ABSTRACT
The synthesis of a series of novel substituted hydroxamates has been described along with their profile of inhibitory activity against 5-lipoxygenase, 12-lipoxygenase, and cyclooxygenase enzymes. The structure--activity relationship suggests that future molecules could be designed to specifically inhibit one or more of these enzymes since there were definite differences in structure--activity relationships for these different enzymes. A representative number of these compounds have been tested in vivo and found to possess potent oral activity in a systemic anaphylaxis model mediated by leukotrienes and topical activity in an arachidonic acid induced inflammation model. One of these molecules, compound 20, demonstrated that a leukotriene antagonist pharmacophore can be modified such that it contains both antagonist activity and 5-lipoxygenase inhibitory activity.
Subject(s)
Anaphylaxis/prevention & control , Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Cyclooxygenase Inhibitors , Hydroxamic Acids/chemical synthesis , Lipoxygenase Inhibitors , Animals , Blood Platelets/drug effects , Blood Platelets/enzymology , Chemical Phenomena , Chemistry , Guinea Pigs , Humans , Hydroxamic Acids/pharmacology , In Vitro Techniques , Leukotriene Antagonists , Male , Mice , Neutrophils/drug effects , Neutrophils/enzymology , Rats , Rats, Inbred StrainsABSTRACT
The value of cytology as a diagnostic tool in uterine MMMT has been tested in order to reach an earlier diagnosis. From 10 endocervical scrapings we were able to obtain 7 positive smears, two of them diagnostic for mixed tumour at first examination, 1 detected upon revision. In one case the positive smear was obtained from a direct scraping of the neoplasia protruding through the cervical os.
Subject(s)
Neoplasms, Germ Cell and Embryonal/pathology , Uterine Neoplasms/pathology , Aged , Aged, 80 and over , Female , Follow-Up Studies , Humans , Middle Aged , Neoplasms, Germ Cell and Embryonal/diagnosis , Uterine Neoplasms/diagnosis , Uterus/pathologyABSTRACT
REV 5901 [alpha-pentyl-3-(2-quinolinylmethoxy)-benzene-methanol] has been shown to be a competitive antagonist of peptidoleukotrienes. In vitro it has a Ki value of 0.7 microM vs. [3H]leukotriene D4 ([3H]-LTD4) binding to membranes from guinea pig lung. Against LTC4-, LTD4- and LTE4-induced contractions of guinea pig parenchymal strips, it has Kb values of ca 3 microM and was relatively ineffective against contractions induced by other spasmogens. The peptiodoleukotriene-antagonist activity is also demonstrable against the hemodynamic and vasoconstriction effects of LTD4 in isolated guinea pig hearts. Oral antagonist activity has been shown with an LTD4-induced bronchoconstriction model and with an LTD4-induced wheal response model in guinea pigs. Unlike other reported antagonists, REV 5901 is ineffective against the multiple forms of cyclic nucleotide phosphodiesterases. Thus, in addition to its previously reported activity as a 5-lipoxygenase inhibitor, REV 5901 is a p.o. active antagonist of peptidoleukotrienes and represents a good tool for understanding the role of peptidoleukotrienes in disease.
