Warfarin resistance

It was also essential to determine how effective bromethalin was against warfarin-resistant rats and mice. Such animals, whose resistance to anticoagulants had been determined by World Health Organization tests,(17) were subjected to a standard EPA choice feeding efficacy test with bromethalin at 0.005% in the treated diet. The results indicate (Appendix 6) that 90% of the animals were killed and that consumption patterns were similar to those observed in other choice tests. 

Efficacy of 0.005% Bromethalin Against Warfin-Resistant Rodents Laboratory 3-Day Choice Test With Warfarin-Resistant Wild Norway Roats and House Mice... 

Warfarin has hccn drlcrmiiicd from plasma 3f>7). Siinlics of iis metabolic fate due to the action of hepatic mixed function oxidases have profited from the use of reversed-phase columns for the determination of metabolites (368). Related studies on warfarin resistance have utilized vitamin Kt 2,3-epoxide to examine the rate of its reduction in rats to form X ilamin h the rraxMion was follitwcil x liromalxtitrapliii allv... 

This synthetic compound, as well as natural coumarin anticoagulants (Box 15-F), inhibits both the vitamin K reductase and the epoxide reductase.518 519 The matter is of considerable practical importance because of the spread of warfarin-resistant rats in Europe and the United States. One resistance mutation has altered the vitamin K epoxide reductase so that it is much less susceptible to inhibition by warfarin.519 520... 

Vitamin K quinone is reduced to the active hydroquinone substrate for the epoxidase reaction by either a dithiol-linked reductase that is almost certainly the same enzyme as the epoxide reductase or NADPH-dependent quinone reductase, like the epoxide reductase, the dithiol-linked reductase is inhibited by warfarin. In warfarin-resistant rats, there is a warfarin-insensitive epoxide reductase, which also has quinone reductase activity (Hildebrandt et al., 1984 Gardill and Suttie, 1990). 

Hildebrand EF, Preusch PC, Patterson JL, and Suttie JW (1984) Solubilization and characterization of vitamin K epoxide reductase from normal and warfarin-resistant rat liver microsomes. Archives of Biochemistry and Biophysics 228,480-92. 

Brodifaeoum has been marketed in several countries for the eontrol of a wide range of rodent pest species. It is available as a 0.005% pellet for rat and mouse control, a smaller 0.001% pellet for field rodent eontrol, and as 29 g wax bloeks for sewer rat eontrol. It is the only anticoagulant rodenticide found to produee 100% mortality in most rodent speeies after only a 24 h dose (Chalermehaikit et al, 1993). Brodifaeoum was effeetive against warfarin-resistant rats and miee in 1984, but the possibility of resistance has been raised (Lund, 1984). 

Neosorexa , and by ICI Plant Protection Division under the trademark Ratak as a 0.005% pelleted bait, and as a wax block. Pure difenacoum is an off-white powder with a solubility of greater than 50 g/1 in acetone, 600 mg/1 in benzene, and less than 10 mg/1 in water. It is more toxic than warfarin, but less palatable (IPCS, 1995c). Difenacoum is still effective against many populations of warfarin-resistant rats (Desideri et al, 1979), but resistance maybe developing in the UK (Greaves et al, 1982). 

Leek, J.B., Park, B.K. (1981). A comparative study of the effects of warfarin and brodifacoum on the relationship between vitamin K1 metabolism and clotting factor activity in warfarin-susceptible and warfarin-resistant rats. Biochem. Pharmacol. 30 123-8. 

Redfem, R., Gill, J.E. (1980). Laboratory evaluation of bromadiolone as a rodenticide for use against warfarin-resistant and non-resistant rats and mice. J. Hyg. (Land.) 84(2) 263-8. 

Hildebrandt, E. R, and Suttie, J. W. (1982). Mechanisms of coumarin action Sensitivity of vitamin K metabolizing enzymes of normal and warfarin-resistant rat liver. BiocfrCFJij sfry 21, 2406-2411. 

Qureshi GD, Reinders TP, Somori GJ, Evans FH. Warfarin resistance with nafcUlin therapy. Ann Intern Med 1984 100(4) 527-9. 

MacLaren R, Wachsman BA, Swift DK, Kuhl DA. Warfarin resistance associated with intravenous hpid administration discussion of propofol and review of the hterature. Pharmacotherapy 1997 17(6) 1331-7. 

Brophy DF, Ford SL, Crouch MA. Warfarin resistance in a patient with short bowel syndrome. Pharmacotherapy 1998 18(3) 646-9. 

Lutomski DM, Palascak JE, Bower RH. Warfarin resistance associated with intravenous lipid administration. J Parenter Enteral Nutr 1987 11(3) 316-18. 

AD MacNicoll, AK Nadian, MG Townsend. Inhibition by warfarin of fiver microsomal vitamin K-reductase in warfarin-resistant and susceptible rats. Biochem Pharmacol 33(8) 1331—1336, 1984. 

Variant alleles predispose to increased warfarin requirements (warfarin resistance) and reduced warfarin requirements. 

Rost S, Fregin A, Ivaskevicius V, et al. Mutations in VKORC1 cause warfarin resistance and multiple coagulation factor deficiency type 2. Nature 2004 427(6974) 537 L... 

Searcey, M.T., Graves, C.G., and Olson, R. 1977. Isolation of a warfarin binding protein from liver endoplasmatic reticulum of Sprague-Dawley and warfarin-resistant rats. J. Biol. Chem., 252, 6260-6267. 

The wide application of anticoagulant rodenticides for more than 20 years has gradually increased the genetic resistance of rodents to these active substances. Warfarin resistance and cross-resistance to similar anticoagulants predominate in certain territories to such an extent that it impedes the practical use of these active substances (Gratz, 1973). 

In contrast, several cases of markedly reduced warfarin effects (warfarin resistance) have been seen with intravenous nafcillin, with a 75% reduction in warfarin half-life documented in one case. Similarly, other studies and cases suggest that dicloxacillin may cause a modest reduction in warfarin effects in many patients, and that some may experience greater reductions, with thrombosis being reported in one case. 

The prothrombin time of a 29-year-old patient stabilised on warfarin fell from a range of 20 to 25 seconds down to 16 seconds live days after intravenous nafcillin 2 g every 4 hours was started for endocarditis. Over the next 2 weeks the prothrombin time ranged between 14 and 17 seconds despite an eventual doubling of the warfarin dose, and heparin was substituted. In this patient the half-life of a single 30-mg dose of warfarin was 11 hours when nafcillin was taken, 17 hours 4 days after stopping nafcillin, and 44 hours eight months after the nafcillin was discontinued. At least 10 other cases of this warfarin resistance have been reported with high-dose nafcillin. " ... 

The reduced effect of warfarin with dicloxacillin and nafcillin appears to be established. If these penicillins are used, increase monitoring of the INR and anticipate the need to increase the warfarin dose. Some patients taking nafcillin have been warfarin resistant, and needed heparin treatment. 

Fraser GL, Miller M, Kane K. Warfarin resistance associated with nafcillin therai . AmJ Med( 9S9) 87, 237-8. 

AgostaFG, Liberate NL, ChiofaloF. Warfarin resistance induced by teicoplanin. Haematolog-ica (1997) 82,637-40. 

Havrda DE, Rathbun S, Scheid D. A case report of warfarin resistance due to azathioprine and review of the literature. Pharmacotherapy (2001) 21, 355-7. 

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