bromfenacoum and difenacoum

Exposure to anticoagulant rodenticides (ARs) in dogs is among the most common causes of poisoning in small animal practice, but information about toxicokinetic of these rodenticides in dogs is lacking. We analysed blood and faeces from five accidentally exposed dogs and 110 healthy dogs by reversed phase ultra-high performance liquid chromatography-tandem mass spectrometry. The aim of the study was to estimate elimination of brodifacoum, bromadiolone and difenacoum after acute exposure, calculate the half-lives of these rodenticides in dogs, estimate faecal elimination in a litter of puppies born, and further to identify the extent of AR exposure in a healthy dog population.. Three dogs were included after single ingestions of brodifacoum; two dogs ingested bromadiolone and one dog ingested difenacoum. Maximum concentrations in faeces were found after day 2-3 for all ARs. The distribution half-lives were 1-10 days for brodifacoum, 1-2 days for bromadiolone and 10 days for difenacoum. Brodifacoum and difenacoum had estimated terminal half-lives of 200-330 days and 190 days, respectively. In contrast, bromadiolone had an estimated terminal half-life of 30 days. No clinical signs of poisoning or coagulopathy were observed in terminal elimination period. In blood, the terminal half-life of brodifacoum was estimated to 8 days. Faeces from a litter of puppies born from one of the poisoned dogs were examined, and measurable concentrations of brodifacoum were detected in all samples for at least 28 days after parturition. A cross-sectional study of 110 healthy domestic dogs was performed to estimate ARs exposure in a dog population. Difenacoum was detected in faeces of one dog. Blood and faecal samples from the remaining dogs were negative for all ARs.. Based on the limited pharmacokinetic data from these dogs, our results suggest that ARs have a biphasic elimination in faeces using a two-compartment elimination kinetics model. We have shown that faecal analysis is suitable and reliable for the assessment of ARs exposure in dogs and a tool for estimating the AR half-lives. Half-lives of ARs could be a valuable indicator in the exposed dogs and provides important information for veterinarians monitoring AR exposure and assessment of treatment length in dogs.

Topics: 4-Hydroxycoumarins; Animals; Anticoagulants; Chromatography, High Pressure Liquid; Dogs; Feces; Mass Spectrometry; Rodenticides

Anticoagulant rodenticides (ARs) are used worldwide for rodent population control to protect human health and biodiversity, and to prevent agricultural and economic losses. Rodents may develop a metabolic resistance to ARs. In order to help understand such metabolic resistance, mass spectrometry was used to position the hydroxylated group of hydroxyl metabolites of second-generation ARs (SGARs).. Most AR pesticides are derived from the 4-hydroxycoumarin/thiocoumarin family. We used low-resolution and high-resolution mass spectrometry to understand the fragmentation pathways of the ARs and their respective metabolites, and to better define the structure of their tandem mass spectrometry product ions.. Seven specific product ions were evidenced for five ARs, with their respective chemical structures. Those ions were obtained as well from the mass spectra of the hydroxyl metabolites of four SGARs, difenacoum (DFM), brodifacoum (BFM), difethialone (DFTL) and flocoumafen (FLO), with different positions of the hydroxyl group.. The differences in chemical structure between DFM on the one hand and BFM, FLO and DFTL on the other could explain the differences in bioavailability between these two groups of molecules. The defined product ions will be used to investigate the part played by the metabolic issue in the field resistance of SGARs.

Topics: 4-Hydroxycoumarins; Animals; Anticoagulants; Biological Availability; Hydroxylation; Liver; Male; Rats, Sprague-Dawley; Rodenticides; Tandem Mass Spectrometry

Superwarfarins, second-generation long-acting anticoagulant rodenticides, are 4-hydroxycoumarin analogues of warfarin that contain a large hydrophobic side chain. These compounds contain two chiral centers and are synthesized for commercial use as two pairs of diastereomer.. To support studies of superwarfarin pharmacokinetics and other efforts to improve clinical care for poisoning victims, a quantitative assay was developed for the measurement of diastereomer of bromadiolone, difenacoum, flocoumafen, brodifacoum, and difethialone in human plasma.. Based on ultrahigh-pressure liquid chromatography-tandem mass-spectrometry (UHPLC-MS/MS), this method was validated according to U.S. Food and Drug Administration (FDA) guidelines. Sample preparation involved simple protein precipitation followed by reversed phase UHPLC, which resolved all five pairs of cis/trans diastereomer in less than 10 min. Superwarfarins were measured using negative ion electrospray followed by selected-reaction monitoring on a triple quadrupole mass spectrometer.. Calibration curves covered 3-4 orders of magnitude with linear regression coefficients of >0.999. The lower limits of quantitation were from 0.013 to 2.41 ng/mL, and intra-day and inter-day accuracy and precision coefficients of variation were <12%.. A 10-min UHPLC-MS/MS assay was developed and validated for the separation and quantitative analysis of the pairs of diastereomer of five superwarfarins in human plasma.. This method was used to identify and measure superwarfarins and their cis/trans diastereomers in plasma obtained from patients treated for coagulopathy following consumption of contaminated synthetic cannabinoid products.

Topics: 4-Hydroxycoumarins; Anticoagulants; Chromatography, High Pressure Liquid; Humans; Reproducibility of Results; Rodenticides; Tandem Mass Spectrometry

Topics: 4-Hydroxycoumarins; Adult; Blood Coagulation Disorders; Cannabinoids; Drug Contamination; Female; Humans; Rodenticides

Anticoagulant rodenticides (ARs) have been used for decades for rodent control worldwide. Research on the exposure of the environment and accumulation of these active substances in biota has been focused on terrestrial food webs, but few data are available on the impact of ARs on aquatic systems and water organisms. To fill this gap, we analyzed liver samples of bream (Abramis brama) and co-located suspended particulate matter (SPM) from the German Environmental Specimen Bank (ESB). An appropriate method was developed for the determination of eight different ARs, including first- and second-generation ARs, in fish liver and SPM. Applying this method to bream liver samples from 17 and 18 sampling locations of the years 2011 and 2015, respectively, five ARs were found at levels above limits of quantifications (LOQs, 0.2 to 2 μg kg

Topics: 4-Hydroxycoumarins; Animals; Anticoagulants; Aquatic Organisms; Cyprinidae; Environmental Monitoring; Food Chain; Fresh Water; Germany; Liver; Particulate Matter; Rodenticides; Seafood; Water Pollutants, Chemical

A large-scale outbreak of life-threatening, inhaled synthetic cannabinoids (Spice/K2)-associated coagulopathy with bleeding complications was recently reported in Illinois. The causative agents were brodifacoum, difenacoum, and bromadiolone, potent, long-acting, 4-hydroxycoumarin anticoagulant rodenticides (LAAR) that were mixed with Spice/K2 products procured and then inhaled by the victims. We report on 3 poisoned patients who reside in underserved, socioeconomically disadvantaged neighborhoods of Chicago that were admitted and treated successfully at two inner-city, tertiary care hospitals in Chicago. The patients were discharged from the hospitals on daily long-term high-dose oral vitamin K

Topics: 4-Hydroxycoumarins; Administration, Inhalation; Adult; Aftercare; Anticoagulants; Antifibrinolytic Agents; Blood Coagulation Disorders; Cannabinoids; Chicago; Female; Hemorrhage; Humans; International Normalized Ratio; Lost to Follow-Up; Male; Medication Adherence; Middle Aged; Patient Compliance; Synthetic Drugs; Vitamin K 1

As a result of legal protection and population recovery, European polecats (Mustela putorius) in Great Britain are expanding into areas associated with greater usage of second-generation anticoagulant rodenticides (SGARs). We analysed polecat livers collected from road casualties from 2013 to 2016 for residues of five SGARs. We related variation in residues to polecat traits and potential exposure pathways, by analysing stable isotopes of carbon (δ

Topics: 4-Hydroxycoumarins; Animals; Animals, Wild; Anticoagulants; Environmental Exposure; Environmental Monitoring; Ferrets; Liver; Probability; Rodenticides; United Kingdom

In March and April 2018, more than 150 patients presented to hospitals in Illinois with coagulopathy and bleeding diathesis. Area physicians and public health organizations identified an association between coagulopathy and synthetic cannabinoid use. Preliminary tests of patient serum samples and drug samples revealed that brodifacoum, an anticoagulant, was the likely adulterant.. We reviewed physician-reported data from patients admitted to Saint Francis Medical Center in Peoria, Illinois, between March 28 and April 21, 2018, and included in a case series adult patients who met the criteria used to diagnose synthetic cannabinoid-associated coagulopathy. A confirmatory anticoagulant poisoning panel was ordered at the discretion of the treating physician.. A total of 34 patients were identified as having synthetic cannabinoid-associated coagulopathy during 45 hospitalizations. Confirmatory anticoagulant testing was performed in 15 of the 34 patients, and superwarfarin poisoning was confirmed in the 15 patients tested. Anticoagulant tests were positive for brodifacoum in 15 patients (100%), difenacoum in 5 (33%), bromadiolone in 2 (13%), and warfarin in 1 (7%). Common symptoms at presentation included gross hematuria in 19 patients (56%) and abdominal pain in 16 (47%). Computed tomography was performed to evaluate abdominal pain and revealed renal abnormalities in 12 patients. Vitamin K. Our data indicate that superwarfarin adulterants of synthetic cannabinoids can lead to clinically significant coagulopathy. In our series, in most of the cases in which the patient presented with bleeding diathesis, symptoms were controlled with the use of vitamin K

Topics: 4-Hydroxycoumarins; Abdominal Pain; Adult; Anticoagulants; Blood Coagulation Disorders; Blood Transfusion; Cannabinoids; Female; Hematuria; Hemorrhage; Humans; Illinois; International Normalized Ratio; Male; Middle Aged; Patient Readmission; Vitamin K; Warfarin

An analytical method based on ultra-high performance liquid chromatography (UHPLC) coupled to Orbitrap high resolution mass spectrometry was developed for the determination of rodenticides (bromadiolone, brodifacoum, difenacoum, chlorophacinone, diphacinone, coumachlor and warfarin) in liver matrix. Different extraction conditions were tested, obtaining the best results when the "dilute and shoot" method (acidified acetonitrile as extraction solvent) and a clean-up step with primary secondary amine (PSA) were used. The optimized method was validated, obtaining recoveries ranging from 60 to 120%. Repeatability and reproducibility were evaluated obtaining values lower than 20%, except for brodifacoum at 10μg/kg. Limits of quantification (LOQs) ranged from 0.1 to 0.5μg/kg, except for brodifacoum, which was 100μg/kg. Six liver samples were analyzed and diphacinone and chlorophacinone were detected in three samples at concentrations ranging from 4μg/kg to 13μg/kg. Moreover a retrospective screening of rodenticide metabolites in those samples and in animal forensic samples was developed based on Orbitrap capabilities. Brodifacoum was detected in three samples, and warfarin alcohol, which is a metabolite of warfarin, was also detected in one sample.

Topics: 4-Hydroxycoumarins; Acetonitriles; Animals; Chromatography, Liquid; Coumarins; Indans; Liver; Mass Spectrometry; Phenindione; Rabbits; Reproducibility of Results; Retrospective Studies; Rodenticides; Warfarin

The occurrence of 10 commonly used anticoagulant rodenticides in centrifuged sludge of 27 wastewater treatment plants was evaluated using solid-liquid extraction (SLE) and liquid chromatography-tandem mass spectrometry (LC-MS/MS). Activated carbon, alumina, and Florisil cartridges with methanol/dichloromethane as eluting solvents were tested in combination with primary-secondary amine (PSA) to optimize an efficient sample cleanup. PSA in combination with Florisil was the best methodology to extract anticoagulant rodenticides in sludge providing recoveries between 42 ± 0.5 and 100 ± 2 %. Warfarin, bromadiolone, ferulenol, and coumachlor were the most ubiquitous compounds in sludge at concentrations up to 84.2 ng g(-1) for the latter. Coumatetralyl, dicoumarol, and brodifacoum were detected sporadically at levels between 6.1 and 17.4 ng g(-1). On the contrary, acenocoumarol, difenacoum, and flocoumafen were not detected in any sample. Finally, we estimated the amount of anticoagulant rodenticides discharged via sludge in order to determine the potential impact to agricultural soil according to different sludge usage practices in the region investigated. This study demonstrates that anticoagulant rodenticides are accumulated in sludge during activated sludge treatment and that the application of sludge as fertilizers may pose a future environmental risk, if not controlled.

Topics: 4-Hydroxycoumarins; Anticoagulants; Chromatography, High Pressure Liquid; Coumarins; Rodenticides; Sewage; Tandem Mass Spectrometry; Warfarin; Wastewater

Anticoagulant rodenticides (ARs) are commonly used to control rodent infestations for biocidal and plant protection purposes. This can lead to AR exposure of non-target small mammals and their predators, which is known from several regions of the world. However, drivers of exposure variation are usually not known. To identify environmental drivers of AR exposure in non-targets we analyzed 331 liver samples of red foxes (Vulpes vulpes) for residues of eight ARs and used local parameters (percentage of urban area and livestock density) to test for associations to residue occurrence. 59.8% of samples collected across Germany contained at least one rodenticide, in 20.2% of cases at levels at which biological effects are suspected. Second generation anticoagulants (mainly brodifacoum and bromadiolone) occurred more often than first generation anticoagulants. Local livestock density and the percentage of urban area were good indicators for AR residue occurrence. There was a positive association between pooled ARs and brodifacoum occurrence with livestock density as well as of pooled ARs, brodifacoum and difenacoum occurrence with the percentage of urban area on administrative district level. Pig holding drove associations of livestock density to AR residue occurrence in foxes. Therefore, risk mitigation strategies should focus on areas of high pig density and on highly urbanized areas to minimize non-target risk.

Topics: 4-Hydroxycoumarins; Animals; Anticoagulants; Arvicolinae; Environmental Exposure; Environmental Monitoring; Foxes; Germany; Liver; Rodenticides

The extensive use of anticoagulant rodenticides (ARs) for rodent control has led to widespread secondary exposure in nontarget predatory wildlife species. We investigated exposure rates and concentrations of five ARs in liver samples from five raptors and six owls from Denmark. A total of 430 birds were analysed. ARs were detected in 84-100 % of individual birds within each species. Multiple AR exposure was detected in 73 % of all birds. Average number of substances detected in individual birds was 2.2 with no differences between owls and raptors. Difenacoum, bromadiolone, and brodifacoum were the most prevalent substances and occurred in the highest concentrations. Second-generation ARs made up 96 % of the summed AR burden. Among the six core species (sample size >30), summed AR concentrations were lower in rough-legged buzzard (Buteo lagopus) and long-eared owl (Asio otus) than in barn owl (Tyto alba), buzzard (B. buteo), kestrel (Falco tinnunculus), and tawny owl (Strix aluco). There was a strong tendency for seasonal variations in the summed AR concentration with levels being lowest during autumn, which is probably related to an influx of less-exposed migrating birds from northern Scandinavia during autumn. High hepatic AR residue concentrations (>100 ng/g wet weight), which have been associated with symptoms of rodenticide poisoning and increased mortality, were recorded high frequencies (12.9-37.4 %) in five of the six core species. The results suggest that the present use of ARs in Denmark, at least locally, may have adverse effects on reproduction and, ultimately, population status in some raptors and owls.

Topics: 4-Hydroxycoumarins; Animals; Anticoagulants; Birds; Denmark; Environmental Exposure; Environmental Pollutants; Female; Male; Raptors; Rodenticides; Strigiformes

Topics: 4-Hydroxycoumarins; Anticoagulants; Blood Coagulation; Blood Coagulation Tests; Blood Component Transfusion; Contusions; Epistaxis; Female; Gastrointestinal Hemorrhage; Humans; Middle Aged; Rodenticides; Vitamin K 1

Polecats (Mustela putorius) in Britain are currently expanding their range eastwards from Wales to reoccupy central and eastern areas of England. Second-generation anticoagulant rodenticides (SGARs), to which polecats are exposed by eating contaminated prey, are used more extensively in these central and eastern regions, leading to fears of increased exposure, and possible resultant mortality. We measured bromadiolone, difenacoum, flocoumafen and brodifacoum concentrations in the livers of 50 polecats from areas that included newly recolonised habitats and found that at least one SGAR was detected in the livers of 13 out of 37 (35.1%) male and 5 out of 13 (38.5%) female polecats. Difenacoum and bromadiolone were detected most frequently. We then combined these data with measurements on another 50 individuals from earlier studies to create a dataset for 100 polecats collected throughout the 1990s from across the whole of their current range. Using this dataset, we determined if there was any evidence that contamination in polecats had increased during the 1990s and whether animals from England were more contaminated than those from Wales, as might be expected given regional differences in the patterns of SGAR use. Overall, 31 of the 100 polecats analysed to date contained SGAR residues. The incidence was a little higher (40%) in animals that died between January and June and this probably better reflects the overall proportion of animals that are sub-lethally exposed. There was no statistically significant change during the 1990s in the proportion of polecats exposed to SGARs nor any evidence that greater use of SGARs in England resulted in more contamination of polecats. Contrary to expectation, the proportion of animals that contained difenacoum was marginally higher in Wales than elsewhere.

Topics: 4-Hydroxycoumarins; Animals; Anticoagulants; Female; Ferrets; Liver; Male; Pesticide Residues; Rodenticides; Time Factors; United Kingdom

Second-generation anticoagulant rodenticides can give rise to unexpected casualties in nontarget species in zoos. The first two offspring of a pair of turkey vultures (Cathartes aura) died of brodifacoum toxicosis. The adult birds fed rodenticide-killed mice to their offspring. There are previous case reports of small carnivorous birds (Dacelo novae-guinae and Tockus deckeni) killed eating poisoned (difenacoum and brodifacoum) mice. Even a granivorous species (Rollulus roulroul) died, probably by contamination of its food by cockroaches that transported the rodenticide.

Topics: 4-Hydroxycoumarins; Animal Feed; Animals; Animals, Zoo; Anticoagulants; Bird Diseases; Birds; Fatal Outcome; Muridae; Poisoning; Raptors; Rodenticides

Topics: 4-Hydroxycoumarins; Animals; Anticoagulants; Cats; Liver; Reference Standards; Rodenticides; Structure-Activity Relationship; Warfarin

This prospective study was undertaken to determine the incidence, severity, time of onset, and duration of coagulopathy in children following accidental ingestion of long-acting anticoagulant rodenticides, often called "superwarfarins." Of 110 children, who ingested superwarfarins and in whom one or more prothrombin time values were obtained, 8 had a prothrombin time ratio (patient to control) of greater than or equal to 1.2, indicative of anticoagulation. Prothrombin time values obtained 48 hours after ingestion were more likely to be prolonged (6/34, 17.6%) than values obtained 24 hours after ingestion (2/104, 1.9%) (P less than .005). The occurrence of an abnormal prothrombin time could not be predicted based on the history of amount ingested or on the presence of the characteristic green-blue product dye in or around the child's mouth. Acute toxicity was evidenced by transient abdominal pain, vomiting, and heme positive stools in 2 patients. The duration of prothrombin time prolongation could not be determined because of the few values obtained after 48 hours. To detect all possible abnormal prothrombin time values, 24- and 48-hour determinations are recommended after a child has ingested a superwarfarin.

Topics: 4-Hydroxycoumarins; Anticoagulants; Blood Coagulation Disorders; Child, Preschool; Humans; Infant; Prospective Studies; Prothrombin Time; Rodenticides; Time Factors

The case histories of two patients exposed to the novel anticoagulants brodifacoum and difenacoum are reported. Abnormal vitamin K1 metabolism, as indicated by elevated vitamin K1 2,3-epoxide plasma concentrations after i.v. administration of vitamin K1, could be detected for more than 18 months after exposure to the anticoagulants. There was a marked prolongation of prothrombin time (greater than 50 s) in both cases, at the time of exposure. However, subsequent haematological investigations (prothrombin time and vitamin K-dependent clotting factor activity) have been shown to be normal in both cases for at least 18 months. These cases confirm the long-acting nature of brodifacoum and difenacoum and present an apparent dissociation between the effect of coumarin anticoagulants on vitamin K1 metabolism and clotting factor activity.

Topics: 4-Hydroxycoumarins; Adult; Blood Coagulation Disorders; Blood Coagulation Tests; Humans; Male; Occupational Diseases; Prothrombin Time; Vitamin K 1

The pharmacokinetics and pharmacodynamics of the 4-hydroxycoumarin anticoagulants, brodifacoum, difenacoum, and warfarin have been studied in the rabbit. Sensitive (50 ng ml-1) and specific high performance liquid chromatography assays have been developed for the determination of plasma concentrations of warfarin, brodifacoum and difenacoum. After administration of a single intravenous dose (20 mumol kg-1), plasma concentrations of warfarin underwent mono-exponential decay, with a terminal half-life of 5.6 +/- 0.7 h (mean +/- s.e. mean), whereas plasma concentrations of brodifacoum and difenacoum underwent bi-exponential decay with terminal half-lives of 60.8 +/- 1.9 h and 83.1 +/- 10.3 h respectively. The plasma half-life of brodifacoum in a single patient poisoned with the compound was 487 h. The pharmacological response to the anticoagulants was measured as changes in prothrombin complex activity, from which the rate of clotting factor synthesis was determined. Clotting factor synthesis recovered in a monophasic fashion after a single intravenous dose of warfarin, compared with a more complex biphasic, pattern of recovery of clotting factor synthesis after administration of either brodifacoum or difenacoum. The slope (m) of the intensity of effect-log (amount of drug in the body) curve was derived for each anticoagulant. There was no significant difference in the value of m after single intravenous doses of racemic, R-, and S-warfarin, difenacoum and brodifacoum, which is consistent with the hypothesis that all the 4-hydroxycoumarin anticoagulants produce their anticoagulant effect by acting at the same receptor site, vitamin K epoxide reductase. Determination of the minimum plasma concentration of each anticoagulant that corresponded with the complete inhibition of clotting factor synthesis indicated that racemic warfarin, R-warfarin and brodifacoum have similar potencies in the rabbit and are less potent than S-warfarin and difenacoum.

Topics: 4-Hydroxycoumarins; Animals; Chromatography, High Pressure Liquid; Kinetics; Male; Prothrombin; Rabbits; Warfarin

The efficacy of five rodenticides for use in bait against the golden hamster (Mesocricetus auratus Waterhouse) was investigated in the laboratory. The species proved to be resistant to warfarin (up to 0.5%) and difenacoum (0.005%), but brodifacoum (0.005%) gave complete mortality after three days' feeding. Calciferol (0.1%), though toxic, was significantly unpalatable. Zinc phosphide (5.0%) presented in a choice test for two days against unpoisoned feed gave 100% mortality, and appears to be the most suitable of these compounds for the control of M. auratus in the field.

Topics: 4-Hydroxycoumarins; Animals; Cricetinae; Ergocalciferols; Mesocricetus; Phosphines; Rodenticides; Warfarin; Zinc Compounds

The response of Meriones shawi to seven rodenticides was investigated in laboratory feeding tests. The species proved to be much less susceptible to anticoagulants than most other species of rodent pests. Brodifacoum (at 0.005%), although giving complete mortality after only 8 days' continuous feeding, was more toxic than warfarin (0.025%), coumatetralyl (0.0375%), difenacoum (0.005%) and bromadiolone (0.005%). Calciferol (0.1%), though toxic, was significantly unpalatable. Zinc phosphide (5.0%) presented for 2 days in a choice test against unpoisoned food gave 80% mortality and appears to be the most suitable of these compounds for the control of M. shawi in the field.

Topics: 4-Hydroxycoumarins; Animals; Ergocalciferols; Gerbillinae; Phosphines; Rodent Control; Rodenticides; Warfarin; Zinc Compounds

The rodenticides brodifacoum, difenacoum, coumatetralyl and warfarin are determined in animal relicta by high-performance exclusion chromatography on porous silica. The first three compounds are not separated, but are subsequently differentiated by adsorption or reversed-phase high-performance liquid chromatography of the appropriate eluate fraction collected from the exclusion column. The method is rapid, and clean-up (on Sep-Pak silica cartridges) is simple. Mean recoveries from spiked substrates were generally above 80% at levels of 0.1-1.0 mg/kg. Routine limits of determination are about 0.05-0.1 mg/kg for warfarin and about 0.02 mg/kg for the other compounds. If analysis for warfarin is not required, the latter limit can be lowered to about 1 microgram/kg by a slight modification to the clean-up step.

Topics: 4-Hydroxycoumarins; Animals; Anticoagulants; Chromatography, High Pressure Liquid; Liver; Reference Values; Rodenticides; Stomach; Swine; Warfarin

Trials of rodenticidal baits containing 50 p.p.m. difenacoum, 50 p.p.m. bromadiolone or 20 p.p.m. brodifacoum were carried out on farmsteads against populations of Rattus norvegicus containing difenacoum-resistant individuals. Six difenacoum treatments failed in 14--42 days of baiting. Two treatments with bromadiolone succeeded in 23 and 33 days, but four further treatments lasting 35--56 days failed to eradicate the populations. Brodifacoum gave virtually complete control of six populations in 21--73 days and of the ten residual populations left behind by the other two compounds, after baiting for a further 11--85 days. The performance of both bromadiolone and brodifacoum was well below that reported by previous investigators, indicating the possibility of low-grade resistance to these compounds in the difenacoum-resistant strain.

Topics: 4-Hydroxycoumarins; Animal Population Groups; Animals; Animals, Wild; Anticoagulants; Drug Resistance; Eating; England; Rats; Rodenticides

The pharmacological response to vitamin K1 (Konakion) in anticoagulated (prothrombin complex activity less than 30%) New Zealand white rabbits was determined by measuring prothrombin complex activity (P.C.A.) in peripheral plasma. In animals pretreated with either brodifacoum (1 mg/kg or 10 mg/kg) or difenacoum (0.85 mg/kg or 8.5 mg/kg) P.C.A. reached a maximum 4 hr after administration of vitamin K1 (0.5 mg/kg) and declined at a rate indicating complete inhibition of clotting factor synthesis. A different response to vitamin K1 (0.5 mg/kg) was observed in rabbits pretreated with warfarin (63 mg/kg); after an initial rise P.C.A. appeared to plateau for 11 hr and then fall at a rate which indicated incomplete inhibition of clotting factor synthesis. The response to several doses of vitamin K1(0.5, 1,2.5 and 5.0 mg/kg) was investigated in the same group of brodifacoum (1 mg/kg) anticoagulated animals. There was a linear relationship between the duration of clotting factor synthesis and the logarithm of the dose of the vitamin K; the pharmacological half-life of vitamin K1 was only 1.7 +/- 0.1 hr. The duration of action of brodifacoum and difenacoum was much longer than that of warfarin. Six weeks after administration of brodifacoum (1 mg/kg) animals were still anticoagulated (P.C.A. less than 30%). In conclusion, we have found that brodifacoum and difenacoum are both more potent and persistent antagonists of vitamin K1 than warfarin in vivo. In cases of poisoning with these compounds it will be necessary to give repeated and frequent doses of vitamin K to maintain clotting factor synthesis.

Topics: 4-Hydroxycoumarins; Animals; Anticoagulants; Male; Prothrombin; Rabbits; Time Factors; Vitamin K; Warfarin

Short laboratory feeding tests were carried out with the anticoagulants warfarin, difenacoum, and brodifacoum on a number of European rodent species: Clethrionomys glareolus, Microtus agrestis, M. arvalis, Apodemus flavicollis, A. sylvaticus, Mus musculus, Rattus rattus and R. norvegicus. It was found that the toxicity to all species was highest with brodifacoum and lowest with warfarin, and that only 0.005% brodifacoum would give a complete mortality in most species after one day's feeding. The potential of this compound for the control of microtine field rodents is suggested.

Topics: 4-Hydroxycoumarins; Animals; Arvicolinae; Mice; Rats; Rodenticides; Warfarin

The response of Acomys cahirinus to three anticoagulant rodenticides was investigated in the laboratory. In contrast to the other commensal rodents Rattus rattus and R. norvegicus, this species appears to be naturally very resistant to warfarin, difenacoum and brodifacoum. It is considered unlikely that anticoagulant poisons would be effective in the field for the control of A. cahirinus.

Topics: 4-Hydroxycoumarins; Animals; Drug Resistance; Female; Male; Mice; Rats; Rodenticides; Warfarin

Laboratory feeding tests were carried out to determine the efficacy of the anticoagulant rodenticide bromadiolone against Rattus norvegicus, R. rattus and Mus musculus. Using 0.005% bromadiolone, complete kills of R. norvegicus and R. rattus not resistant to warfarin were obtained after exposure to the poison for 1 and 5 days respectively. Warfarin-resistant R. norvegicus were all killed in 4 days, and resistant M. musculus in 12 days. In general, the results resembled those obtained with difenacoum. Acceptance of bromadiolone was very good.

Topics: 4-Hydroxycoumarins; Animals; Anticoagulants; Drug Resistance; Female; Male; Mice; Rats; Rodenticides; Warfarin