ABSTRACT
A series of potent and selective factor Xa inhibitors was synthesized using various readily available amino acids as central templates. The most potent compound displays IC(50) of 3 nM.
Subject(s)
Factor Xa Inhibitors , Serine Proteinase Inhibitors/pharmacology , Drug Design , Inhibitory Concentration 50 , Models, Molecular , Serine Proteinase Inhibitors/chemical synthesis , Serine Proteinase Inhibitors/chemistry , Structure-Activity RelationshipABSTRACT
A series of glycolic and mandelic acid derivatives was synthesized and investigated for their factor Xa inhibitory activity. These analogues are highly potent and selective inhibitors against fXa. In a rabbit deep vein thrombosis model, compound 26 showed significant antithrombotic effects (81% inhibition of thrombus formation) at 1.1 microM plasma concentration following intravenous administration.
Subject(s)
Acetanilides , Amidines/chemistry , Amidines/pharmacology , Factor Xa Inhibitors , Mandelic Acids/chemistry , Phenylacetates/chemistry , Phenylacetates/pharmacology , Serine Proteinase Inhibitors/chemistry , Serine Proteinase Inhibitors/pharmacology , Amidines/chemical synthesis , Animals , Biological Availability , Blood Coagulation Tests , Drug Design , Drug Evaluation, Preclinical/methods , Fibrinolysin/antagonists & inhibitors , Inhibitory Concentration 50 , Injections, Intravenous , Phenylacetates/chemical synthesis , Rabbits , Rats , Rats, Sprague-Dawley , Serine Proteinase Inhibitors/chemical synthesis , Structure-Activity Relationship , Venous Thrombosis/drug therapyABSTRACT
Two three-dimensional quantitative structure-activity relationship (3D-QSAR) methods, comparative molecular field analysis (CoMFA) and hypothetical active site lattice (HASL), were compared with respect to the analysis of a training set of 154 artemisinin analogues. Five models were created, including a complete HASL and two trimmed versions, as well as two CoMFA models (leave-one-out standard CoMFA and the guided-region selection protocol). Similar r2 and q2 values were obtained by each method, although some striking differences existed between CoMFA contour maps and the HASL output. Each of the four predictive models exhibited a similar ability to predict the activity of a test set of 23 artemisinin analogues, although some differences were noted as to which compounds were described well by either model.
Subject(s)
Antimalarials/chemistry , Antimalarials/metabolism , Artemisinins , Sesquiterpenes/chemistry , Sesquiterpenes/metabolism , Antimalarials/pharmacology , Binding Sites , Models, Molecular , Molecular Conformation , Sesquiterpenes/pharmacology , Structure-Activity RelationshipABSTRACT
With assisted suicide now legally sanctioned, health care professionals in Oregon face the challenge of implementing Oregon's Death with Dignity Act. Physicians, hospice professionals, pharmacists, and other caregivers may find their relationships with patients, families, and fellow professionals changing in unanticipated ways as all learn what it means to make aid in dying openly and compassionately available to patients at the end of life.
Subject(s)
Suicide, Assisted/legislation & jurisprudence , Aged , Aged, 80 and over , Bioethics , Consensus , Disclosure , Dissent and Disputes , Ethics, Medical , Euthanasia, Active , Family , Female , Group Processes , Hospices , Humans , Male , Oregon , Pharmacists , Religion and MedicineABSTRACT
Thirty (10 male, 20 female) children, ages 41 to 71 months, were observed simultaneously in a freeplay setting by two observers using a validated assessment of physical activity in children (i.e. the FATS). One observer utilized a whole interval time sampling method of data recording and the second observer used a hand-held computer and continuously entered observations whenever a child's activity level changed, while the computer simultaneously calculated elapsed time (in tenths of seconds) spent in each behavioral category. Overall activity scores generated by the two approaches correlated 0.90 although the time sampling method produced lower estimates of physical activity. It is concluded that whole interval time sampling is a reliable cost-effective method of assessing physical activity levels in children and may be preferable to the continuous computer-assisted approach that was utilized.
Subject(s)
Psychiatry/standards , Research Design/standards , Adult , Aged , Evaluation Studies as Topic , Female , Humans , Male , Middle AgedABSTRACT
We investigated the relationship between selected parent behaviors, child mealtime behavior, and infant relative weight. Subjects were 7 male and 7 female children varying in age from 12 to 30 months (mean = 23.9 months). Each subject and parents were observed during the dinnertime meal on two occasions using the BATMAN (Bob and Tom's Method of Assessing Nutrition). The children spent 58% of the mealtime eating. They spent very little time making active decisions about what and how much they ate (food requests = 2% of the time; food refusals = 1% of the time). We found significant correlations between child relative weight and (a) parental prompts to eat (r = .81, p less than .001), (b) parental food offers (r = .51, p less than .05), and (c) parental encouragement to eat (r = .82, p less than .001). Thus, the present study suggests a relationship between certain parental variables and the relative weight of their children.
