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Biomedical subjects

E Ferguson

Publications and source records attributed to E Ferguson.

At least 19 recordsLinked to original sources
PubMed1992

Lipoprotein lipase-mediated lipolysis of very low density lipoproteins increases monocyte adhesion to aortic endothelial cells.

Lipoprotein lipase (LPL) bound to vascular endothelial cells hydrolyses triglycerides in plasma lipoproteins. To explore the role of LPL in atherogenesis, the effect of LPL-mediated lipolysis of very low density lipoproteins (VLDL) on monocyte adhesion to endothelial cells was examined. Adhesion of U937 monocytes to porcine aortic endothelial cells that were incubated with VLDL and purified bovine milk LPL was markedly higher than endothelial cells that were incubated with VLDL alone. The increase in monocyte adhesion obtained with VLDL was dependent on the concentration of the lipoprotein, monocyte dose and time of incubation. The increase in adhesion correlated with generation of free fatty acids from the hydrolysis of triglycerides in VLDL by LPL. Furthermore, direct addition of oleic acid to endothelial cells also increased adhesion of monocytes. We postulate that LPL-derived lipolytic products increase monocyte adhesion to vascular endothelium and thereby promote atherogenesis.

Animals↗
PubMed1992

Hepatic and nonhepatic sterol synthesis and tissue distribution following administration of a liver selective HMG-CoA reductase inhibitor, CI-981: comparison with selected HMG-CoA reductase inhibitors.

Since cholesterol biosynthesis is an integral part of cellular metabolism, several HMG-CoA reductase inhibitors were systematically analyzed in in vitro, ex vivo and in vivo sterol synthesis assays using [14C]acetate incorporation into digitonin precipitable sterols as a marker of cholesterol synthesis. Tissue distribution of radiolabeled CI-981 and lovastatin was also performed. In vitro, CI-981 and PD134967-15 were equipotent in liver, spleen, testis and adrenal, lovastatin was more potent in extrahepatic tissues than liver and BMY21950, pravastatin and PD135023-15 were more potent in liver than peripheral tissues. In ex vivo assays, all inhibitors except lovastatin preferentially inhibited liver sterol synthesis; however, pravastatin and BMY22089 were strikingly less potent in the liver. CI-981 inhibited sterol synthesis in vivo in the liver, spleen and adrenal while not affecting the testis, kidney, muscle and brain. Lovastatin inhibited sterol synthesis to a greater extent than CI-981 in the spleen, adrenal and kidney while pravastatin and BMY22089 primarily affected liver and kidney. The tissue distribution of radiolabeled CI-981 and lovastatin support the changes observed in tissue sterol synthesis. Thus, we conclude that a spectrum of liver selective HMG-CoA reductase inhibitors exist and that categorizing agents as liver selective is highly dependent upon method of analysis.

Animals↗
PubMed1992

Noninvasive in vivo percutaneous absorption measurements using X-ray fluorescence.

X-ray fluorescence (XRF) has been used to determine in vivo the percutaneous absorption of 5-iodouracil (5IU) in dimethyl sulfoxide (DMSO) on female Sprague-Dawley rats. An average absorption rate constant of 122 +/- 34 micrograms/cm2-hr was obtained from the XRF measurements on four rats. A comparative study was performed with radiolabeled (125I) 5IU in which the absorption rate constant was determined to be 126 +/- 20 micrograms/cm2-hr. The XRF system described provides a simple, noninvasive means of measuring the percutaneous absorption rate of select compounds by the surface disappearance method.

Animals↗
PubMed1992

The role of a saliva control clinic in the management of drooling.

This paper describes a saliva control clinic which has been established at the Royal Children's Hospital, Melbourne. A team involving two speech pathologists, a paediatrician, a plastic surgeon and a dentist has assessed and managed 68 young people over a period of 2 years. Treatment options have included behavioural programmes, trial of oral appliances, medication and surgery. This multidisciplinary approach has been useful in developing assessment techniques and formulating recommendations.

Adolescent↗
PubMed1991

Vitreous replacement by gas as a therapeutic modality in bacterial endophthalmitis.

We investigated vitreous replacement by long-lasting gas in the management of severe Staphylococcus aureus endophthalmitis in 19 rabbits randomized for vitrectomy (9 animals) and for vitrectomy followed by replacement of the vitreous by a 20% perfluoropropane-80% air mixture (10 animals). Both groups received systemic antibiotics and achieved comparable intraocular antibiotic levels. Clinically and histopathologically, gas-filled eyes demonstrated less inflammation than did eyes without gas (P less than 0.01). Replacement of vitreous by gas offers an effective adjunct to vitrectomy by eliminating a culture medium, preventing vitreous abscess formation, enabling fundus visualization, and delaying the onset of retinal detachment.

Air↗
PubMed1991

Dietary and mechanically induced rabbit iliac-femoral atherosclerotic lesions: a chemical and morphologic evaluation.

The effect of combining chronic endothelial injury and intermittent meal feeding of a high and low cholesterol, coconut oil, peanut oil diet on plama lipid and lipoprotein content and on the formation of atherosclerotic lesions within the iliac-femoral artery of rabbits was studied. Alternate feeding of a 1 or 0.1% cholesterol, 3% coconut oil, 3% peanut oil diet for 3 to 14 weeks resulted in a 4- to 11-fold increase in plasma cholesterol with 59 to 79% of the plasma cholesterol eluting in a molecular weight fraction comparable to human low density lipoproteins (LDL). In the iliac-femoral artery, an atherosclerotic intimal lesion with an average cross-sectional area of 0.452 mm2 was present in 98% of the animals. The lesion was typically eccentric in location and contained both superficial- and deep-intimal lipid-filled monocyte-macrophages, extracellular lipid, smooth muscle cells, and extracellular connective tissue matrix. The relative percent lipid composition of the iliac-femoral lesion was 62% cholesteryl ester, 21% free cholesterol, and 17% phospholipid. Thus, we conclude that the combination of meal feeding a cholesterol/fat diet, dietary regimen and chronic mild endothelial injury in the rabbit results in (1) a diet-induced hypercholesterolemia in which LDL appear to be the predominant lipoprotein; and (2) a lesion within the iliac-femoral artery comparable in histologic and chemical composition to a human fatty streak.

Animals↗
PubMed1991

Inhibitors of cholesterol biosynthesis. 3. Tetrahydro-4-hydroxy-6-[2-(1H-pyrrol-1-yl)ethyl]-2H-pyran-2-one inhibitors of HMG-CoA reductase. 2. Effects of introducing substituents at positions three and four of the pyrrole nucleus.

A series of trans-tetrahydro-4-hydroxy-6-[2-(2,3,4,5-substituted-1H-pyrrol-1-yl) ethyl]-2H-pyran-2-ones and their dihydroxy acids were prepared and tested for their ability to inhibit the enzyme HMG-CoA reductase in vitro. Inhibitory potency was found to increase substantially when substituents were introduced into positions three and four of the pyrrole ring. A systematic exploration of structure-activity relationships at these two positions led to the identification of a compound ((+)-33,(+)-(4R)-trans-2-(4-fluororphenyl)-5-(1-methylethyl)-N,3- diphenyl-1- [(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1H-pyrrole-4- carboxamide) with five times the inhibitory potency of the fungal metabolite compactin.

Animals↗
PubMed1991

Inhibitors of cholesterol biosynthesis. 4. trans-6-[2-(substituted-quinolinyl)ethenyl/ethyl]tetrahydro-4-hydroxy-2 H-pyran-2-ones, a novel series of HMG-CoA reductase inhibitors.

A series of substituted quinoline mevalonolactones were prepared and evaluated for their ability to inhibit the enzyme HMG-CoA reductase both in vitro and (cholesterol biosynthesis) in vivo. Since previous studies suggested that the 4-(4-fluorophenyl) and 2-(1-methylethyl) substituents afforded optimum potency, attention was focused on variations at position 6 of the quinoline ring. Biological evaluation of a small number of analogues bearing a variety of 6-substituents showed that modification at this position had little effect on potency. Several compounds (8b, 8e, and 11) were identified that showed comparable potency to compactin and mevinolin in both the in vitro and in vivo assays.

Animals↗
PubMed1990

Hep-G2 cells and primary rat hepatocytes differ in their response to inhibitors of HMG-CoA reductase.

CI-981, a novel synthetic inhibitor of HMG-CoA reductase, was previously reported to be highly liver-selective using an ex vivo approach. In order to determine liver-selectivity at the cellular level, CI-981 was evaluated in cell culture and compared to lovastatin, pravastatin, fluvastatin and BMY-21950. Using human cell lines, none of the compounds tested showed liver-selectivity, i.e. strong inhibition of cholesterol synthesis in Hep-G2 cells (liver model) but weak inhibition in human fibroblasts (peripheral cell model). In contrast, all drugs tested produced equal and potent inhibition of sterol synthesis in primary cultures of rat hepatocytes, and CI-981, pravastatin and BMY-21950 were more than 100-fold more potent in rat hepatocytes compared to human fibroblasts. Since all compounds were also equally potent at inhibiting sterol synthesis in a rat subcellular system and in vivo, the data suggest that the use of Hep-G2 cells may not be the cell system of choice in which to study inhibition of hepatic cholesterogenesis or to demonstrate liver selectivity of inhibitors of HMG-CoA reductase.

Animals↗
PubMed1990

Effects of single doses of alpidem, lorazepam, and placebo on memory and attention in healthy young and elderly volunteers.

The aim of the present study was to compare the effects of alpidem, a new imidazopyridine derivative with benzodiazepine-like anxiolytic effects, with those of lorazepam and placebo on memory and attention in two age groups of healthy volunteers. The study design was that of a randomized double-blind crossover trial with 12 young (18-30 years old) and 12 elderly (65-80) subjects. At weekly intervals, each subject was administered single oral doses of 25 mg alpidem, 50 mg alpidem, 1 mg lorazepam, and placebo in a randomized sequence. Computerized memory and attention tests were performed 90 minutes before and 320 minutes after drug administration. Lorazepam and alpidem 50 mg produced memory impairments: for verbal memory tests the difference against placebo was highly significant for both drugs, while for visual memory this impairment was significant for lorazepam only. No memory effects were seen with 25 mg alpidem. There were no significant drug effects on attention, suggesting a specific amnestic effect not explained by general sedation. Performance of the elderly subjects was much lower than that of the younger ones in both memory and attention tasks. It was not possible to observe any interaction effects between drug and age.

Adolescent↗