Novel anticoagulant rodenticides devoid of causing rodenticide-resistance – A potential solution to an increasing and worldwide problem

| July 12, 2015

Dietrich C. Gulba1, Henrik Luessen2

1Katholisches Klinikum Oberhausen GmbH, Oberhausen, D
2Tytonis BV, Alkmaar, NL

Abstract: Rodent associated annual agricultural loss is estimated to exceed 10% up to 25 % of the annual food production in the world. In addition, these animals serve as carriers of severe human diseases and epidemic plagues of which (Ebola) – an infection causing hemorrhagic fever with a >90% case fatality – has recently received mournful attention. To minimize rodent associated agricultural and human damages pest control has been sought from periodic rodenticide campaigns.

During the past 5 decades, oral anticoagulants (coumarin- and indandione- derivatives) have been the rodenticide of choice due to their safety and efficacy to eradicate entire rodent colonies. Meanwhile, however, an increasing number of rodent tribes have developed resistance mechanisms rendering the current anticoagulants completely insensitive to such rodenticides.

The number of territories with the majority of rodents that are found resistant to the current coumarin- and indandione type rat poisons is expanding fast and even complete resistance has become a fact in some areas. Just recently, within our research a new type of rodenticides have been discovered that are devoid of the limitations of the current anticoagulant type rodenticides.

Current coumarin- and indandione- type rodenticides exert delayed toxicity via Vitamin K antagonism. Vitamin K is essential for the synthesis of active coagulation factors II, VII, IX and X. Associated with this synthesis Vitamin K is oxidized to an epoxide and later in the process recycled in a NADPH dependent manner. High doses of coumarin- and indandione-type anticoagulants prevent the vitamin K epoxide from recycling and as a consequence, rodents can no longer synthesize the functionally active coagulation factors II, VII, IX and X, which get them into a fatal hemophilic state. Coumarin- and indandione resistance emerges from genetic selection of such animals that can activate an alternative, disulfide dependent (instead of the NADPH-dependent) reduction pathway.

New rodenticide approach:
We identified five families of novel rodenticides covered by our recently submitted patent [1], which are basically derivatives of:
1. benzimidazolcarbonylpyridylaminopropionate
2. hydroxycarbaminidoylphenylmethylcarbamylaztidinaminoazetate
3. methyloxohydrobenzolisobenzfurancarbamat
4. cyclopropyloxoethylthienopyridinacetat or
5. cyclopropylaminotriazolopyrimidincyclopentan.

Their major advantages are that they
a) are readily orally available
b) do not interfere with the synthesis of coagulation factors
c) inhibit blood coagulation by direct interaction with the coagulation factors
d) act by a mechanism independent from Vitamin K and Vitamin K recycling; and
e) are devoid of any existing or foreseeable mechanism of resistance

Summary and Conclusion: We describe five families of novel anticoagulant type rodenticides that exert their activity by direct molecular interactions with specific coagulation proteins (factors) and that are completely devoid of any existing and foreseeable resistance -mechanism. These novel anticoagulant-type of rodenticides may create the solution to the increasing worldwide problem of rodenticide resistance.

[1] Gulba, DC, Patent application DE 10 2014 108 210.9 (2014).

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Novel anticoagulant rodenticides devoid of causing rodenticide-resistance – A potential solution to an increasing and worldwide problem


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