Page 618 - Veterinary Toxicology, Basic and Clinical Principles, 3rd Edition

VetBooks.ir Chapter 46

Anticoagulant Rodenticides

Michael J. Murphy

INTRODUCTION expected anticoagulation effects (Fraigui et al., 2002).
The single oral LD 50 of ferulenol in albino mice is 2100
The origin of oral anticoagulant therapy and anticoagulant
mg/kg (Fraigui et al., 2002). This value is similar to oral
rodenticides traces back to investigations of moldy sweet
LD 50 values of 1650 and 2000 for rats and mice, respec-
clover poisoning in the 1920s. This cattle disease was
tively, using fessoukh, the resinous gum of Ferula
characterized by high mortality and internal bleeding;
(Fraigui et al., 2001). These reports supported prior stud-
investigations revealed that the cattle had been fed moldy
ies in rats (Tagliapietra et al., 1989; Aragno et al., 1988).
sweet clover hay. Anticoagulation activity of the plant in sheep was
An association between vitamin K and coagulopathies
reported in 1985 (Shlosberg and Egyed, 1985).
was made in the mid 1930s (Dam, 1935; Fieser et al.,
Subsequently, ferulenol has been measured in the serum
1939). Soon thereafter, Professor Link reported the
of sheep experimentally dosed with 600 g of powdered
discovery of dicoumarol in moldy hay (Last, 2002).
plant material (Tligui et al., 1994). Ferulenol was detected
Naturally occurring coumarin in the sweet clover hay is
at 6 h after dosing and for about 12 h after cessation of
reportedly converted by fungi to dicoumarol. Dicoumarol
dosing. The prothrombin time (PT) was elevated to 6
was found to be the causative agent of moldy sweet
times normal about 70 h after the last dose, then returned
clover toxicosis. The elements of the toxicosis were
to normal by day 5 postdosing (Tligui and Ruth, 1994;
coumarin-containing plant material plus conversion of
Tligui et al., 1994).
coumarin to dicoumarol by mold; subsequently, a range
Ferula has also been examined for chemotherapy (Poli
of molecules were synthesized, one of which, named war-
et al., 2005), antimycobacterial (Appendino et al., 2004;
farin, became popular as both an oral anticoagulant and a
Mossa et al., 2004), microtubule effects (Bocca et al.,
rodenticide. (Duxbury and Poller, 2001) Warfarin takes
2002) and testicular and epididymal changes in rams (Gil
its name, in part, from the Wisconsin Alumni Research
et al., 2002), much like the warfarin and other oral antic-
Foundation.
oagulants now have. It is found in Morocco (Fraigui
Sweet clover requires the action of molds to cause a
et al., 2001), Israel (Shlosberg and Egyed, 1983), and
toxicosis giant fennel does not.
Italy (Tagliapietra et al., 1989).
Giant fennel, Ferula communis, grows in Mediterranean
The phrase oral anticoagulants normally refer to these
countries. It has a naturally occurring anticoagulant effect.
chemicals when used therapeutically. The oral anticoagu-
An association between the plant and anticoagulation was
lants are briefly discussed before the detailed discussion
first reported in the 1950s (Costa, 1950a,b; Carta, 1951),
of the application of the progeny of dicoumarol as antico-
then further investigated in Italy (Cannava, 1958;
agulant rodenticides.
Mazzetti and Cappelletti, 1957; Corticelli and Deiana,
Warfarin, and its congeners, are still used as thera-
1957; Corticelli et al., 1957) and Israel (Shlosberg and
peutic agents. Oral anticoagulants available therapeuti-
Egyed, 1983). The anticoagulant activity of the plant in
cally in Europe include warfarin, phenprocoumaron,
Morocco has recently been reviewed (Lamnaouer, 1999).
and nicoumalone—also called acenocoumarol (Shetty
Five coumarins and 11 daucane derivatives have been
et al., 1993). Oral anticoagulants are used therapeuti-
isolated from F. communis.(Arnoldietal.,2004). Previously
cally to reduce thromboembolic events. Warfarin exam-
identified chemicals included allohedycaryol, fercoperol
ples include a reduction in catheter-related thrombosis
(Miski et al., 1986), and ferulenol.
(Magagnoli et al., 2006; Guidry et al., 1991), early venous
The toxicity of ferulenol in rats, mice, and sheep
thrombosis after operations (Pan et al., 2005; Calnan and
has been reported. It is a 4-hydroxycoumarin, with the
Veterinary Toxicology. DOI: http://dx.doi.org/10.1016/B978-0-12-811410-0.00046-5
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