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Biomedical subjects

D R Blake

Publications and source records attributed to D R Blake.

At least 217 records · Page 12Linked to original sources
PubMed1989

Investigation of the anti-inflammatory properties of hydroxypyridinones.

Synovial iron deposition associated with rheumatoid disease may result in the production of highly reactive oxygen free radicals, leading to tissue damage. This chain of events can be interrupted by iron chelation. Families of strong iron (III) chelators have been tested for their iron scavenging properties in vitro and their effects assessed in vivo using a rat model of inflammation. All the chelators competed successfully for iron with apotransferrin, and some removed up to 34% of iron from ferritin. The best anti-inflammatory effects were achieved with the most hydrophilic chelators and those which chelated iron most avidly. Activity was dependent on dose. The route of administration was also an important factor with lower affinity chelators. This work introduces a range of simple bidentate iron chelators, which under certain conditions exceed desferrioxamine in their iron scavenging abilities, and some of which, in this simple animal model, approach indomethacin in their anti-inflammatory capabilities.

Animals↗
PubMed1989

Ocular toxicity of desferrioxamine--an example of copper promoted auto-oxidative damage?

Three patients with rheumatoid disease were given the 'iron chelating' drug desferrioxamine (DFX), which also has an appreciable affinity for copper. The drug was injected cautiously, in lower doses than in patients with thalassaemia, and intramuscularly to evaluate its anti-inflammatory effects. Two of the three patients developed ocular abnormalities. One patient, who also received methyldopa, developed severe but reversible visual failure associated with an abnormal electro-oculogram (EOG); another showed reversible depression of the EOG. Analysis of the cerebrospinal fluid (CSF) of this patient showed an increase in phenanthroline detectable (non-caeruloplasmin-bound) copper. Analysis of the CSF of the third patient, who did not develop any clinical or electrophysiological ocular abnormalities, was normal. Haematological assessments indicated that all three patients probably had reduced iron stores. With in-vitro systems DFX was shown to mobilise copper from albumin and to facilitate copper movement across a cell membrane model, a property that was enhanced by methyldopa. Our observations are consistent with the concept that in rheumatoid patients low iron stores may result in binding of copper by DFX and that this may be of central importance in causing the ocular toxicity of DFX.

Aged↗
PubMed1989

Lipoprotein oxidation and induction of ferroxidase activity in stored human extracellular fluids.

It was observed that during the storage of human extracellular fluids at -20 degrees C the azide-inhibitable ferroxidase activity of caeruloplasmin declined, whilst a new azide-resistant ferroxidase activity (ARFA) developed. The literature suggested that storage-induced ARFA might be due to either a poorly defined enzymatic activity of a low density lipoprotein (LDL) or to lipid peroxides formed within the different lipoprotein fractions. To study this further, the major lipoprotein classes were separated from human serum by density gradient centrifugation. After storage of the lipoprotein fractions, it was found that the LDL fraction had the highest specific activity of ARFA and the highest content of lipid peroxidation products, as assessed by diene conjugates. The ARFA of LDL correlated with its content of diene conjugates and TBA reactive material, which initially suggested that the Fe(II) oxidising activity of peroxidase LDL arose from the reduction of peroxides by Fe(II) in the classical reaction between the metal ion and free radical reduction of lipid peroxides. However, steady state kinetic analysis indicated an enzymic role of LDL in Fe(II) oxidation, with lipid peroxides acting as a substrate for the enzyme. These results indicate that LDL may contain a peroxidase activity, catalysing the oxidation of Fe(II) by lipid peroxides, as well as a ferrous oxidase activity where O2 is the oxidising substrate.

Acetylation↗
PubMed1989

Cytoskeletal rearrangement by oxidative stress.

The cytoskeleton is susceptible to oxidative stress and this occurs prior to membrane blebbing and cell lysis. Vimentin intermediary filaments in rheumatoid synoviocytes are more susceptible than in normal synoviocytes and this may have pathological significance. They are however no more susceptible to heat shock than other cell types.

Cells, Cultured↗
PubMed1988

Oxidants, inflammation, and anti-inflammatory drugs.

Species such as superoxide radical (O2-), hydrogen peroxide (H2O2), hydroxyl radical (.OH), and hypochlorous acid (HOCl) can be formed in vivo, e.g., by activated phagocytic cells. Generation of .OH from H2O2 in vivo usually involves iron-dependent reactions. Good evidence exists for increased generation of oxidants in vivo in patients with active rheumatoid disease, but the contribution of these oxidants to the disease process is still uncertain. The likelihood that anti-inflammatory drugs used in the treatment of arthritis could act by scavenging oxidants or preventing their formation is discussed.

Anti-Inflammatory Agents↗
PubMed1988

An automated method for the kinetic measurement of ferroxidase activity.

The oxidase activity of caeruloplasmin towards Fe II (ferroxidase) appears to be of physiological significance both in iron metabolism and as a serum anti-oxidant. We have developed an automated assay for ferroxidase using a centrifugal analyser. The method is quick and precise, and is not subject to interference by haemolysis, jaundice or lipaemia. Ferroxidase activities correlate significantly with caeruloplasmin and copper concentrations. Normal reference ranges have been measured.

Adult↗
PubMed1988

Mechanisms of persistent synovitis.

Rheumatoid arthritis is characterised by persistent and symmetrical synovitis. In this article we propose two linked hypotheses to explain these observations. A mechanism to explain symmetry of synovitis is described whereby fine afferent nerve fibres from joints become bilaterally sensitized to movement with resultant release of neuropeptides promoting an inflammatory response. Clinical and experimental evidence is reviewed and shows that movement and resulting hypoxic reperfusion injury leads to a persistent synovitis.

Animals↗
PubMed1987

Evidence of enhanced lipid peroxidation in the cerebrospinal fluid of patients taking phenothiazines.

Products of lipid peroxidation in the cerebrospinal fluid are found in higher concentrations in patients receiving phenothiazines than in control subjects matched for age and sex. Especially high concentrations are found in patients experiencing ill-effects from phenothiazine therapy. Raised concentrations of cerebrospinal fluid "phenanthroline copper" in these patients suggest that metal-catalysed mechanisms may promote the lipid peroxidation. It is suggested that lipid-soluble antioxidants, such as vitamin E, may be useful for the prevention and treatment of phenothiazine side-effects.

Adult↗