Development warfarin

In a search for even more potent anticoagulants. Link developed warfarin (named after the Wisconsin Alumni Research Foundation), now used primarily as... 

In a search for even more potent anticoagulants. Link developed warfarin (named for the Wisconsin Alumni Research Foundation), now used primarily as a rat poison. When rats consume it, their blood fails to clot, and they bleed to death. Warfarin is also used as a blood anticoagulant in humans. The S enantiomer shown here is more active than the R enantiomer. The commercial product is sold as a racemic mixture. The synthesis of racemic warfarin is described in Problem 19.59. 

A new brush-type CSP, the Whelk-0 1, was used by Blum et al. for the analytical and preparative-scale separations of racemic pharmaceutical compounds, including verapamil and ketoprofen. A comparison of LC and SFC revealed the superiority of SFC in terms of efficiency and speed of method development [50]. The Whelk-0 1 selector and its homologues have also been incorporated into polysiloxanes. The resulting polymers were coated on silica and thermally immobilized. Higher efficiencies were observed when these CSPs were used with sub- and supercritical fluids as eluents, and a greater number of compounds were resolved in SFC compared to LC. Compounds such as flurbiprofen, warfarin, and benzoin were enantioresolved with a modified CO, eluent [37]. 

Dicoumarol is found in sweet clover and can cause hemorrhaging in cattle because of its anticoagulant action. It acts as a vitamin K antagonist and has served as a model for the development of warfarin and related anticoagulant rodenticides. 

Patients with cancer who develop a venous thromboembolism may benefit from long-term therapy with a low molecular weight heparin (at least the first 3-6 mo of pharmacotherapy) instead of oral warfarin... 

While generally not of major concern, omeprazole may inhibit the metabolism of warfarin, diazepam, and phenytoin lansoprazole may decrease theophylline concentrations. Drug interactions with omeprazole are of particular concern in patients who are considered slow metabolizers, as are approximately 3% of the Caucasian population. Unfortunately, it is unclear which patients have the polymorphic gene variation that makes them slow metabolizers.17 The metabolism of esomeprazole may also be altered in patients with this polymorphic gene variation. Patients on potentially interacting drugs should be monitored for development of drug-related problems. 

Isoniazid Adults S mg/kg (300 mg) Children 1 0-1 S mg/kg (300 mg) Asymptomatic elevation of aminotransferases, clinical hepatitis, fatal hepatitis, peripheral neurotoxicity, CNS system effects, lupus-like syndrome, hypersensitivity, monoamine poisoning, diarrhea LFT monthly in patients who have preexisting liver disease or who develop abnormal liver function that does not require discontinuation of drug Dosage adjustments may be necessary in patients receiving anticonvulsants or warfarin... 

The enantioselective reduction of unsaturated alcohol derivatives has been applied to the synthesis of several biologically active compounds (Scheme 24.12). Warfarin (123, R=H) is an important anticoagulant that is normally prescribed as the racemate, despite the enantiomers having dissimilar pharmacological profiles. One of the earliest reported uses of DuPhos was in the development of a chiral switch for this bioactive molecule, facilitating the preparation of (R)- and (S)-warfarin [184]. Although attempted reduction of the parent hydroxycoumarin 122 (R=H) led to formation of an unreactive cyclic hemiketal, hydrogenation of the sodium salt proceeded smoothly with Rh-Et-DuPhos in 86-89% ee. 

Aging is one of the major risk factors for developing gastric ulcers because of an increased incidence of Helicobacter pylori infections and a widely spread use of non-steroidal anti-inflammatory drugs (NSAID). Co-morbidity, with the need for prophylactic medication with antiplatelet therapy, warfarin and other anticoagulants, also increases the risk of gastrointestinal bleeding and ulcerations (Murakami et al. 1968). 

More recent developments in the field of the Pirkle-type CSPs are the mixed r-donor/ r-acceptor phases such as the Whelk-Of and the Whelk-02 phases.The Whelk-Of is useful for the separation of underiva-tized enantiomers from a number of families, including amides, epoxides, esters, ureas, carbamates, ethers, aziridines, phosphonates, aldehydes, ketones, carboxylic acids, alcohols and non-steroidal anti-inflammatory drugs.It has been used for the separation of warfarin, aryl-amides,aryl-epoxides and aryl-sulphoxides. The phase has broader applicability than the original Pirkle phases. The broad versatility observed on this phase compares with the polysaccharide-derived CSPs... 

Zheng, J., and Shamsi, S. A. (2003). Combination of chiral capillary electrochromatography with electrospray ionization mass spectrometry method development and assay of warfarin enantiomers in human plasma. Anal. Chem. 75, 6295—6305. 

Warfarin provides us with a slightly incongruous state of affairs it is used as a drug and also as a rat poison. It was developed from a natural product, dicoumarol, and provides us with a nice example of how pyrone chemistry resembles that of conjugated lactones rather than aromatic systems. 

Animals fed spoiled sweet clover were prone to fatal haemorrhages. The canse was traced to the presence of dicoumarol. This compound interferes with the effects of vitamin K in blood coagulation, the blood loses its ability to clot, and minor injnries can lead to severe internal bleeding. Synthetic dicoumarol has been nsed as an oral blood anticoagnlant in the treatment of thrombosis, where the risk of blood clots becomes life threatening. It has since been snperseded by warfarin, a synthetic development based on the natnral prodnct. 

Warfarin was initially developed as a rodenticide, and has been widely employed for many years as the first-choice agent, particularly for destruction of rats. After consumption of warfarin-treated bait, rats die from internal haemorrhage. Warfarin is synthesized from 4-hydroxycoumarin by a Michael reaction on benzalacetone, again exploiting the nucleophilicity of the hydroxypyrone. Benzalacetone is the product from an aldol reaction between benzaldehyde and acetone (see Section 10.3). 

The discovery of the anticoagulant properties of dicoumarin (j ) led to the development of the more potent anticoagulant warfarin (2), (Structure 1). The subsequent discovery that the anticoagulants can be successfully used as multiple dose... 

Very rapidly, a number of other anticoagulants, including the indanediones (4), (Structure 2), were developed as rodenticides. Warfarin first came into wide usage as a rodenticide in 1950 and virtually supplanted all other materials then in use. In the case of all these early materials, multiple bait applications were needed to control rodent populations which, while making the materials safer to use than the available acute poisons, curtailed their use in underdeveloped and less affluent countries because of the large quantities of bait that must be placed to destroy the populations of rodents. 

Rodenticides are a broad class of chemicals designed to kill mammals, particularly rats and mice. Compounds that inhibit blood clotting, anticoagulants, are commonly used to control rat populations. One of the first was warfarin, which is related to the plant-derived coumadin (from spoiled sweet clover). In the 1950s rats developed resistance to warfarin, which prompted the development of more potent anticoagulants. Other rodenticides include fluoroacetic acid and zinc phosphide (very toxic) and thiourea-based compounds. The primary alternative to using rodenticides is trapping. 

Enantiomeric pnrity assays have also been performed without chromatographic separation being conducted prior to detection, for example, with circular dichroism (CD) and MS. Bertncci et al. [110] developed a chiral assay for pulegone, oxazepam, and warfarin by combining simnltaneons UV, CD, and g factor detection on an achiral separation system with a Hypersil CN colnmn and a mobile phase of hexane 2-PrOH (90 10). The precision (RSD%) of the method ranged from 0.6% to 2.6%, and the LOQs were between 0.1% and 1% (0.2-2.2 j,g). For fnrther information concerning the application of CD and polarometric detection for chiral detection, see the review by Bobbitt and Linder [111]. 

A 23-year old pregnant woman who has been administered IV heparin for treatment of deep vein thrombosis has developed heparin-induced thrombocytopenia. Altering therapy by removing heparin and adding warfarin is not a viable option, because warfarin can cross the placenta and exert an anticoagulant effect in the fetus. Suggest a treatment approach. 

Zafirlukast and montelukast are well tolerated. Zafirlukast increases plasma concentrations of warfarin and decreases the concentrations of theophylline and erythromycin. In rare cases, treatment of patients with CysLT receptor antagonists is associated with the development of Churg-Strauss syndrome, a condition marked by acute vasculitis, eosinophilia, and a worsening of pulmonary symptoms. Because these symptoms often appear when patients are given the leukotriene receptor antagonists when they are being weaned from oral corticosteroid therapy, it is not clear whether they are related to the action of the antagonists or are due to a sudden reduction in corticosteroid therapy. 

Hydroxylated coumarins are present in grass and contribute to the smell of newly cut hay others have pharmaceutical and rodenticidal activities. The compound warfarin (5.2) was developed to kill rats, but is now often used as a blood anti-coagulant in human patients. 

As noted above, OC failure may lead to accidental pregnancy and exposure of the developing fetus to potentially teratogenic properties of CBZ ( 383). Therefore, OC levels should be closely monitored and patients should notify their physician of spotting, an indicator of OC failure. Prothrombin time and the International Normalized Ratio (INR) should be monitored when patients are on warfarin and CBZ concomitantly. Patients stabilized on an antipsychotic may decompensate when CBZ is added. This may necessitate an increase in the antipsychotic dose and is one indication for TDM of antipsychotic drug levels ( 384). Conversely, when CBZ is discontinued, the dose of these other agents may need to be lowered to avoid toxicity. In summary ... 

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