Biomedical subjects
Publications and source records attributed to R Cowling.
Potent and selective bicyclic heteroaryl hydroxamic acid MMP and TACE inhibitors were synthesized by a novel convergent route. Selectivity and efficacy versus MMPs and TACE could be controlled by appropriate substitution on the scaffolds and by variation of the P1' group. Select compounds were found to be effective in in vivo models of arthritis.
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The SAR of a series of potent sulfonamide hydroxamate TACE inhibitors bearing novel acetylenic P1' groups was explored. In particular, compound 4t bearing a butynyloxy P1' moiety has excellent in vitro potency against isolated TACE enzyme and in cells, good selectivity over MMP-1 and oral activity in an in vivo model of TNF-alpha production.
Anthranilic acid derivatives bearing basic amines were prepared and evaluated in vitro and in vivo as inhibitors of MMP-1, MMP-9, MMP-13, and TACE. Piperazine 4u has been identified as a potent, selective, orally active inhibitor of MMP-9 and MMP-13.
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A novel series of anthranilic acid-based inhibitors of MMP-1, MMP-9, MMP-13, and TACE was prepared and evaluated. Selective inhibitors of MMP-9, MMP-13, and TACE were identified, including the potent, orally active MMP-13 inhibitor 4p.
A novel series of anthranilic acid-based inhibitors of MMP-1, MMP-9, and MMP-13 was prepared and evaluated both in vitro and in vivo. The most potent compound, 6e, has in vivo activity in a rat sponge-wrapped cartilage model.
Heteroaryl and cycloalkyl sulfonamide-hydroxamic acid MMP inhibitors were investigated. Of these, the pyridyl analogue 2 is the most potent and selective inhibitor of MMP-9 and MMP-13 in vitro.
The microtubular element of the plant cytoskeleton undergoes dramatic architectural changes in the course of the cell cycle, specifically at the entry into and exit from mitosis. These changes underlie the acquisition of specialized properties and functions involved, for example, in the equal segregation of chromosomes and the correct positioning and formation of the new cell wall. Here we review some of the molecular mechanisms by which the dynamics and the organization of microtubules are regulated and suggest how these mechanisms may be under the control of cell cycle events.
The pasticcino (pas) mutants of Arabidopsis thaliana are a new class of plant developmental mutants; members of this class show ectopic cell proliferation in cotyledons, extra layers of cells in the hypocotyl, and an abnormal apical meristem. This phenotype is correlated with both cell division and cell elongation defects. There are three complementation groups of pas mutants (pas1, pas2, and pas3, with, respectively 2, 1, and 4 alleles). Here we describe in more detail the pas1-1 allele, which was obtained by insertional mutagenesis. The PAS1 gene has been cloned and characterized; it encodes an immunophilin-like protein similar to the p59 FK506-binding protein (FKBP52). PAS1 is characterized by an FKBP-like domain and three tetratricopeptide repeat units. Although the presence of immunophilins in plants has already been demonstrated, the pas1-1 mutant represents the first inactivation of an FKBP-like gene in plants. PAS1 expression is altered in pas1 mutants and in the pas2 and pas3 mutants. The expression of the PAS1 gene is increased in the presence of cytokinins, a class of phytohormones originally discovered because of their ability to stimulate cell division. These results are of particular relevance as they show for the first time that an FKBP-like protein plays an important role in the control of plant development.
A computerized database for pacemaker follow-up has been designed to run on IBM compatible hardware and to accept pulse generator and lead models of all manufacturers. Stored data includes patient, physician and implant details, indications for pacing, underlying rhythm, complications and management, program settings, and follow-up measurements. Typing is minimized by the use of "pop-up" lists and prepared pulse generator template displays. At each follow-up visit a patient's file is retrieved by surname or number, a visit record created, and measurements documented. As the template of the previous visit is used, recording of the clinic visit takes less than 1 minute. Changes in pacing rates (base or magnet), pulse widths, lead thresholds, lead impedance, and battery cell impedance can be displayed graphically for immediate recognition of end-of-life parameters or suspected malfunction. The program will print patient, implantation and clinic visit summary reports, clinic appointment lists, letters to patients, and annual reports. Two Melbourne hospitals have now entered over 3,600 patients into the database. Valuable information has been obtained regarding implantation details and trends with pulse generator and lead usage. Pacecare is a sophisticated, yet user friendly, computerized database for pacemaker follow-up. Recording of clinic visits is fast and changes in testing parameters can be recognized immediately.
This study evaluated the clinical performance of leads with a drug-eluting (less than 0.5 mg of dexamethasone sodium phosphate) collar (DEC) placed adjacent to a 4-mm2 Pt/Ir coated electrode (Telectronics model 030-368). Ten trailing tined ventricular silicone DEC leads and ten control leads (model 030-359) were implanted transvenously in patients of comparable age, sex, and indication for pacing. Early threshold rise, chronic thresholds (Vario), and lead impedances were monitored by pacer telemetry. The DEC lead had substantially lower thresholds in the first few weeks (P less than 0.0005) as well as chronically (P less than 0.025). The study has shown that a drug dose of less than 0.5 mg, released from a drug-eluting collar (DEC), is effective in reducing thresholds.