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C G Knight

Publications and source records attributed to C G Knight.

78 records · Page 5Linked to original sources
PubMed1967

The macromolecular properties of blood-group substances. Sedimentation-velocity and viscosity measurements.

1. Sedimentation-velocity, intrinsic-viscosity and partial-specific-volume measurements on a typical blood-group-specific glycoprotein are reported for a range of environmental conditions. 2. The sedimentation coefficients, S, are strongly concentration-dependent, and follow the reciprocal law; the limiting values at 2 degrees , 25 degrees and 45 degrees , after correction to 25 degrees , show slight dependence on temperature. 3. The intrinsic viscosities, [eta], at 25 degrees and 45 degrees show more marked temperature-dependence, and correspond to a very asymmetric or very expanded molecular conformation. 4. From the value of the ratio K/[eta], where K=S(0).d(1/S)/dc, it is concluded that the molecular conformation is roughly spherical; application of the Einstein viscosity equation then suggests an expansion factor of about 60, compatible with a flexible configuration approaching that of a random coil. 5. The sedimentation coefficient is not affected by variation of ionic strength in the range 0.01-0.50, nor by pH in the range 3-10. 6. Sodium dodecyl sulphate at 1.5% produces a small decrease in S; the effect is greater than would be expected from the observed extent of binding, but is too small to correspond to a significant change in secondary structure; the serological activity is unaffected by sodium dodecyl sulphate. 7. All the properties observed indicate the absence of any secondary structure in blood-group substances.

Journal Article↗
PubMedDate not supplied

The effect of side chain structure on the biochemical and therapeutic properties of intra-articular dexamethasone 21-esters.

The prolonged anti-rheumatic effects produced by some higher 21-esters of intra-articular corticosteroids have been ascribed to their low aqueous solubility or, alternatively, to their slow release of free (21-OH) steroid in the inflamed synovium. Experiments were designed to test this hypothesis. Twelve 21-carboxyl esters of dexamethasone and [3H]dexamethasone were prepared. Their side-chain structures were chosen to provide systematic steric hindrance of the scissile bond. Four dexamethasone/[3H]dexamethasone 21-carbamates were also prepared. When incubated with a 10% (w/v) homogenate of rabbit synovial tissue, esters providing steric hindrance, e.g. t-butylacetate, were more slowly hydrolysed than those which were linear, e.g. n-hexanoate, or cyclic e.g. cyclohexane acetate. Carbamate esters remained unhydrolysed during 24 hours' incubation. The partition coefficients of these compounds, derived using reversed-phase thin-layer chromatography and hydrophobic fragmental constants, were not correlated with their hydrolysis rates. Isomeric 21-substituents had similar partition coefficients. The affinity of the isomers, dexamethasone n-hexanoate and dexamethasone t-butylacetate, for the glucocorticoid receptor of mouse fibroblast cytosol, was determined by a competitive binding assay using [3H]triamcinolone acetonide. Dexamethasone t-butylacetate had 1/10 binding affinity relative to that of dexamethasone. Dexamethasone n-hexanoate was inactive. The therapeutic activities of dexamethasone n-hexanoate and dexamethasone t-butylacetate were compared at a single dose (2 mg), injected into experimentally-arthritic rabbit knee joints. These preparations reduced the swelling and histopathological changes in the treated joints by the same extent, indicating that the local anti-rheumatic activity of corticosteroid 21-esters is unrelated to their hydrolysis rates in vitro.

Animals↗
PubMedDate not supplied

Effect of the intra-articular injection of lutetium-177 in chelator liposomes on the progress of an experimental arthritis in rabbits.

The treatment of rheumatoid arthritis by radiosynovectomy has been restricted by the difficulty of preventing leakage of the radioisotope from the joint cavity. We have previously shown that this leakage can be reduced to very low levels by delivering the radioisotope in liposomes containing the lipophilic chelator, 3-cholesteryl 6-[N'-iminobis-(ethylenenitrilo)tetraacetic acid]hexyl ether. The present study investigates the effectiveness of the beta-emitting isotope lutetium-177, delivered in chelator liposomes, in treating an experimental arthritis in rabbits. Chelator liposomes containing 0.35 mCi, 0.175 mCi Or 0.087 mCi of the isotope were injected into the synovial cavities of the knees of rabbits with an established experimental arthritis. The retention of the lutetium and the progress of the arthritis were followed for 47 days, and samples of the joint tissues were taken for histology at the end of the experiment. Results showed that losses of radioactivity averaged less than 1% per day over 47 days and that joints treated with 0.175 mCi showed significant reductions in both diameter and surface temperature compared with controls treated with a non-radioactive preparation. Post-mortem histology revealed that, whereas control joints showed a highly active synovitis, synovia of joints treated with 0.175 or 0.35 mCi lutetium-177 had very little inflammatory activity. Although some joints which had received 0.35 mCi showed signs of damage to the articular cartilage, this damage was not apparent wih either of the two lower doses. We conclude that, in this animal model, chelator liposomes complexed with a suitable radioisotope are capable of effecting an efficient synovectomy.

Animals↗
PubMedDate not supplied

The retention and distribution in the rabbit knee of a radionuclide complexed with a lipophilic chelator in liposomes.

The application of radiosynovectomy to patients with rheumatoid arthritis has been severely restricted by the difficulty of preventing leakage of the radioisotope from the joint cavity. We have synthesised a lipophilic chelator, 3-cholesteryl 6-[N'-iminobis(ethylenenitrilo)-tetraacetic acid]hexyl ether (Chol-DTTA) which can complex with a variety of beta-emitting radionuclides and is incorporated into the lipid phase of liposomes. The retention in the synovial cavities of rabbit knees of liposomes containing Chol-DTTA, complexed with the gamma-emitting tracer 51Cr, has been measured over a period of 21 days and compared with colloidal and water-soluble preparations. The distribution of the radionuclide between the tissues of the joint was also examined. Results show retention of 51Cr delivered in chelator liposomes to be greater than 99% after 24 h. At this time, over 93% of the radioactivity had become associated with the synovium. We conclude that chelator liposomes offer considerable promise as vehicles for radioisotopes in radiosynovectomy.

Animals↗
PubMedDate not supplied

The hydrolysis of cortisol 21-esters by a homogenate of inflamed rabbit synovium and by rheumatoid synovial fluid.

Long chain esters of cortisol have shown prolonged anti-inflammatory activity in both clinical and animal studies. This effect has been ascribed to the decreased water-solubility of the higher esters, but an alternative explanation is that the higher esters are hydrolysed more slowly to free steroid by the synovial tissue enzymes. In order to investigate the influence of chain length on hydrolysis rate we synthesized a series of cortisol 21-esters. When incubated in a 0.1% (w/v) homogenate of inflamed rabbit synovial tissue the esters with chain lengths of 4, 6, 8 and 10 carbon atoms were hydrolysed much faster than those with 2, 12, 14 and 16 carbon atoms. At tissue concentrations of 10% (w/v), however, the breakdown of cortisol acetate was greatly accelerated, whereas cortisol palmitate remained quite stable. Although cortisol esters were hydrolysed in 50% (v/v) rheumatoid synovial fluid, the rates of hydrolysis were relatively slow. The chain length dependence was similar to that seen with the tissue homogenate.

Animals↗