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OBJECTIVES - Several in vitro and in vivo studies have shown that low molecular weight heparin and warfarin may directly inhibit tumour cell growth and prevent metastatic spread. However, the clinical evidence in support of an anti-cancer effect is less conclusive. We summarize the evidence from clinical studies that examine the effect of these anticoagulants on cancer development and briefly describe the current understanding of the potential mechanisms by which anticoagulants may exert an anti-cancer effect.
METHODS - English-language articles reporting on warfarin, coumarin or low molecular weight heparin for the treatment or prevention of cancer were selected from PUBMED. All randomized clinical trials, case-control studies, cohort studies, and meta-analyses were retrieved. Detailed data review and abstraction was performed according to pre-specified criteria.
RESULTS - Of ninety-nine articles retrieved, 12 warfarin and 17 low molecular weight heparin articles were included in the review. We found no consistent evidence that warfarin may improve cancer survival, though there is indirect evidence that prolonged warfarin use may decrease the risk of urogenital cancer. Low molecular weight heparin may improve survival of patients with small cell lung cancer and those with advanced malignancy who have more favorable prognoses.
CONCLUSION - Clinical evidence exists in support of an anti-neoplastic effect of anticoagulants. However, more research is needed to further define which cancer type and stage would most benefit from low molecular weight heparin, as well as to explore the role of warfarin in urogenital tumour development.
CONTEXT - Prior risk stratification schemes for atrial fibrillation (AF) have been based on randomized trial cohorts or Medicare administrative databases, have included patients with established AF, and have focused on stroke as the principal outcome.
OBJECTIVE - To derive risk scores for stroke alone and stroke or death in community-based individuals with new-onset AF.
DESIGN, SETTING, AND PARTICIPANTS - Prospective, community-based, observational cohort in Framingham, Mass. We identified 868 participants with new-onset AF, 705 of whom were not treated with warfarin at baseline. Risk scores for stroke (ischemic or hemorrhagic) and stroke or death were developed with censoring when warfarin initiation occurred during follow-up. Event rates were examined in low-risk individuals, as defined by the risk score and 4 previously published risk schemes.
MAIN OUTCOME MEASURES - Stroke and the combination of stroke or death.
RESULTS - During a mean follow-up of 4.0 years free of warfarin use, stroke alone occurred in 83 participants and stroke or death occurred in 382 participants. A risk score for stroke was derived that included the following risk predictors: advancing age, female sex, increasing systolic blood pressure, prior stroke or transient ischemic attack, and diabetes. With the risk score, 14.3% of the cohort had a predicted 5-year stroke rate < or =7.5% (average annual rate < or =1.5%), and 30.6% of the cohort had a predicted 5-year stroke rate < or =10% (average annual rate < or =2%). Actual stroke rates in these low-risk groups were 1.1 and 1.5 per 100 person-years, respectively. Previous risk schemes classified 6.4% to 17.3% of subjects as low risk, with actual stroke rates of 0.9 to 2.3 per 100 person-years. A risk score for stroke or death is also presented.
CONCLUSION - These risk scores can be used to estimate the absolute risk of an adverse event in individuals with AF, which may be helpful in counseling patients and making treatment decisions.
S-Warfarin 7-hydroxylation, S-flurbiprofen 4'-hydroxylation, and diclofenac 4'-hydroxylation activities were determined in liver microsomes of 30 humans of which 19 were wild-type (Arg144.Ile359), 8 were heterozygous Cys (Cys144.Ile359), and 3 were heterozygous Leu (Arg144.Leu359) allelic variants of the cytochrome P450 2C9 (CYP2C9) gene. All of the human samples examined contained P450 protein(s) immunoreactive with anti-CYP2C9 antibodies in liver microsomes. Individuals with the Cys144 allele of CYP2C9 had similar, but slightly lower, activities for the oxidations of these substrates than those of wild-type CYP2C9. One of the three human samples heterozygous for the Leu359 allele had very low Vmax and high Km values for the oxidation of three substrates examined, while the other two individuals gave kinetic parameters comparable to those seen in the wild-type and Cys144 CYP2C9. Reverse transcriptase-polymerase chain reaction analysis, however, showed that all of the three human samples with the heterozygous Leu359 variant were found to express both Ile359 and Leu359 variants at relatively similar extents in liver RNA of three humans. These results suggest that the Cys144 variant of CYP2C9 catalyzes the CYP2C9 substrates at rates comparative to, but slightly lower than, those of wild-type CYP2C9, while the Leu359-allelic variant has slower rates for the oxidation of these drug substrates. Activities for the oxidation of these CYP2C9 substrates in humans with heterozygous Leu359 allele is likely to be dependent on the levels of expression of each of the wild- and Leu-variants in the livers. However, one of the humans with a heterozygous Leu allele was found to have very low activities towards the oxidation of CYP2C9 substrates. The basis of this defect in catalytic functions towards CYP2C9 substrates is unknown.
Tolbutamide methyl hydroxylation and S-warfarin 7-hydroxylation activities were reconstituted in systems containing recombinant human cytochrome P450 (P450 or CYP) 2C10(2C9) and the optimal conditions for the systems were compared with those of bufuralol 1'-hydroxylation by CYP1A1, theophylline 8-hydroxylation by CYP1A2, bufuralol 1'-hydroxylation by CYP2D6, chlorzoxazone 6-hydroxylation by CYP2E1, and testosterone 6 beta-hydroxylation by CYP3A4. CYP2C10 required cytochrome b5 (b5) for optimal rates of tolbutamide and S-warfarin oxidations and b5 could be replaced by apo-b5; apo-b5 and b5 effects on the reconstituted systems have already been reported in systems containing CYP3A4 for the oxidation of testosterone and nifedipine and for the rapid reduction of CYP3A4 by NADPH-P450 reductase (H. Yamazaki et al., 1996, J. Biol. Chem. 271, 27438-27444). Stopped-flow studies, however, suggested that apo-b5 as well as b5 did not cause stimulation of the reduction of CYP2C10 by NADPH-P450 reductase, while the reduction rates were dependent on the substrates in reconstituted systems. Chlorzoxazone 6-hydroxylation by CYP2E1 was stimulated by b5, but not by apo-b5, in reconstituted systems. Neither apo- nor holo-b5 increased bufuralol 1'-hydroxylation activity by CYP1A1 or 2D6 or theophylline 8-hydroxylation by CYP1A2. Interestingly, we found that testosterone 6 beta-hydroxylation by CYP3A4 was stimulated by CYP1A2 (and also by a modified form in which the first 36 residues of the native human protein were removed) and CYP1A1 as well as by b5, and such stimulations were not seen when other P450 proteins (e.g., CYP2C10, 2D6, or 2E1) were added to the reconstituted systems. In contrast, substrate oxidations by CYP2C10 and CYP2E1 were not stimulated by other P450 proteins. The present results suggest that there are differences in optimal conditions for reconstitution of substrate oxidations by various forms of human P450 enzymes, and in some P450-catalyzed reactions protein-protein interactions between P450 and b5 and other P450 proteins are very important in some oxidations catalyzed by CYP2C10, 2E1, and 3A4.
To quantify physician practices in the care of patients with presumed pulmonary embolism or deep venous thrombosis, we analyzed heparin sodium orders, the intensity of anticoagulation, and complications in 65 patients with the diagnosis of deep venous thrombosis or pulmonary embolism. All patients were given heparin, for a mean (+/- SEM) period of 8.8 +/- 0.4 days. A high percentage of patients (60%) did not have a single partial thromboplastin time (PTT) greater than 1.5 times control within the first 24 hours of heparin therapy. Not until day 8 were 90% of PTTs in therapeutic range. We identified five common practices that led to delays in achieving a PTT greater than 1.5 times the laboratory control: (1) failure to start heparin therapy at the time of initial clinical suspicion, (2) choice of a heparin sodium bolus (mean, 5861 +/- 365 U) and continuous infusion (1026 +/- 148 U/h) insufficient to elevate the PTT to greater than 1.5 times control, (3) delay in obtaining the first PTT (mean, 11.7 +/- 1 h after start of heparin therapy), (4) insufficient heparin dosing in response to a low PTT, and (5) excessive and prolonged reductions in heparin therapy in response to a PTT greater than three times control, leading to subtherapeutic levels in 56% of subsequent PTTs. We think that poor understanding of heparin kinetics, overcautious behavior of physicians, and high heparin requirements in this selected population account for the findings.