digoxin and Leukemia

Topics: Analgesics; Anti-Bacterial Agents; Anticoagulants; Asthma; Blood Transfusion; Contraceptives, Oral; Digoxin; Drug Interactions; Drug Therapy; Humans; Infusions, Parenteral; Leukemia; Lymphoma; Prostaglandins

Topics: Anemia, Macrocytic; Anti-Arrhythmia Agents; Anticoagulants; Azathioprine; Chemical and Drug Induced Liver Injury; Cholelithiasis; Clofibrate; Colitis, Ulcerative; Dextrans; Digoxin; Drug Therapy; Fibrinolytic Agents; Halothane; Heparin; Hepatitis B Antigens; Humans; Hyperthyroidism; Iodine Isotopes; Leukemia; Myocardial Infarction; Platelet Adhesiveness; Pulmonary Embolism; Thrombosis; Venoms

The discovery of inhibitors of bromodomain and extra terminal domain (BET) has achieved great progress, and at least seven inhibitors have progressed into clinical trials for the treatment of cancer or inflammatory diseases. Here, we describe the identification, optimization, and evaluation of benzo[cd]indol-2(1H)-one containing compounds as a new class of BET bromodomain inhibitors, starting from structure-based virtual screening (SBVS). Through structure-based optimization, potent compounds were obtained with significantly improved activity. The two most potent compounds bind to the BRD4 bromodomain, with Kd values of 124 and 137 nM. Selected compounds exhibited high selectivity over other non-BET subfamily members. Notably, compound 85 demonstrated a reasonable antiproliferation effect on MV4;11 leukemia cells and exhibited a good pharmacokinetic profile with high oral bioavailability (75.8%) and moderate half-life (T1/2 = 3.95 h). The resulting lead molecule 85 represents a new, potent, and selective class of BET bromodomain inhibitors for the development of therapeutics to treat cancer and inflammatory diseases.

Topics: Animals; Antineoplastic Agents; Cell Cycle Proteins; Cell Line, Tumor; Cell Proliferation; Crystallography, X-Ray; Drug Discovery; Humans; Indoles; Leukemia; Molecular Docking Simulation; Nuclear Proteins; Rats; Structure-Activity Relationship; Transcription Factors

An adaptation of a previously published program for nonlinear regression analysis of serum drug concentrations which can utilize data obtained during multiple-dose administration is described. Specific programs have been developed for aminoglycosides, digoxin, and theophylline. The programs provide initial parameter estimates (for a one-compartment linear model) for each drug based on mean population parameters and refined estimates based on observed concentration data. Clinical examples which demonstrate the flexibility of these programs are provided. The programs may also be employed for fitting data for any drug that can be adequately described by a one-compartment linear model.

Topics: Adult; Aged; Amikacin; Aminophylline; Asthma; Atrial Fibrillation; Computers; Digoxin; Female; Humans; Leukemia; Male; Microcomputers; Pharmaceutical Preparations; Regression Analysis; Software

A patient with acute nonlymphoblastic leukemia in relapse and anthracycline cardiomyopathy was treated with AMSA in combination with cytosine arabinoside and thioguanine (AAT). Induction of remission was accomplished after one course of therapy without development of congestive heart failure. Radionuclide studies done prior to and subsequent to the reinduction with AAT revealed that the combination did not induce further deterioration of myocardial function. Although the exact risk of AMSA causing additional cardiac damage will require more extensive experience, this case suggests that AMSA may be safely given to patients with anthracycline cardiomyopathy and may be the treatment of choice for this group of patients.

Topics: Acute Disease; Adult; Aminoacridines; Amsacrine; Antibiotics, Antineoplastic; Antineoplastic Agents; Digoxin; Female; Furosemide; Heart Diseases; Humans; Leukemia; Naphthacenes

Topics: Acute Disease; Digitalis Glycosides; Digoxin; DNA; Humans; Leukemia; Leukocytes; Ouabain; Radioimmunoassay; Time Factors