Page 619 - Veterinary Toxicology, Basic and Clinical Principles, 3rd Edition

584 SECTION | VIII Rodenticides

VetBooks.ir Allenby, 1975), including hip surgery, atrial fibrillation possum (Trichosurus vulpecula) dosed with the anticoagu-
lant rodenticide pindone (Jolly et al., 1994). Pindone has
(Reiffel, 2000; Middlekauff et al., 1995), and myocardial
also been associated with an increased frequency of sex
infarction (Asperger and Jursic, 1970). Dicoumarol is also
used in the therapy of thrombotic occlusion of intracoron- chromosome loss in Drosophila melanogaster (Santoro
ary stents (Alonso Martin et al., 1997), prosthetic valves et al., 1993). The remainder of the chapter is devoted to
(Dalla, 1994), and other types of venous thromboses the application of the chemical progeny of dicoumarol as
(Ferlito, 1996; Piovella et al., 1995) or thrombophlebitis anticoagulant rodenticides.
(Creutzig, 1993; Byrne, 1970).
Warfarin has been reported to be associated with a HISTORY AND CHEMICAL CLASSES
reduction of the recurrence of malignant melanoma
In the 1940s, a small British pharmaceutical company
(Thornes et al., 1994) or small cell lung cancer (Aisner
suggested that dicoumarol might have rodenticide prop-
et al., 1992). This antimetastatic activity may be associ-
erties. Trials carried out by Armour and Barnett (1950)
ated with distribution of metastatic cells on thrombi
supported that idea, starting the era of anticoagulant
(Smith et al., 1988; McNiel and Morgan, 1984).
rodenticides. Warfarin was the first anticoagulant rodenti-
Low-dose warfarin therapy has been adopted by the
cide introduced into the market shortly after World War
United States, Europe, and the World Health Organization
II, and became widely used in many countries. Other anti-
(Duxbury and Poller, 2001). International normalized
coagulant compounds with potency similar to that of
ratio (INR) is now used to measure therapeutic anticoagu-
warfarin were also synthesized. These early anticoagulant
lation (Duxbury and Poller, 2001).
rodenticides have often been called “first-generation
Oral anticoagulants have been used for decades, and a
anticoagulant rodenticides.” These first-generation com-
number of adverse events have been recognized, most of
pounds generally have moderate toxicity, with acute LD 50
which are related to drug interactions (Dayton and Perel,
values ranging from 10 to 50 mg/kg body wt. They often
1971). A controversy exists as to whether acetaminophen
needed continuous bait exposure for effective rodent
induces an adverse effect on warfarinized patients in ther-
control.
apeutic doses (Toes et al., 2005). The acetaminophen
Many rodent species developed a resistance to
metabolite NAPQI (N-acetyl-para-benzoquinoneimine)
warfarin (Jackson et al., 1975), presumably associated
seems to interfere with vitamin K-dependent gamma car-
with continuous bait exposure and widespread use.
boxylase. Such interference may lead to potentiation of
Consequently, new chemical structures were synthesized
the anticoagulant effect of warfarin (Thijssen et al.,
and used as anticoagulant rodenticides. These newer com-
2004). COX-2 inhibitors may also interfere with control
pounds are generally more toxic than warfarin, with acute
of warfarin anticoagulation in elderly patients (Savage,
LD 50 s of 0.2 3.9 mg/kg body wt. For example, a bait
2005), and rifampin may interfere with P-450 associated
concentration of only 50 ppm of brodifacoum is adequate
warfarin metabolism (Finch et al., 2002; Strayhorn et al.,
to give control in a single feeding for most rodents and
1997). Inconsistent anticoagulation has been recognized
noncommensal species (Matolesy et al., 1988). These
in generic versus prescription warfarin (Burns, 1999),
newer compounds were oftenreferredto as“second-
and a single case of hemothorax with eosinophilia has
generation anticoagulant rodenticides,” and are often now
been reported in a warfarin overdose (Nasilowski and
referred to as “superwarfarins” in the contemporary medi-
Krenke, 2002).
cal literature (Chong et al., 1986; Chua and Friedenberg,
Complementary or alternative medical therapies may
1998; Dolin et al., 2006; Exner et al., 1992; Gallo, 1998;
also interfere with warfarin metabolism (Wood et al.,
Greeff et al., 1987; Hui et al., 1996; Pavlu et al., 2005;
2003; Tumova, 2000). For example, passionflower, hydro-
Rauch et al., 1994; Routh et al., 1991; Sharma and
alcoholic extracts, juniper, and verbena contain vitamin
Bentley, 2005; Swigar et al., 1990; Tecimer and Yam,
K 1 , so they can lessen the anticoagulation effect of warfa-
1997; Wallace et al., 1990; Wilton, 1991).
rin therapy (Argento et al., 2000). On the other hand,
Anticoagulant rodenticides are also categorized by
genoderma, japonicum, papaw, Salvia miltiorrhiza,ginseng,
chemical structure. The chemical structure of currently
devil’s claw, garlic, quinine, ginkgo, ginger, red clover, and
marketed products fits in one of two chemical classes: (1)
horse chestnut may reinforce the anticoagulant effect of
hydroxycoumarins and (2) indanediones.
warfarin by various mechanisms (Argento et al., 2000).
A “coumarin-induced hepatitis” has been reported a 1. Hydroxycoumarins. This group of compounds have a
number of times in warfarinized patients (Ehrenforth 4-hydroxycoumarin ring, with different side-chain
et al., 1999; Hohler et al., 1994; Matsukawa et al., 1994; substituents at the 3-position. Commonly used antico-
Bamanikar and Hiremath, 2002; Biagini et al., 2006; Bint agulant rodenticides in this group are bromadiolone,
and Burtt, 1980; Rehnqvist, 1978; Tanaka et al., 1985). brodifacoum, coumafuryl, coumatetralyl, difenacoum,
Liver damage has also been reported in a brushtail and warfarin.