Enhancing the toxicity of warfarin in rodents

Details Enhancing the toxicity of warfarin in rodents Enhancing the toxicity of warfarin in rodents

1999-02-03

2001-06-19

Robinson, Allen J. (Department: 1616)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

3,10-dihydroxy-2-naphthacene carboxamide or derivative doai

C514S152000, C514S457000

Reexamination Certificate

active

06248730

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to methods for enhancing the toxicity of warfarin in rodenticidal compositions and to warfarin-containing rodenticidal compositions which are effective against warfarin-resistant rodents.
BACKGROUND OF THE INVENTION
Warfarin, 3-&agr;-phenyl-&bgr;-acetylethyl-4-hydroxycoumarin, which has the chemical structure
has, since the 1950s been in use as an active ingredient in rodenticidal compositions. In addition to its use as a rodenticide, warfarin is also used, in generally smaller amounts, in humans to provide similar anti-coagulating effects.
The basis for the effectiveness of warfarin as a rodenticide lies in the fact that it is effective in small, multiple doses. One or two doses of the compound are seldom fatal if taken at the recommended concentration; thus the hazard of acute toxicity to man, domestic animals, and wildlife is greatly reduced. In practical use, warfarin has been sold as a “concentrate” containing 0.5 percent of the active ingredient. This is diluted for use with a suitable bait, to a concentration of about 0.025 percent. Baits commonly used are cereal products, corn meal, rolled oats, mixed animal feeds, and similar products. Baits containing warfarin can be placed in stations and left there for considerable periods of time, so that the rodent populations may partake of several doses in sequence. Usually the rodents begin to die after four or five daily doses of the materials, and the population is greatly reduced or eradicated in approximately three weeks. Death is caused by hemorrhages, brought about by the action of the warfarin in reducing the clotting power of the blood. These hemorrhages may be external or internal and can be initiated by very slight injury or capillary damage. One of the other advantages of warfarin is that, because multiple ingestions are required to kill the rodents, they do not develop bait shyness.
Beginning in 1969, rodents— particularly rats and, to a somewhat lesser extent, mice— began showing resistance to warfarin baits. The general assumption was that such resistance had a genetic basis. Similar resistance was found regarding the use of warfarin as an anti-coagulant in treating humans and, to a certain extent, a possible genetic, or at least familial, basis for the decrease in effectiveness of warfarin in treating humans has been substantiated.
As far as warfarin in rodenticides is concerned, the development of resistance has spawned the search for other rodenticidal compounds, including particularly other coumarin derivatives such as flocoumafen, difenacoum and brodifacoum. Brodifacoum currently appears to be the compound of choice in rodenticidal compositions, although others are used. Unfortunately, many of these other compounds also exhibit toxicity toward household pets and therefore use of brodifacoum-containing rodenticidal compositions has to be carefully controlled in a household environment.
As noted above, warfarin, which is often referred to as a “first generation anti-coagulant rodenticide”, has the advantage of very low toxicity toward household pets and wildlife and its use does not involve the need to take excessive precautions to avoid contact with household pets or wildlife. Since warfarin has been available for over 40 years and there have been extensive studies of its effectiveness and toxicological properties, it would be extremely advantageous to be able again to use warfarin in commercial rodenticide formulations.
SUMMARY OF THE INVENTION
It has now been discovered that the efficacy of warfarin in rodenticidal compositions can be enhanced by adding an antibiotic to the warfarin-containing composition. A wide range of antibiotics may be used in the practice of this invention and the choice of antibiotic will depend on various factors including availability, cost, etc. Obviously, the antibiotic chosen should be one whose anti-bacterial effectiveness is not weakened by warfarin. An example of an appropriate antibiotic is tetracycline, or one of its salts or one of its derivatives, and the antibiotic should be added in sufficient amount to inhibit the action of bacteria present in the gastrointestinal tract of the rodent.
Accordingly, this invention provides a rodenticidal composition which comprises a rodenticidally effective amount of warfarin and an antibiotic in sufficient amount to inhibit the action of bacteria present in the gastrointestinal tract of the rodent. The antibiotic may be tetracycline, or one of its salts or a derivative thereof. In these compositions, only a relatively small amount of antibiotic is required, generally ranging from about 0.05% to 1.0% based on the weight of the bait.
The invention further provides a method for killing rodents, particularly rats and mice, by causing the rodents to ingest a composition containing a rodenticidally effective amount of warfarin and an antibiotic in an amount sufficient to inhibit the action of bacteria present in the gastrointestinal tract of said rodent. The antibiotic may be tetracycline, or one of its salts or derivatives, or others such as cotrimoxazole, metronidazole, erythromycin, fluconazole, isoniazid, miconazole, ciprofloxacin, and itraconazole.
DETAILED DISCLOSURE
Without wishing to be bound by any scientific theory, it is believed that warfarin “resistance” in rodents may not be true resistance, but rather the result of bacterial action which rapidly metabolizes the warfarin so that the substance no longer acts against the rodents in its customary manner. Reducing the number of bacteria present also significantly reduces the amount of vitamin K available to the rodent. (Vitamin K is an antidote for warfarin.) Thus, the addition of a small amount of an antibiotic agent to the rodenticidal composition has the effect of substantially inhibiting the action of such bacteria, thereby allowing warfarin to metabolize in its usual manner and act as an effective rodenticide. It is therefore not necessary to kill off all of the bacteria which act against warfarin, but only to inhibit such action for sufficient time to enable the warfarin to metabolize normally. Thus, the amount of antibiotic required in the bait composition need only be in the range of, for example, from about 0.05% to 1.0% by weight of the bait compositions. Warfarin used at a level of 0.005-0.05% in said bait compositions is usually sufficiently effective in controlling rodents.
Any antibiotic which acts against the warfarin-inhibiting bacteria is suitable for use in the practice of this invention. These include the well known tricyclic and tetracyclic antibiotics such as tetracycline, its salts and derivatives, for example, tetracycline hydrochloride. Other usable antibiotics include cotrimoxazole, metronidazole, erythromycin, fluconazole, isoniazid, miconazole, itraconazole and ciprofloxacin, as well as their salts and derivatives. The choice of the antibiotic to be used will depend on various factors, including compatibility with other ingredients in the rodenticidal composition, stability, cost, palatability toward the target species, etc. The choice of the particular antibiotic to be employed is well within the knowledge of persons skilled in the art.
Warfarin-containing rodenticidal compositions are typically formulated as granular bait compositions containing from 50-300 ppm, preferably about 250 ppm, of warfarin. The amount of antibiotic to be added to such composition should be from about 0.005 to 0.05% by weight of the warfarin. The bait is typically formulated with from 0.5% to 2.5% of warfarin concentrate in a suitable binder such as corn oil. If corn oil is used as a binder, it can be present in an amount of from about 0.5% to about 2% of the total composition. The binder and warfarin are then mixed in with a grain-based bait composition of the type known in the art. Prior to mixing the composition, an appropriate amount of an antibiotic, such as tetracycline hydrochloride, is added. In addition, an antioxidant may be added to the composition as a preservative for both the warfarin and the antibiotic.
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