambuterol and terbutaline binding. Removal of the charge with the mutation D74N caused a reduction in the reaction rate constants for Ro 02-0683 and bambuterol. Substitution of tyrosine-124 with glutamine in the AChE peripheral site significantly increased the inhibition rate for both carbamates. Substitution of phenylalanine-297 with alanine in the AChE acyl pocket decreased the inhibition rate by Ro 02-0683. Computational docking of carbamates provided plausible orientations of the inhibitors inside the active site gorge of mouse AChE and human BChE, thus substantiating involvement of amino acid residues in the enzyme active sites critical for the carbamate binding as derived from kinetic studies.
        
Title: An explanation for the different inhibitory characteristics of human serum butyrylcholinesterase phenotypes deriving from inhibition of atypical heterozygotes Simeon-Rudolf V, Kovarik Z, Skrinjaric-Spoljar M, Evans RT Ref: Chemico-Biological Interactions, 119-120:159, 1999 : PubMed
The time course of inhibition of butyrylcholinesterase (EC 3.1.1.8) by the dimethylcarbamate Ro 02-0683 in sera taken from patients heterozygous for the usual (U), atypical (A), K or J variants was followed using propionylthiocholine as substrate. Data obtained were used to determine rate constants of inhibition together with the contribution made by each variant to total enzyme activity. The findings substantiate earlier reports that J and K mutations lead to quantitative changes in the concentration of usual enzyme in contrast to the qualitative changes of the atypical variant. The contribution of the atypical enzyme to the total activity in serum from UA, AK and AJ heterozygotes was respectively 17-20, 24-31 and 34-53%. The altered ratios of atypical to usual, K or J enzyme in UA, AK and AJ together with the constants on the usual enzyme alone, explain the differences in observed inhibitor numbers which enable these heterozygotes to be identified.
        
Title: Identification of human plasma cholinesterase variants in 6,688 individuals using biochemical analysis Jensen FS, Skovgaard LT, Viby-Mogensen J Ref: Acta Anaesthesiologica Scandinavica, 39:157, 1995 : PubMed
In 1973, a Cholinesterase Research Unit was established in Denmark (DCRU). The primary aim was to provide a central service for determining genotypes and activity of plasma cholinesterase (BChE) in patients showing abnormal response after succinylcholine. The purpose of the present study was, on the basis of 20 years experience with this Unit, to establish accurate reference intervals for BChE activity and inhibition values for the different genotypes of BChE. Also we wanted to evaluate the influence of age and sex on the BChE activity in genotypically normal patients. Plasma cholinesterase activity was measured using benzoylcholine as substrate. The genetic variations of the enzyme were identified using differential inhibitors, i.e.: Dibucaine, Sodium Fluoride, Succinylcholine, Urea and Ro-2-0683. We investigated 6,688 patients. The reference values for the 13 genotypes represented agree with previous findings. In genotypically normal patients, no age or sex differences were found in BChE activity in children below the age of 10 years. From the age of 10 years the activity decreased significantly in both males and females, the activity in females being significantly lower than in males. In females the activity was lowest in the age group 30-40 years, returning to prepuberty level at about 60 years of age. In males the activity decreased slightly up to 50-60 years of age. Hereafter the activity was stable or tended to increase slightly. Most genotypes could be recognized using the results of the different inhibition studies. We found the inhibitors Dibucaine, Sodium fluoride, Urea and Ro-2-0683 most helpful, whereas succinylcholine was of less value.
An improved method for the identification of butyrylcholinesterase phenotypes is proposed. It is based on modifications of a method that uses alpha-naphthyl acetate as substrate and DL-propranolol and Ro2-0683 as inhibitors. The proposed modifications make the method more rapid and increase the accuracy of the determinations of the phenotypes tested (BCHE U, BCHE UF, BCHE UA, BCHE AK, BCHE AF, and BCHE A). These modifications make the method even more adequate for population studies and clinical routine.
        
Title: Plasma cholinesterase: gene and variations Pantuck EJ Ref: Anesthesia & Analgesia, 77:380, 1993 : PubMed
The traditional tests that have been used for the past 30 yr to determine plasma cholinesterase phenotype--measurement of esterase activity with a variety of substrates, dibucaine inhibition, fluoride inhibition, and Ro2-0683 inhibition--are inadequate for identifying some variants of this enzyme and leave many cases of prolonged response to succinylcholine unexplained. The application of the techniques of molecular genetics has permitted precise identification of plasma cholinesterase variants and has resulted in the discovery of previously unrecognized variants. It is now possible, in cases of prolonged response to succinylcholine resulting from genetically determined alterations in plasma cholinesterase, to ascertain the nature of the mutations in the alleles, and from them to deduce the structural changes in the enzymes responsible for the impairment in drug metabolism.
        
Title: CHE1 UF serum cholinesterase phenotype in whites and non-whites from southern Brazil as determined by a new method Alcantara VM, Chautard-Freire-Maia EA, Culpi L Ref: Hum Hered, 41:103, 1991 : PubMed
A sample of 251 Whites and 818 Non-Whites, from Curitiba (southern Brazil), was typed with a new method with the aim of estimating the frequency of the CHE1*F allele. The frequency of this allele did not differ between Whites (0.60 +/- 0.34%) and Non-Whites (0.49 +/- 0.17%), being estimated as 0.51 +/- 0.15% for the whole sample. The use of the inhibitors DL-propranolol and RO2-0683 with alpha-naphthylacetate as substrate (at 37 degrees C) was efficient for discriminating between the CHE1 U and CHE1 UF phenotypes.
        
Title: Kinetics of the inhibition of human serum cholinesterase phenotypes with the dimethylcarbamate of (2-hydroxy-5-phenylbenzyl)-trimethylammonium bromide (Ro 02-0683) Prester L, Simeon V Ref: Biochemical Pharmacology, 42:2313, 1991 : PubMed
The inhibition of the human serum cholinesterase phenotypes, usual (U), atypical (A) and heterozygous (UA), by the dimethylcarbamate of (2-hydroxy-5-phenylbenzyl)-trimethylammonium bromide (Ro 02-0683), was followed with benzoylcholine, acetyl-, butyryl- and propionyl-thiocholine as substrates. The first-order rate constants were calculated from the linear part of the inhibition curves and were independent of the substrate used for measuring the enzyme activity. The second-order rate constants for the U, UA and A phenotypes were 8.3 x 10(6), 6.1 x 10(6) and 0.05 x 10(6) M-1 min-1, respectively. The constant of the enzyme-inhibitor complex for the atypical serum was 7.7 microM, and the rate of carbamylation of the enzyme was 0.386 min-1. The rate of reactivation of carbamylated usual and atypical enzyme was found to be same; the half-time of reactivation was about 3.5 hr. The deviation from the linearity of the inhibition course was explained by spontaneous reactivation of the inhibited enzyme; the theoretical inhibition curves were in good agreement with the experimentally obtained values. The three phenotypes could be distinguished by the rate of inhibition by the dimethylcarbamate, Ro 02-0683, in the progressive phase of inhibition or by the degree of inhibition in the apparent steady-state.
        
Title: Genetic variants of human serum cholinesterase influence metabolism of the muscle relaxant succinylcholine. Lockridge O Ref: Pharmacol Ther, 47:35, 1990 : PubMed
People with genetic variants of cholinesterase respond abnormally to succinylcholine, experiencing substantial prolongation of muscle paralysis with apnea rather than the usual 2-6 min. The structure of usual cholinesterase has been determined including the complete amino acid and nucleotide sequence. This has allowed identification of altered amino acids and nucleotides. The variant most frequently found in patients who respond abnormally to succinylcholine is atypical cholinesterase, which occurs in homozygous form in 1 out of 3500 Caucasians. Atypical cholinesterase has a single substitution at nucleotide 209 which changes aspartic acid 70 to glycine. This suggests that Asp 70 is part of the anionic site, and that the absence of this negatively charged amino acid explains the reduced affinity of atypical cholinesterase for positively charged substrates and inhibitors. The clinical consequence of reduced affinity for succinylcholine is that none of the succinylcholine is hydrolyzed in blood and a large overdose reaches the nerve-muscle junction where it causes prolonged muscle paralysis. Silent cholinesterase has a frame shift mutation at glycine 117 which prematurely terminates protein synthesis and yields no active enzyme. The K variant, named in honor of W. Kalow, has threonine in place of alanine 539. The K variant is associated with 33% lower activity. All variants arise from a single locus as there is only one gene for human cholinesterase (EC 3.1.1.8). Comparison of amino acid sequences of esterases and proteases shows that cholinesterase belongs to a new family of serine esterases which is different from the serine proteases.
        
Title: Recognition of the Ek1Ek1 homozygote for plasma cholinesterase Whittaker M, Britten JJ Ref: Hum Hered, 40:247, 1990 : PubMed
A family is reported in which the propositus was found to be sensitive to suxamethonium. Both parents were heterozygote each having genotype Ea1Ek1. The sibling of the propositus had the most common phenotype as defined by dibucaine, fluoride and RO2 numbers. Genetic analysis, however, indicated that this sibling must be an Ek1Ek1 homozygote.
        
Title: Differential inhibition of plasma cholinesterase variants using the dibutyrate analogue of pancuronium bromide Whittaker M, Britten JJ Ref: Hum Hered, 31:242, 1981 : PubMed
A steroid, the dibutyrate analogue of pancuronium bromide (9.8 X 10(-8)M), has been used as differential inhibitor in the study of the plasma cholinesterase variants. Pancuronium dibutyrate numbers have been measured for 190 individuals, and the mean values for six of the known genotypes, E1uE1u, E1uE1f, E1uE1a, E1fE1a, E1aE1a, and E1fE1f, have been calculated. Evidence is presented that a combination of the pancuronium dibutyrate number and the fluoride number give better resolution of the six genotypes than the combination of the pancuronium dibutyrate and the dibucaine number. This new differential inhibitor has real potential for revealing the probable existence of new genotypes.
        
Title: Cholinergic effects on bull and chimpanzee sperm motility McGrady AV, Nelson L Ref: Biol Reprod, 15:248, 1976 : PubMed
Title: The effects of anticholinesterases on synaptic transmission through nicotinic and muscarinic receptors in rat sympathetic ganglia in vivo Drew GM, Leach GD Ref: British Journal of Pharmacology, 52:51, 1974 : PubMed
1 Stimulation of the entire spinal sympathetic outflow at supramaximal voltage and 25-100 Hz, in the chlorisondamine-treated, pithed, adrenalectomized rat produced a delayed pressor response (late pressor response; LPR).2 The LPR was abolished by phenoxybenzamine, bretylium or a small dose of atropine (25-50 mug/kg), suggesting the involvement of ganglionic muscarinic receptors.3 In the presence of atropine at a dose level (15 mug/kg) which did not influence the LPR, the anticholinesterases physostigmine, neostigmine and Ro 02-0683 but not BW 284C51 markedly enhanced and prolonged the LPR, whereas all of them reduced the pressor responses to AHR-602.4 After blockade of the ganglionic muscarinic receptors with a large dose of atropine (250 mug/kg) the four anticholinesterases did not influence responses to DMPP or noradrenaline and only slightly enhanced responses to preganglionic nerve stimulation at 6 Hz in the absence of chlorisondamine.5 It is concluded that inhibition of butyrylcholinesterase accounts for the enhancement and prolongation of the LPR by anticholinesterases.
        
Title: The activity of various esterase inhibitors towards atypical human serum cholinesterase Kalow W, Davies R0 Ref: Biochemical Pharmacology, 1:183, 1958 : PubMed
Title: Tubocurarine antagonism and inhibition of cholinesterases Blaschko H, Bulbring E, Chou TC Ref: British Journal of Pharmacology, 4:29, 1949 : PubMed
Title: Action decurarisante du bromure de dimethylcarbamate de (2-hydroxy-5-phenylbenzyl)-trimethylammonium (Nu-683) Mazella H, Migliaro E Ref: Archives Internationales de Pharmacodynamie et de Therapie, 79:362, 1949 : PubMed
Title: Studies on cholinesterase: 5. The selective inhibition of pseudo-cholinesterase in vivo Hawkins RD, Gunter JM Ref: Biochemical Journal, 40:192, 1946 : PubMed