warfarin and Precursor-Cell-Lymphoblastic-Leukemia-Lymphoma

Topics: Antidepressive Agents; Child; Dideoxynucleosides; Drug Hypersensitivity; Drug-Related Side Effects and Adverse Reactions; Evidence-Based Medicine; Genetic Testing; HIV Infections; HLA-B Antigens; Humans; Male; Mercaptopurine; Pharmacogenetics; Precision Medicine; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Primaquine; Purine-Pyrimidine Metabolism, Inborn Errors; Succinylcholine; Warfarin

Recently, we have shown that small molecule dCK inhibitors in combination with pharmacological perturbations of de novo dNTP biosynthetic pathways could eliminate acute lymphoblastic leukemia cells in animal models. However, our previous lead compound had a short half-life in vivo. Therefore, we set out to develop dCK inhibitors with favorable pharmacokinetic properties. We delineated the sites of the inhibitor for modification, guided by crystal structures of dCK in complex with the lead compound and with derivatives. Crystal structure of the complex between dCK and the racemic mixture of our new lead compound indicated that the R-isomer is responsible for kinase inhibition. This was corroborated by kinetic analysis of the purified enantiomers, which showed that the R-isomer has >60-fold higher affinity than the S-isomer for dCK. This new lead compound has significantly improved metabolic stability, making it a prime candidate for dCK-inhibitor based therapies against hematological malignancies and, potentially, other cancers.

Topics: Animals; Antineoplastic Agents; Binding Sites; Chemistry, Pharmaceutical; Computer Simulation; Crystallography, X-Ray; Deoxycytidine; Deoxycytidine Kinase; Drug Design; Female; Humans; Inhibitory Concentration 50; Mice; Mice, Inbred C57BL; Microsomes; Phosphorylation; Positron-Emission Tomography; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Protein Kinase Inhibitors; Stereoisomerism; Thiazoles

Itraconazole is a potent inhibitor of CYP3A4 and P-glycoprotein, but not CYP2C9. Herein, we report a case study in which the plasma concentration of the CYP2C9 substrate (S)-warfarin, and not the CYP3A4 substrate (R)-warfarin, increased with itraconazole coadministration.. A 67-y-old man received an allogenic bone marrow transplant for acute lymphoid leukemia. He was taking oral itraconazole (200mg/day) and was started on a warfarin dose of 2.0mg/day. The plasma concentrations of (S)- and (R)-warfarin 3 days after starting warfarin administration were 216 and 556 ng/mL, respectively (INR 0.98), and after 10 days, the concentrations were 763 and 545 ng/mL, respectively (INR 2.43). On day 11 after withdrawal of itraconazole, the concentrations of (S)- and (R)-warfarin were 341 and 605ng/mL, respectively (INR 1.38). The concentration of (R)-warfarin was not affected by itraconazole; however, the final (S)-warfarin concentration had increased 7.3-fold. The (S)-warfarin/(S)-7-hydroxywarfarin ratio decreased to 2.45 from 8.40 after discontinuation of itraconazole. The permeability of warfarin enantiomers across Caco-2 cells was not influenced by itraconazole and showed no difference between enantiomers.. Careful INR monitoring is necessary for warfarin co-administration with itraconazole. Further examination is necessary to elucidate mechanisms of the interaction between warfarin and itraconazole.

Topics: Aged; Aryl Hydrocarbon Hydroxylases; Bone Marrow Transplantation; Caco-2 Cells; Cytochrome P-450 CYP2C9; Humans; Itraconazole; Male; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Stereoisomerism; Transplantation, Homologous; Warfarin

The use of pharmacogenomics to individualize drug therapy offers the potential to improve drug effectiveness, reduce adverse side effects, and provide cost-effective pharmaceutical care. However, the combinations of disease, drug, and genetic test characteristics that will provide clinically useful and economically feasible therapeutic interventions have not been clearly elucidated. The purpose of this paper was to develop a framework for evaluating the potential cost-effectiveness of pharmacogenomic strategies that will help scientists better understand the strategic implications of their research, assist in the design of clinical trials, and provide a guide for health care providers making reimbursement decisions. We reviewed concepts of cost-effectiveness analysis and pharmacogenomics and identified 5 primary characteristics that will enhance the cost-effectiveness of pharmacogenomics: 1) there are severe clinical or economic consequence that are avoided through the use of pharmacogenomics, 2) monitoring drug response using current methods is difficult, 3) a well-established association between genotype and clinical phenotype exists, 4) there is a rapid and relatively inexpensive genetic test, and 5) the variant gene is relatively common. We used this framework to evaluate several examples of pharmacogenomics. We found that pharmacogenomics offers great potential to improve patients' health in a cost-effective manner. However, pharmacogenomics will not be applied to all currently marketed drugs, and careful evaluations are needed on a case-by-case basis before investing resources in research and development of pharmacogenomic-based therapeutics and making reimbursement decisions.

Topics: Anticholesteremic Agents; Anticoagulants; Antimetabolites, Antineoplastic; Cardiovascular Diseases; Carrier Proteins; Child; Cholesterol Ester Transfer Proteins; Cost-Benefit Analysis; Drug Therapy; Genotype; Glycoproteins; Hepatitis C; Humans; Interferons; Mercaptopurine; Methyltransferases; Pharmacogenetics; Pharmacology, Clinical; Phenotype; Pravastatin; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Ribavirin; Warfarin

Warfarin given as a single dose of 20 mg induces lysis of mitochondria in lymphocytes from chronic and acute lymphocytic leukemias studied under the electron microscope. Normal lymphocytes remain unchanged. This cytotoxic actin may be due to superoxide radicals produced in the malignant cells by warfarin, which is a potent electron-transferring substance.

Topics: Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphocytes; Mitochondria; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Warfarin