Second-generation Anticoagulants Research Articles

Delayed Symptoms of Rodenticide Poisoning in a 16-Year-Old: A Case Report

Anticoagulant rodenticides, a key tool in pest control since the 1940s, have undergone significant evolution to overcome resistance and improve efficacy. However, resistance in rodent populations led to the development of second-generation anticoagulants such as Brodifacoum and Difenacoum, which are more potent but pose increased risks to non-target species, including humans. This case report describes the management of a 16-year-old Iranian male who deliberately ingested a super warfarin rodenticide, resulting in severe coagulopathy and delayed clinical presentation. Despite the initial absence of overt symptoms, the patient’s condition required immediate intervention with intravenous vitamin K and blood products, demonstrating the complexity of diagnosing and managing rodenticide poisoning. Recovery was achieved with comprehensive medical and psychological interventions, demonstrating the need for high clinical suspicion and prompt treatment in similar cases. This report highlights the ongoing public health challenges posed by highly potent rodenticides and the critical need for awareness and preparedness among healthcare providers to effectively manage such emergencies.

The Enigma of Norbormide, a Rattus-Selective Toxicant.

Norbormide (NRB) is a Rattus-selective toxicant, which was serendipitously discovered in 1964 and formerly marketed as an eco-friendly rodenticide that was deemed harmless to non-Rattus species. However, due to inconsistent efficacy and the emergence of second-generation anticoagulants, its usage declined, with registration lapsing in 2003. NRBs' lethal action in rats entails irreversible vasoconstriction of peripheral arteries, likely inducing cardiac damage: however, the precise chain of events leading to fatality and the target organs involved remain elusive. This unique contractile effect is exclusive to rat arteries and is induced solely by the endo isomers of NRB, hinting at a specific receptor involvement. Understanding NRB's mechanism of action is crucial for developing species-selective toxicants as alternatives to the broad-spectrum ones currently in use. Recent research efforts have focused on elucidating its cellular mechanisms and sites of action using novel NRB derivatives. The key findings are as follows: NRB selectively opens the rat mitochondrial permeability transition pore, which may be a factor that contributes to its lethal effect; it inhibits rat vascular KATP channels, which potentially controls its Rattus-selective vasoconstricting activity; and it possesses intracellular binding sites in both sensitive and insensitive cells, as revealed by fluorescent derivatives. These studies have led to the development of a prodrug with enhanced pharmacokinetic and toxicological profiles, which is currently undergoing registration as a novel efficacious eco-sustainable Rattus-selective toxicant. The NRB-fluorescent derivatives also show promise as non-toxic probes for intracellular organelle labelling. This review documents in more detail these developments and their implications.

From problem to progress: Rodent management in agricultural settings of sub-Saharan Africa and calling for an urban perspective

In sub-Saharan Africa, agricultural intensification and urbanization have increased the risk of proliferation of rodents in rural and urban habitats. Management of rodent populations is a challenge in terms of food security and public health. However, conventional efforts to manage rodents are currently reactive and based on the inadequate use of synthetic chemical rodenticides, including first- and second-generation anticoagulants and acute rodenticides. This approach carries substantial environmental and health risks and has yielded limited success in terms of reduction of rodent populations sustainably. In this paper, which is the second part of a diptych, we advocate for a shift towards more sustainable and environmentally friendly approaches, such as Ecologically-Based Rodent Management (EBRM), as a realistic alternative to synthetic rodenticides. This method is based on a good knowledge of habitat use, species diversity and population dynamics of major rodent pests, and involves community-based interventions aimed at reducing rodent abundance to economically and hygienically acceptable levels in the long term. We present for the first time a comprehensive compilation of published and unpublished information derived from observational field studies conducted in Ethiopia, Niger, Nigeria, Benin, Mali, Mauritania and Senegal with the aim to provide an overview of EBRM case studies in these countries of sub-Saharan Africa. This paper intends to serve as a catalyst for change, encouraging the transformation of rodent management practices towards sustainable methods. We aim at stimulating further research and interventions that promote EBRM in Africa, ultimately fostering more environmentally conscious and effective solutions.

Analysis of some trends of the pharmaceutical market of rodenticides in Ukraine and the peculiarities of their use for deratization

Analysis of some trends of the pharmaceutical market of rodenticides in Ukraine and the peculiarities of their use for deratization

Testing two forms of rodenticide baits based on brodifacoum in vitro on Norway rats Rattusnorvegicus

The chemical method is the most common to control rodents. Fast acting rodenticides (zinc phosphide and krysid) and slow-acting rodenticides divided into first- and second-g eneration anticoagulants are used for deratization practice. The aim of the study was to evaluate the results of rodenticidal activity of brodifacum for two forms of rodenticidal baits in order to control rodents in settlements and adjacent territories, on agricultural land and reduce their harm. In case of high numbers, they carry such dangerous diseases as plague, typhoid fever, paratyphs, encephalitis, rabies, tuberculosis, tularemia, etc. Fleas and ticks parasitizing mouse-like rodents transmit pathogens to pets and humans. The economic damage caused by rodents is high. They destroy and spoil food and fodder, destroy the seedlings of agricultural crops. In a year, a gray rat eats 2024 kg of food and pollutes 10 times more products. In total, two forms of baits based on brodifacoum were prepared against rodents. We proposed and tested the rodenticidal activity of the forms of baits developed in loose and soft forms. The assessment established that both forms had high biological activity, reaching 90.17 and 89.67 %. Consumption rates of poisoned baits in the form of soft briquettes were lower compared to grain baits, showing high efficiency and saving the food base for preparation of poisoned rodenticidal baits.

Widespread resistance to anticoagulant rodenticides in Mus musculus domesticus in the city of Barcelona

Control of rodent populations is a big challenge because of the rapid evolution of resistance to commonly used rodenticides and the collateral negative impacts that these products may have on biodiversity. Second-generation anticoagulants are very efficient but different single nucleotide polymorphisms (SNPs) in the Vkorc1 gene may confer resistance in rodents. We sequenced exons 1, 2 and 3 of the Vkorc1 gene from 111 mice (Mus musculus domesticus) captured across the city of Barcelona and found SNPs associated with resistance to first- and second-generation anticoagulants in all of them. Although most of the SNPs were associated with resistance to bromadiolone, we also found SNPs associated with resistance to brodifacoum. Out of all the individuals analyzed, 94.59 % carried mutations associated to introgression events with Mus spretus, a sympatric rodent species. Currently most of the chemical products for rodent control commercialized in the area are based on bromadiolone, although recent public control campaigns have already shifted to other products. Thus, the widespread occurrence of resistant mice to bromadiolone represents a challenge for rodent control in Barcelona and may increase the risk of secondary poisoning of animals preying on this species. Public health managers, pest control companies and citizens should be aware that the use of bromadiolone based products is ineffective and represents a risk for the environment, including human and animal health.

Уровень мутирования гена резистентности VKORC1 к антикоагулянтам у домовых мышей и серых крыс г. Москвы и Московской области

The resistance of house mice (M. musuclus linnaeus, 1758) and norway rats (R. norvegicus berkenhout, 1769) to anticoagulants of the 1st and 2nd generation in the VKORC1 gene in Moscow and the Moscow region was studied. House mice had two previously unknown mutations in exon 1: Lys175Arg и Ser94Trp. We assume that these mutations can increase the resistance of rodents to second-generation anticoagulants. the percentage of individuals with mutations in exon 1 in Moscow is 87.5 %, in Noginsk and Podolsk – 100 %. Of the 18 norway rats studied in Moscow, only three individuals in a heterozygous state were found to have one of the mutations (Tyr139Ser), usually associated with genetic resistance of rodents to the first generation anticoagulant warfarin. the percentage of resistant individuals in Moscow was 15.7 %. the rats in which the resistance mutation was found were captured in three districts of moscow: southwestern, northern and eastern.

House Mice as a Real Sanitary Threat of Human and Animal Leptospirosis: Proposal for Integrated Management

Leptospirosis is a reemerging zoonosis and ranges in severity from benign to sometimes fatal. In cattle, infection may be responsible for abortion and infertility cases causing economic losses. Humans may be contaminated through direct contact with urine of infected animals or indirectly though interaction with urine-contaminated environment. Many wildlife species living close to cattle, especially commensal rodents may play a role in the transmission of leptospires. Because little is known on the epidemiology of nonmaintenance Leptospira serovars, appropriate management is still limited. On a French farm where human and cattle leptospirosis were detected, the transmission cycle was explored to propose appropriate mitigation measures. For that, commensal rodents present on the farm were trapped and their leptospires carriage was studied by molecular methods. Trapped mice were shown to carry two pathogenic Leptospira species (L. interrogans and L. kirschneri). Since these 2 serogroups were simultaneously detected in the trapped mice and in the cows of this farm, we suspected an initial Leptospira transmission from mice to cows requiring an effective management of mice on this farm. Because resistance to anticoagulant rodenticides due to Vkorc1 mutations has been largely described in rodents and first-generation anticoagulant rodenticides seemed to be inefficient in controlling mice on this farm, susceptibility of these mice to anticoagulants has been characterized by Vkorc1 sequencing. 50% of the trapped mice carried mutations in the Vkorc1 gene leading to severe resistance to first-generation anticoagulants. The management of such mice that are a real sanitary threat can be achieved only by using the most toxic second-generation anticoagulants or nonanticoagulant solutions.

Redevelopment of a Rat Specific Rodenticide Norbormide

Norbormide is a rat specific toxicant. It causes vasoconstriction of small arteries and vasodilation of large arteries in rats, which results in a rapid fall in blood pressure and death from heart failure. It is an extraordinary compound in that it is only toxic to rats. The lack of toxicity of this compound to birds and other mammals is unique. It was originally researched in the 1960s and initially marketed in the USA. Problems with taste aversion slowed its continued use and sales it and was largely forgotten when anticoagulant rodenticides became more effective and popular. Following the emergence of anticoagulant resistance in some populations of rodents, residues of the second-generation anticoagulants in wildlife and concerns regarding humaneness, interest in non-anticoagulants, such as norbormide, has revived. Research has been conducted to help identify and understand a formulation of norbormide which is palatable, effective, and fast acting in rats. Further research is underway to determine methods for large scale synthesis of an improved form of norbormide. Field trials are planned in 2018/19. The ability to target rats with no risk to non-target species presents considerable advantages in many settings and warrants further investment and completion of the current scale-up phase of research and development.

Control of invasive rats on islands and priorities for future action.

Invasive rats are one of the world's most successful animal groups that cause native species extinctions and ecosystem change, particularly on islands. On large islands, rat eradication is often impossible and population control, defined as the local limitation of rat abundance, is now routinely performed on many of the world's islands as an alternative management tool. However, a synthesis of the motivations, techniques, costs, and outcomes of such rat-control projects is lacking. We reviewed the literature, searched relevant websites, and conducted a survey via a questionnaire to synthesize the available information on rat-control projects in island natural areas worldwide to improve rat management and native species conservation. Data were collected from 136 projects conducted over the last 40 years; most were located in Australasia (46%) and the tropical Pacific (25%) in forest ecosystems (65%) and coastal strands (22%). Most of the projects targeted Rattus rattus and most (82%) were aimed at protecting birds and endangered ecosystems. Poisoning (35%) and a combination of trapping and poisoning (42%) were the most common methods. Poisoning allows for treatment of larger areas, and poison projects generally last longer than trapping projects. Second-generation anticoagulants (mainly brodifacoum and bromadiolone) were used most often. The median annual cost for rat-control projects was US$17,262 or US$227/ha. Median project duration was 4 years. For 58% of the projects, rat population reduction was reported, and 51% of projects showed evidence of positive effects on biodiversity. Our data were from few countries, revealing the need to expand rat-control distribution especially in some biodiversity hotspots. Improvement in control methods is needed as is regular monitoring to assess short- and long-term effectiveness of rat-control.

Vkorc1 sequencing suggests anticoagulant resistance in rats in New Zealand.

Anticoagulant toxins are used globally to control rats. Resistance of Rattus species to these toxins now occurs in at least 18 countries in Europe, America and Asia. Resistance is often associated with single nucleotide polymorphisms (SNPs) in the Vkorc1 gene. This study gives a first overview of the distribution and frequency of Vkorc1 SNPs in rats in New Zealand. New Zealand is unusual in having no native rodents but three species of introduced Rattus-norvegicus Berk., rattus L. and exulans Peale. Sequence variants occurred in at least one species of rat at all 30 of the sites sampled. Three new SNPs were identified, one in kiore and two in ship rats. No SNPs previously associated with resistance were found in Norway rats or kiore, but seven ship rats were heterozygous and one homozygous for the A74T variant. Its resultant Tyr25Phe mutation has previously been associated with resistance to both first- and second-generation anticoagulants in ship rats in Spain. This is the first evidence of potential resistance to anticoagulant toxins in rats in New Zealand. Further testing using blood clotting response times in dosed rats is needed to confirm resistance potentially conferred by the Tyr25Phe mutation. Assessment is also needed of the potential of the other non-synonymous variants (Ala14Val, Ala26Val) recorded in this study to confer resistance to anticoagulant toxins. © 2016 Society of Chemical Industry.

The potential of coumatetralyl enhanced by cholecalciferol in the control of anticoagulant-resistant Norway rats (Rattus norvegicus).

We evaluated the potential of cholecalciferol as an enhancer of the first-generation anticoagulant coumatetralyl in the Westphalia anticoagulant-resistant strain of the Norway rat (Rattus norvegicus Berkenhout), characterised by the Tyr139Cys polymorphism on the VKOR enzyme. Because today only the most potent, but also most persistent anticoagulant rodenticides of the second generation remain available to control this strain, new rodenticide solutions are required. Feeding trials in the laboratory confirmed a significant level of efficacy, which was corroborated by field trials in the Münsterland resistance area. After frequency and level of resistance were assessed by blood clotting response tests, field trials were conducted with bait containing coumatetralyl at 375 mg kg-1 and cholecalciferol at 50 mg kg-1 or 100 mg kg-1 . Control success was 94% when a large rat infestation comprising 42% resistant animals was treated. Another field trial applying the combination to a rat population that had survived a preceding treatment with bromadiolone resulted in a 99.5% control success according to the first census day, but with some increase in rat activity during subsequent census days. The combination of coumatetralyl and cholecalciferol is a promising alternative approach to the most potent second-generation anticoagulants in resistance management, particularly in respect of environmental risks, such as secondary poisoning. © 2016 Society of Chemical Industry.

Anticoagulant resistance in the United Kingdom and a new guideline for the management of resistant infestations of Norway rats (Rattus norvegicus Berk.)

Anticoagulant resistance was first discovered in UK Norway rats (Rattus norvegicus Berk.) in 1958 and has been present ever since. The possible detrimental impact of resistance on effective rodent control was quickly recognised, and, for almost three decades, extensive research was conducted on the geographical distribution and severity of anticoagulant resistance in UK rats. Various schemes for the eradication of resistant rats were also implemented. At first, surveys showed resistance only to the first-generation anticoagulants, such as warfarin, chlorophacinone and coumatetralyl, but, later, resistance to the more potent second-generation anticoagulants, such as difenacoum and bromadiolone, was also discovered. Unlike some European countries, where only one or two resistance mutations occur, virtually all known rat resistance mutations occur in the United Kingdom, and five (Leu128Gln, Tyr139Ser, Tyr139Cys, Tyr139Phe and Leu120Gln) are known to have significant impacts on anticoagulant efficacy. Little is currently known of the geographical extent of anticoagulant resistance among Norway rats in the United Kingdom because no comprehensive survey has been conducted recently. At an operational level, anticoagulants generally retain their utility for Norway rat control, but it is impossible to control resistant rats in some areas because of restrictions on the use of the more potent resistance-breaking compounds. This paper reviews the development of resistance in Norway rats in the United Kingdom, outlines the present situation for resistance management and introduces a new resistance management guideline from the UK Rodenticide Resistance Action Group.

Efficacy of Rodenticide Baits for the Control of Three Invasive Rodent Species in Hawaii

We tested the efficacy and palatability of nine commercial rodenticide bait formulations on Polynesian rats (Rattus exulans), roof rats (R. rattus), and house mice (Mus musculus). Efficacy varied by rodenticide tested and rodent species. Generally, rodenticides were more effective against mice than for either of the rat species, and mice tended to consume more rodenticide bait than the laboratory chow alternative food. Efficacy was generally highest for the second-generation anticoagulants tested; however, this varied across products and one-first-generation rodenticide had similar effectiveness. Bait acceptance (palatability) also varied both by rodenticide and by rodent species. Acceptance was the lowest for the acute rodenticides. Bait acceptance appeared to substantially affect the efficacy of rodenticides; materials that were not well accepted produced lower mortality rates. Rodenticide products currently registered for use in Hawaii performed less effectively in this study than other available products not yet registered. Although markets for rodent control products for use on islands are limited, there are advantages to having additional products registered for island use in agriculture, conservation, and public health.

Alternatives to brodifacoum and 1080 for possum and rodent control—how and why?

The risks of vertebrate pesticides to non-target animals are determined by intrinsic susceptibility, the toxicokinetics of the compounds used, and the degree and frequency of exposure. Metabolism and persistence studies coupled with field surveys have provided us with an improved understanding of the toxicokinetics and non-target effects of different anticoagulants. This has enabled improved choice of tools for island versus mainland use in New Zealand, and has stimulated the development of low-residue tools. Brodifacoum is a potent second-generation rodenticide used worldwide for commensal rodent control, and has been widely used to eradicate rodents from islands. The risks associated with ‘one-off’ application of baits containing second-generation anticoagulants for rodent eradication on islands are considered to be outweighed by the potential benefits to their ecosystems. Possums are susceptible to bait containing brodifacoum, but not to first-generation anticoagulants, hence brodifacoum has been the only alternative to 1080 that effectively targets both possums and rodents. On the mainland, contamination of wildlife and game species and secondary poisoning of non-target species has been substantial where brodifacoum has been used repeatedly. We are extending the current range of low residue alternatives to reduce reliance on brodifacoum and sodium fluoroacetate (1080). Currently, suitable alternatives available include encapsulated cyanide Feratox® and cholecalciferol paste Feracol®. Other compounds being developed as alternatives include micro-encapsulated zinc phosphate and low dose cholecalciferol and coumatetralyl, or C+C.

Assessing Some Potential Environmental Impacts from Agricultural Anticoagulant Uses

This study was designed to give us a better understanding of the relationship between agricultural anticoagulant ro denticide uses and related occurrence of these materials in raptor tissues. The project utilized data from raptor carcasses collected, both in urban San Diego County and in largely agricultural Fresno, Kern, and Madera Counties, as part of the public health surveillance programs of the County Veterinarian(s) and/or Departments of Environmental Health. Most raptors contained detectible levels of secondgeneration anticoagulants, which are registered only for commensal rodent control in and around structures; very few contained firstgeneration anticoagulants, which are the only anticoagulants registered for use in agricultural production in California. This suggests that secondary hazards to raptors and other wildlife from anticoagulants stems primarily from retail sale of commensal rodent baits, particularly in residential areas, and not from anticoagulant rodenticide uses in agricultural regions.

Concerns Regarding Proposed Restrictions in the Use of Second-Generation Anticoagulant Rodenticides for Commensal Rodent Control

Author(s): Kaukeinen, Dale E.; Colvin, Bruce A. | Abstract: The development of second-generation anticoagulant rodenticides for commensal rodent control arose from the need to overcome genetic resistance to earlier anticoagulants, to improve efficacy, and to reduce hazard over older acute rodenticide materials. Over the past three decades, the second-generation anticoagulant products have become the principal commensal rodenticides used in the U.S. and elsewhere. During this long usage, individual cases of human and nontarget wildlife exposure have been documented, and the significance has been debated. Following a lengthy re-registration and review process, the U.S. Environmental Protection Agency in January 2007 proposed restrictions on the use of second-generation anticoagulant rodenticides for commensal rodent control. The proposed restrictions would shift emphasis to other rodenticides, including those with inherent problems that were the basis for developing second-generation anticoagulants. Reduced efficacy, prolonged public exposure to rodents, limitations in bait formulations and placements, increased genetic resistance, and greater application rates (exposure) are anticipated if these restrictions are adopted. Various nontarget concerns will remain with alternative products and use patterns by professional users and consumers, including use of products without specific antidotes. These impacts would occur amidst increasing rodent problems in many U.S. municipalities with declining management resources and aging infrastructure. Alternative measures should include use of human taste deterrents in baits and revised label statements to limit the use of all commensal rodenticide from sensitive areas, including placement along fence lines, and bordering natural habitats.

Reflections on Improvements in the Use of Vertebrate Pesticides in New Zealand: 1996-2006

Vertebrate pesticides for wild animal control in New Zealand came under scrutiny in the 1980s and 1990s, which engendered considerable research to update the toxicology databases of older compounds, such as 1080 or diphacinone, to meet current international registration standards. In parallel there was a focus on identifying “use patterns” and formulations that are effective at killing pests and less hazardous to other wildlife. Improved bait quality and reduced sowing rates for 1080 bait for possum control in New Zealand, down from 10-15 kg of bait per hectare to 1-3 kg, has been accompanied by increased effectiveness and reduced non-target risk. This has been coupled with an improved understanding of 1080 toxicology and risk communication amongst pest control professionals and with the community. In addition, in vivo metabolism and persistence studies coupled with field surveys have improved understanding of the toxicokinetics and non-target effects of different anticoagulants. This enabled improved choice of tools for island versus mainland use in New Zealand. The risks associated with “one-off” applications of baits containing second-generation anticoagulants for rodent eradication on islands are considered to be very substantially outweighed by the potential benefits to their ecosystems. On the mainland, contamination of wildlife and game species and risk of secondary poisoning have been substantially reduced by switching from second- to first-generation anticoagulants. Finally, these developments were coupled with the identification of improved baits for ground control of possums and rodents, such as encapsulated cyanide and gel baits containing cholecalciferol, which in turn reduced an over-reliance on 1080 and anticoagulants alone. Nevertheless, safer use patterns, improved formulations and target specificity, and new vertebrate pesticides are still required, and this will be a major challenge for the 21st Century.

Successful reversal of anticoagulant effect of superwarfarin poisoning with recombinant activated factor VII

The use of second-generation anticoagulants termed "superwarfarins" as rodenticides, although widespread, is poorly controlled. Products containing superwarfarin have been marketed in over-the-counter rodenticides and can be easily purchased. Poor control potentiates the risk of accidental or intentional poisoning, but clinicians may underestimate the incidence of superwarfarin toxicity. Therefore, when cases of unexplained acquired coagulopathy and selective deficiency of vitamin K-dependent clotting factors occur in patients in the absence of liver disease or inhibitors, physicians should consider the possibility of superwarfarin poisoning as a cause. According to our own experience, recombinant activated factor VII (NovoSeven; Novo Nordisk, Bagsvaerd, Denmark) appears to be a safe and effective therapy for acute bleeding caused by superwarfarin poisoning. Due to the extended half-life of the second-generation rodenticides, follow-up therapy with oral vitamin K1 should be of long-term duration.

Choice of agents to limit the coagulation cascade in acute coronary syndromes.

Arterial thrombosis, the predominant event in acute coronary syndromes (ACS), is the end-result of endothelial cell dysfunction, impaired vascular thromboresistance, and sudden atheromatous plaque disruption, each occurring amid a backdrop of inflammation and inflammatory mediators. Because the contribution of individual coagulation proteins to coronary arterial thrombosis varies from modest to marked, selective pharmacologic targeting is both pathobiologically sound and clinically preferred. The development of second-generation anticoagulants with broadened therapeutic windows represents an advance in the management of ACS.