Biomedical subjects
Publications and source records attributed to D Farr.
Thrombin inhibitors have been designed with the replacement of the strongly basic guanidine P1 pharmocophore with a group that exploits the lipophilicity of the S1 pocket. The approach has lead to the discovery of potent thrombin inhibitors demonstrating good intra-duodenal absorption.
The application of selection criteria, based on potency and physicochemical parameters, to a candidate library of thrombin inhibitors is described. The utility of the approach is exemplified by the discovery of a potent, selective and bioavailable thrombin inhibitor 62.
The chemical optimisation of CGH1668 1 is described employing an in vivo model of absorption to determine the influence on bioavailability of single point modifications to five key molecular templates. The discovery of an orally bioavailable and selective thrombin inhibitor, 24, highlights the utility of this approach.
All previous studies of residual strain in the ventricular wall have been based on one- or two-dimensional measurements. Transmural distributions of three-dimensional (3-D) residual strains were measured by biplane radiography of columns of lead beads implanted in the midanterior free wall of the canine left ventricle (LV). 3-D bead coordinates were reconstructed with the isolated arrested LV in the zero-pressure state and again after local residual stress had been relieved by excising a transmural block of tissue. Nonhomogeneous 3-D residual strains were computed by finite element analysis. Mean +/- SD (n = 8) circumferential residual strain indicated that the intact unloaded myocardium was prestretched at the epicardium (0.07 +/- 0.06) and compressed in the subendocardium (-0.04 +/- 0.05). Small but significant longitudinal shortening and torsional shear residual strains were also measured. Residual fiber strain was tensile at the epicardium (0.05 +/- 0.06) and compressive in the subendocardium (-0.01 +/- 0.04), with residual extension and shortening, respectively, along structural axes parallel and perpendicular to the laminar myocardial sheets. Relatively small residual shear strains with respect to the myofiber sheets suggest that prestretching in the plane of the myocardial laminae may be a primary mechanism of residual stress in the LV.
The shortcomings of the conventional arch bars for the treatment of maxillomandibular injuries are described. A mesh-backed arch bar bonded to the teeth is recommended as a means of overcoming these problems.
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Osteoclastic (OC) and osteoblastic (OB) cells were isolated by sequential collagenase digestions of new-born rat calvaria. Prostaglandin E2(PGE2) did not alter total calmodulin levels after a 5 or 60 min incubation. The calmodulin antagonists, trifluoperazine (TFP) at 10-50 microM and W-7 (50 microM) inhibited PGE2-induced increases in calcium uptake by OC cells, but had no effect on control OC or OB calcium levels. W-5 (50 microM), a chlorine-deficient analogue of W-7 with weak anti-calmodulin activity, had no effect. Compound 48/80 (100-500 micrograms/ml), a highly effective calmodulin antagonist in other systems, had no effect on PGE2-induced calcium levels or control calcium uptake. There was inhibition of PGE2-induced increases in cyclic AMP by compound 48/80 (100 micrograms/ml) in both OC and OB cells but no effect on control levels. TFP at 50 microM inhibited both control and PGE2-induced increases in cyclic AMP but at 10 microM it lessened only the hormone-induced effect. W-7 (100 microM) inhibited PGE2-induced increases in OC and OB cyclic AMP but had no effect on control levels; W-5 (50 microM) had no effect on either of these. Dibutyryl cyclic AMP had no effect on control calcium uptake, PGE2-induced increases or W-7 inhibition of the PGE-2 effect on calcium uptake. The calmodulin antagonists, at doses which had affected only PGE2-induced increases in calcium uptake and/or cyclic AMP production, had no effect on leucine uptake by OC or OB cells.(ABSTRACT TRUNCATED AT 250 WORDS)
Prostaglandin E2 (PGE2) over the concentration range 10(-5)-10(-7) M stimulated calcium uptake in osteoclastic-enriched populations isolated by sequential collagenase digestions of newborn rat calvaria. This effect was on initial calcium uptake occurring at 5 min at 37 degrees C but was not present when isotopic equilibrium was approached (60 min). Prostacyclin (PGI2, PGE1 and PGF2 alpha) stimulated osteoclastic calcium uptake in a similar manner, but with slightly smaller effects than PGE2. Under identical conditions, significant effects of PG were not observed in osteoblastic cells isolated from the same bones by extended collagenase digestions. Combined treatment with PGE2 and parathyroid hormone (PTH) at concentrations which produced no individual effects resulted in a significant increase in calcium uptake in osteoclastic cells. During a 48-h culture period, osteoblastic populations released significantly greater amounts of PGE2 than osteoclastic populations. Pre-incubation for 1 h at 37 degrees C with the prostaglandin cyclo-oxygenase antagonists, indomethacin and flufenamic acid, had no effect on calcium uptake in osteoclastic cells, but resulted in significant decreases in osteoblastic cells. The PGE2-induced increase in calcium uptake on osteoclastic cells was not altered by indomethacin or flufenamic-acid pretreatment. However, after treatment with these inhibitors, a significant response to PGE2 was observed in osteoblastic cells.
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Explore the source record for details and available documents.
Explore the source record for details and available documents.