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Alan D Macnicoll - One of the best experts on this subject based on the ideXlab platform.
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whole carcass residues of the rodenticide Difenacoum in anticoagulant resistant and susceptible rat strains rattus norvegicus
Environmental Toxicology and Chemistry, 2005Co-Authors: Helen Atterby, Gerard M Kerins, Alan D MacnicollAbstract:The present study investigated the whole-carcass residue carried by resistant and susceptible laboratory rat strains following 5, 10, or 20 d of feeding on a diet of 25 mg Difenacoum/kg bait. The mean whole-carcass residue of Difenacoum was determined by high-performance liquid chromatography to be between 0.52 and 0.74 mg/kg body weight in all three rat strains tested. These values were considerably lower than some comparable data previously reported for other species and second-generation rodenticides as well as from mathematical models. The whole-carcass residue of extractable (i.e., nonrefractory) parent compound carried by highly resistant rats fed for 20 d (0.74 mg/kg body wt) is unlikely to present a significantly increased risk to predators compared to the amount carried by susceptible rats after 5 d of feeding (0.52 mg/kg body wt). However, resistant rats are more likely to be available for predation and to be carrying a whole-carcass residue of anticoagulant throughout the duration of a control program.
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the development of a blood clotting response test for discriminating between Difenacoum resistant and susceptible norway rats rattus norvegicus berk
Comparative Biochemistry and Physiology Part C: Comparative Pharmacology, 1993Co-Authors: Erica J Gill, Gerard M Kerins, Stephen D Langton, Alan D MacnicollAbstract:1. A new test for identifying levels of Difenacoum resistance in the Norway rat is described, based upon the differential physiological response to Difenacoum administration. 2. This test is based on changes in blood clotting activity over 4 days, following administration of the rodenticide Difenacoum in conjunction with menadione (vitamin K3). 3. The anticoagulant effect is reduced only in rats that are resistant or tolerant to Difenacoum. 4. This test procedure is quicker than traditional feeding tests, and identifies the degree of resistance in both laboratory and wild rats that have Difenacoum resistance genes.
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Difenacoum poisoning as a cause of haematuria
Human & Experimental Toxicology, 1992Co-Authors: Graham P Butchery, Alan D Macnicoll, Martin J Shearer, Michael J Kelly, Philip W IndAbstract:A man presented with frank haematuria and a grossly prolonged prothrombin time. He was later found to have taken an overdose of Difenacoum — a 'superwarfarin' rodenticide. The diagnosis was confirmed by a serum concentration of Difenacoum of 0.6 μg ml-1. Overdosage with superwarfarins is discussed and the need for prolonged treatment with vitamin K1 highlighted.
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inheritance of low grade brodifacoum resistance in the norway rat
Journal of Wildlife Management, 1992Co-Authors: Erica J Gill, Gerard M Kerins, Alan D MacnicollAbstract:We conducted a study to ascertain if an observed reduction of susceptibility to brodifacoum in Norway rats (Rattus norvegicus) present on at least 3 farms in Berkshire, United Kingdom, was heritable. This trait was demonstrated in individual rats by their survival after consumption of 0.0005% (m/m) bro difacoum in the diet for 7 days (Gill and MacNicoll 1991) and is termed «low grade» resistance. It is inherited through at least 5 generations and is not associated with vitamin K deficiency. Our data also suggest a different explanation for the inheritance of Difenacoum resistance compared with that reported by Greaves and Cullen-Ayres (1988)
Virginie Lattard - One of the best experts on this subject based on the ideXlab platform.
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elevated Difenacoum metabolism is involved in the Difenacoum resistant phenotype observed in berkshire rats homozygous for the l120q mutation in the vitamin k epoxide reductase complex subunit 1 vkorc1 gene
Pest Management Science, 2018Co-Authors: Maylis Boitet, Etienne Benoit, Abdessalem Hammed, Nolan Chatron, Jean Valery Debaux, Virginie LattardAbstract:BACKGROUND Soon after Difenacoum began to be used, resistance to this rodenticide was detected in rats in northeast Hampshire and northwest Berkshire in England. Resistance to Difenacoum has been reported to be stronger in rats from Berkshire than in rats from Hampshire. Surprisingly, after the discovery of the vitamin K epoxide reductase complex subunit 1 (Vkorc1) gene, rats from Berkshire and Hampshire were all shown to be homozygous for the L120Q mutation in Vkorc1. RESULTS This study aimed to evaluate the resistance of Berkshire rats to confirm their extreme resistance and determine mechanisms supporting this resistance. For this purpose, we created a quasicongenic rat F7 strain by using a Berkshire rat as a donor to introduce the L120Q mutation in Vkorc1 into the genetic background of an anticoagulant-susceptible recipient strain. The use of F7 rats enabled demonstration of (i) the level of resistance to Difenacoum conferred by the L120Q mutation, (ii) co-dominance of the L120 and Q120 alleles, (iii) the extreme resistance of Berkshire rats compared with Q120/Q120 rats as a consequence of additional resistance mechanisms, and (iv) the involvement of cytochrome P 450 (CYP450) enzymes in this extreme resistance. CONCLUSION This study demonstrated that elevated CYP450 oxidative metabolism leading to accelerated Difenacoum detoxification is involved in the Berkshire phenotype. © 2017 Society of Chemical Industry.
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Development of an ecofriendly anticoagulant rodenticide based on the stereochemistry of Difenacoum
Drug Metabolism and Disposition, 2016Co-Authors: Marlène Damin-pernik, Bernadette Espana, Stéphane Besse, Isabelle Fourel, Hervé Caruel, F. Popowycz, Etienne Benoit, Virginie LattardAbstract:Difenacoum, an antivitamin K anticoagulant, has been widely used as rodenticide to manage populations of rodents. Difenacoum belongs to the second generation of anticoagulant, and, as all the molecules belonging to the second generation of anticoagulant, Difenacoum is often involved in primary poisonings of domestic animals and secondary poisonings of wildlife by feeding contaminated rodents. To develop a new and ecofriendly Difenacoum, we explored in this study the differences in properties between diastereomers of Difenacoum. Indeed, the currently commercial Difenacoum is a mixture of 57% of cis-isomers and 43% of transisomers. Cis- and trans-isomers were thus purified on a C18 column, and their respective pharmacokinetic properties and their efficiency to inhibit the coagulation of rodents were explored. Tissue persistence of trans-isomers was shown to be shorter than that of cis-isomers with a half-life fivefold shorter. Efficiency to inhibit the vitamin K epoxide reductase activity involved in the coagulation process was shown to be similar between cis- and trans-isomers. The use of trans-isomers of Difenacoum allowed to drastically reduce Difenacoum residues in liver and other tissues of rodents when the rodent is moribund. Therefore, secondary poisonings of wildlife should be decreased by the use of Difenacoum largely enriched in trans-isomers.
Alan Buckle - One of the best experts on this subject based on the ideXlab platform.
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The Hampshire-Berkshire focus of L120Q anticoagulant resistance in the Norway rat (Rattus norvegicus) and field trials of bromadiolone, Difenacoum and brodifacoum
Crop Protection, 2020Co-Authors: Alan Buckle, Clare R. Jones, David J. Rymer, Emily E. Coan, Colin V. PrescottAbstract:Abstract Anticoagulant resistance has been present in Norway rats (Rattus norvegicus) in Hampshire and Berkshire for forty years. All first-generation anticoagulants and two of the second generation, bromadiolone and Difenacoum, are resisted by rats carrying the L120Q single nucleotide polymorphism (SNP). A regulatory restriction on the use of resistance-breakers brodifacoum, difethialone and flocoumafen in the UK effectively prevented their use against Norway rats for more than 30 years. During this time, L120Q spread from original localised foci eventually to cover most of central-southern England; with other more dispersed foci elsewhere in the UK. We summarise research on L120Q Norway rats and the field performance of anticoagulant baits against them. Bromadiolone (50 ppm), Difenacoum (50 ppm) and brodifacoum (23 ppm) baits were each applied on two farmsteads where it had been established that Norway rats carried the L120Q SNP. Preliminary DNA resistance tests conducted at the farms found only one of 107 rats to be susceptible and 86.9% to be homozygous resistant. The bromadiolone and Difenacoum applications were either partially or wholly ineffective; brodifacoum treatments were fully effective. Quantities of active substances used varied between farms and substances; but more bromadiolone and Difenacoum baits were applied than brodifacoum baits during the treatments. Results confirm the high incidence of resistance and support advice that bromadiolone and Difenacoum should not be used against the L120Q SNP. Prolonged use of resisted anticoagulants has resulted in a high prevalence of homozygosity and resistance spread. Failed treatments result in prolonged feeding on anticoagulant bait and leave Norway rats alive carrying, presumably, high residues. It remains to be seen whether the use of now-permitted effective substances, and the introduction of a rodenticide stewardship regime, will curtail the spread of resistance and reduce anticoagulant residues in wildlife.
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resistance testing and the effectiveness of Difenacoum against norway rats rattus norvegicus in a tyrosine139cysteine focus of anticoagulant resistance westphalia germany
Pest Management Science, 2013Co-Authors: Alan Buckle, Stefan Endepols, Nicole Klemann, Jens JacobAbstract:BACKGROUND: Anticoagulant resistance in Norway rats at foci in Belgium, Denmark, France, Germany, the Netherlands and the United Kingdom is genetically characterised by the same single nucleotide polymorphism (SNP) and consequent amino acid exchange from tyrosine to cysteine at location 139 of the vkorc1 gene (i.e. tyrosine139cysteine or Y139C). The purpose of this study was to assess the degree of resistance among rats at two infested farm sites in the Y139C focus in Westphalia, Germany, using blood clotting response (BCR) tests, and to determine the practical efficacy of applications of a commercial 50 ppm Difenacoum bait (Neokil™) against them. RESULTS: BCR tests showed that the Difenacoum resistance factor (RF) among the Y139C rats was about 2.5. DNA analysis for the Y139C mutation revealed that it was present among rats at the two sites with a prevalence of 75 and 93%. Applications of Difenacoum bait at the two sites achieved 86.8 and 59.9% control. The different outcomes did not appear to be due to differences either in the degree and prevalence of resistance or in the quantities of poisoned bait consumed. CONCLUSION: The study showed that, although the RF for Difenacoum among rats carrying the Y139C SNP was apparently low, an acceptable level of control of resistant Norway rat infestations was not achieved using Difenacoum. Continued use of anticoagulants against rats that are resistant to them will exacerbate resistance problems in terms of both increased severity and prevalence. These conclusions are likely to apply elsewhere in Europe where the Y139C SNP occurs. Copyright © 2012 Society of Chemical Industry
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The Current Status of Anticoagulant Resistance in Rats and Mice in the UK
2012Co-Authors: Alan Buckle, Colin V. PrescottAbstract:Introduction: Resistance to anticoagulants in Norway rats (Rattus norvegicus) and house mice (Mus domesticus) has been studied in the UK since the early 1960s. In no other country in the world is our understanding of resistance phenomena so extensive and profound. Almost every aspect of resistance in the key rodent target species has been examined in laboratory and field trials and results obtained by independent researchers have been published. It is the principal purpose of this document to present a short synopsis of this information. More recently, however, the development of genetical techniques has provided a definitive means of detection of resistant genotypes among pest rodent populations. Preliminary information from a number of such surveys will also be presented. Resistance in Norway rats: A total of nine different anticoagulant resistance mutations (single nucleotide polymorphisms or SNPs) are found among Norway rats in the UK. In no other country worldwide are present so many different forms of Norway rat resistance. Among these nine SNPs, five are known to confer on rats that carry them a significant degree of resistance to anticoagulant rodenticides. These mutations are: L128Q, Y139S, L120Q, Y139C and Y139F. The latter three mutations confer, to varying degrees, practical resistance to bromadiolone and Difenacoum, the two second-generation anticoagulants in predominant use in the UK. It is the recommendation of RRAG that bromadiolone and Difenacoum should not be used against rats carrying the L120Q, Y139C and Y139F mutations because this will promote the spread of resistance and jeopardise the long-term efficacy of anticoagulants. Brodifacoum, flocoumafen and difethialone are effective against these three genotypes but cannot presently be used because of the regulatory restriction that they can only be applied against rats that are living and feeding predominantly indoors. Our understanding of the geographical distribution of Norway rat resistance in incomplete but is rapidly increasing. In particular, the mapping of the focus of L120Q Norway rat resistance in central-southern England by DNA sequencing is well advanced. We now know that rats carrying this resistance mutation are present across a large part of the counties of Hampshire, Berkshire and Wiltshire, and the resistance spreads into Avon, Oxfordshire and Surrey. It is also found, perhaps as outlier foci, in south-west Scotland and East Sussex. L120Q is currently the most severe form of anticoagulant resistance found in Norway rats and is prevalent over a considerable part of central-southern England. A second form of advanced Norway rat resistance is conferred by the Y139C mutation. This is noteworthy because it occurs in at least four different foci that are widely geographically dispersed, namely in Dumfries and Galloway, Gloucestershire, Yorkshire and Norfolk. Once again, bromadiolone and Difenacoum are not recommended for use against rats carrying this genotype and a concern of RRAG is that continued applications of resisted active substances may result in Y139C becoming more or less ubiquitous across much of the UK. Another type of advanced resistance, the Y139F mutation, is present in Kent and Sussex. This means that Norway rats, carrying some degree of resistance to bromadiolone and Difenacoum, are now found from the south coast of Kent, west into the city of Bristol, to Yorkshire in the north-east and to the south-west of Scotland. This difficult situation can only deteriorate further where these three genotypes exist and resisted anticoagulants are predominantly used against them. Resistance in house mice: House mouse is not so well understood but the presence in the UK of two resistant genotypes, L128S and Y139C, is confirmed. House mice are naturally tolerant to anticoagulants and such is the nature of this tolerance, and the presence of genetical resistance, that house mice resistant to the first-generation anticoagulants are considered to be widespread in the UK. Consequently, baits containing warfarin, sodium warfarin, chlorophacinone and coumatetralyl are not approved for use against mice. This regulatory position is endorsed by RRAG. Baits containing brodifacoum, flocoumafen and difethialone are effective against house mice and may be applied in practice because house mouse infestations are predominantly indoors. There are some reports of resistance among mice in some areas to the second-generation anticoagulant bromadiolone, while Difenacoum remains largely efficacious. Alternatives to anticoagulants: The use of habitat manipulation, that is the removal of harbourage, denial of the availability of food and the prevention of ingress to structures, is an essential component of sustainable rodent pest management. All are of importance in the management of resistant rodents and have the advantage of not selecting for resistant genotypes. The use of these techniques may be particularly valuable in preventing the build-up of rat infestations. However, none can be used to remove any sizeable extant rat infestation and for practical reasons their use against house mice is problematic. Few alternative chemical interventions are available in the European Union because of the removal from the market of zinc phosphide, calciferol and bromethalin. Our virtual complete reliance on the use of anticoagulants for the chemical control of rodents in the UK, and more widely in the EU, calls for improved schemes for resistance management. Of course, these might involve the use of alternatives to anticoagulant rodenticides. Also important is an increasing knowledge of the distribution of resistance mutations in rats and mice and the use of only fully effective anticoagulants against them.
Stefan Endepols - One of the best experts on this subject based on the ideXlab platform.
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vkorc1 variation in house mice during warfarin and Difenacoum field trials
Pest Management Science, 2013Co-Authors: Stefan Endepols, Nicole Klemann, Y Song, M H KohnAbstract:BACKGROUND: Field studies guided by genetic monitoring of Vkorc1 need to be done to implicate mutations conclusively with rodent control problems due to the presence of animals resistant to anticoagulant rodenticides. Rodent control success in relation to Vkorc1 genotypes in house mice (Mus musculus domesticus) was studied on two farms (I and II) in Germany. Tests were carried out to determine whether certain resistance profiles and Vkorc1 genotypes displayed dynamics over the course of sequential treatments with warfarin and Difenacoum that were consistent with single nucleotide polymorphisms (SNPs) in Vkorc1 as indicators of resistance. RESULTS: On farms I and II, respectively, three (A to C) and two (A and B) types of control problem with anticoagulants (i.e. proxies for resistance) were encountered in spatially segregated subunits: A = none; B = control problems with warfarin but not with Difenacoum; C = control problems with both anticoagulants. Unexpectedly, resistance was encountered in a population where only Vkorc1 wild-type mice were detected. In addition, the Arg58Gly Vkorc1 variant was found not to correlate with observed control failures. CONCLUSION: Control problems were encountered that cannot be explained by Vkorc1 coding or intronic SNPs, and therefore are likely due to non-coding Vkorc1 SNPs or due to other genetic or non-genetic factors. © 2012 Society of Chemical Industry
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resistance testing and the effectiveness of Difenacoum against norway rats rattus norvegicus in a tyrosine139cysteine focus of anticoagulant resistance westphalia germany
Pest Management Science, 2013Co-Authors: Alan Buckle, Stefan Endepols, Nicole Klemann, Jens JacobAbstract:BACKGROUND: Anticoagulant resistance in Norway rats at foci in Belgium, Denmark, France, Germany, the Netherlands and the United Kingdom is genetically characterised by the same single nucleotide polymorphism (SNP) and consequent amino acid exchange from tyrosine to cysteine at location 139 of the vkorc1 gene (i.e. tyrosine139cysteine or Y139C). The purpose of this study was to assess the degree of resistance among rats at two infested farm sites in the Y139C focus in Westphalia, Germany, using blood clotting response (BCR) tests, and to determine the practical efficacy of applications of a commercial 50 ppm Difenacoum bait (Neokil™) against them. RESULTS: BCR tests showed that the Difenacoum resistance factor (RF) among the Y139C rats was about 2.5. DNA analysis for the Y139C mutation revealed that it was present among rats at the two sites with a prevalence of 75 and 93%. Applications of Difenacoum bait at the two sites achieved 86.8 and 59.9% control. The different outcomes did not appear to be due to differences either in the degree and prevalence of resistance or in the quantities of poisoned bait consumed. CONCLUSION: The study showed that, although the RF for Difenacoum among rats carrying the Y139C SNP was apparently low, an acceptable level of control of resistant Norway rat infestations was not achieved using Difenacoum. Continued use of anticoagulants against rats that are resistant to them will exacerbate resistance problems in terms of both increased severity and prevalence. These conclusions are likely to apply elsewhere in Europe where the Y139C SNP occurs. Copyright © 2012 Society of Chemical Industry
M H Kohn - One of the best experts on this subject based on the ideXlab platform.
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vkorc1 variation in house mice during warfarin and Difenacoum field trials
Pest Management Science, 2013Co-Authors: Stefan Endepols, Nicole Klemann, Y Song, M H KohnAbstract:BACKGROUND: Field studies guided by genetic monitoring of Vkorc1 need to be done to implicate mutations conclusively with rodent control problems due to the presence of animals resistant to anticoagulant rodenticides. Rodent control success in relation to Vkorc1 genotypes in house mice (Mus musculus domesticus) was studied on two farms (I and II) in Germany. Tests were carried out to determine whether certain resistance profiles and Vkorc1 genotypes displayed dynamics over the course of sequential treatments with warfarin and Difenacoum that were consistent with single nucleotide polymorphisms (SNPs) in Vkorc1 as indicators of resistance. RESULTS: On farms I and II, respectively, three (A to C) and two (A and B) types of control problem with anticoagulants (i.e. proxies for resistance) were encountered in spatially segregated subunits: A = none; B = control problems with warfarin but not with Difenacoum; C = control problems with both anticoagulants. Unexpectedly, resistance was encountered in a population where only Vkorc1 wild-type mice were detected. In addition, the Arg58Gly Vkorc1 variant was found not to correlate with observed control failures. CONCLUSION: Control problems were encountered that cannot be explained by Vkorc1 coding or intronic SNPs, and therefore are likely due to non-coding Vkorc1 SNPs or due to other genetic or non-genetic factors. © 2012 Society of Chemical Industry
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field trials to assess resistance to warfarin and Difenacoum of house mice in relation to the occurrence of variants in the vkorc1 gene before and after the treatments
Julius-Kühn-Archiv, 2011Co-Authors: S Endepols, N Klemann, Y Song, M H KohnAbstract:House mice (Mus musculus domesticus) vary considerably in their susceptibility to anticoagulants, and several non-synonymous sequence variants in the coding region of the vitamin K epoxide reductase subcomponent 1 gene (vkorc1) were found in Germany (Rost et al., 2009). It was the aim of our study to characterize the degree of resistance in relation to vkorc1genotypes in local mouse groups, and to test whether certain genotypes were selected by sequential treatments with the two anticoagulant rodenticides warfarin and Difenacoum. Two successive treatments were conducted, the first with bait containing warfarin followed by a second using Difenacoum. Their effects were determined on local sub-groups of mouse infestations in different sub-units on two livestock farms in Westphalia, Germany. The frequency of different vkorc1 genotypes, as determined by Sanger sequencing, was considered relative to the rodenticide treatment results for each sub-group and sampling period. Three tolerance types were identified on farm one: A=warfarin-susceptible, B=resistant to warfarin, but susceptible to Difenacoum, C=approx. one half of animals resistant to both anticoagulants. On farm 2, only type A and B were identified. A high degree of resistance was observed in vkorc1 wild-type mice. In all cases, only the R58G vkorc1 variant was found, which appears not to be a resistance marker in house mice. Hence, in these mouse infestations, practical resistance to anticoagulants was not accompanied by any identifiable vkorc1 resistance marker. The study was funded by the Rodenticide Resistance Action Committee (RRAC) of CropLife International.