Browsing by Author "Jackson, Graham"

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    Apophyllite weathering and the aqueous geochemistry of a Karoo breccia pipe
    (2002) Cavé, Lisa Caryn; Fey, Martin; Jackson, Graham; Nordström, Kirk
    Apophyllite is a phyllosilicate mineral commonly associated with hydrothermal environments. It is a major secondary phase occupying fractures in a dolerite breccia pipe on the farm Kopoasfontein, outside Calvinia in the western Karoo, South Africa. Groundwater abstracted from this breccia is uncharacteristically alkaline (pH 10) and high in fluoride (11 mg/L) for a natural water and the link between the groundwater chemistry and breccia pipe minerals has been investigated.
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    Investigation of the effect of hydroxycitric acid on urinary calcium oxalate risk factors for kidney stone formation in artificial urine: theoretical modelling and in vitro crystallisation experiments
    (2020) Ahmed, Amouna; Ravenscroft, Neil; Jackson, Graham; Rodgers, Allen
    Nephrolithiasis, or urolithiasis, commonly known as kidney stones, is a common medical problem. Kidney stones are composed of different mineral types. Calcium Oxalate is the most common kind of stone. The principal aim of this research was to establish whether hydroxycitrate (HCA) affects and/or inhibits calcium oxalate crystallisation. A three-pronged approach was adopted, involving the determination of thermodynamic binding constants for Ca, Mg and Zn-HCA complexes, theoretical modelling of HCA-complex formation in artificial urine and in vitro crystallisation experiments. A potentiometric analysis was conducted to determine thermodynamic binding constants. These were included in the database of the JESS computer program to model the effect of HCA on the urinary supersaturation of calcium salts. A 1 mM HCA concentrations successfully decreased the concentration of ionised calcium and hence the urinary supersaturation of calcium salts. The solution structures of H+ , Ca 2+, Mg 2+, and Zn 2+ -HCA complexes were investigated using 1H-NMR. For protonation, the results showed that the pKa values were too close to resolve and that several microstates were in rapid exchange. Similarly, for the metal complexes, several species were found to be in rapid exchange. Crystallisation experiments were conducted in artificial urine, to determine the effect of HCA on the thermodynamics and kinetics of crystallisation of calcium oxalate, which is the most common component of kidney stones. The effect of HCA on calcium oxalate metastable limit (MSL) and crystallisation kinetics were measured. The results confirmed those predicted by theoretical modelling. The MSL was significantly affected by 1 mM HCA. Also, 1 mM HCA increased the rate of CaOx crystallisation. Both these effects are favourable and decrease the risk of in vivo crystal and stone formation. This augurs well for the potential application of HCA as a therapeutic agent in the management of kidney stone disease. Such an outcome needs to be tested in human trials.
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    Sulfate but not thiosulfate reduces calculated and measured urinary ionized calcium and supersaturation: implications for the treatment of calcium renal stones
    (Public Library of Science, 2014) Rodgers, Allen; Gauvin, Daniel; Edeh, Samuel; Allie-Hamdulay, Shameez; Jackson, Graham; Lieske, John C
    BACKGROUND: Urinary sulfate (SO 4 2− ) and thiosulfate (S 2 O 3 2− ) can potentially bind with calcium and decrease kidney stone risk. We modeled the effects of these species on the concentration of ionized calcium (iCa) and on supersaturation (SS) of calcium oxalate (CaOx) and calcium phosphate (CaP), and measured their in vitro effects on iCa and the upper limit of stability (ULM) of these salts. METHODS: Urine data from 4 different types of stone patients were obtained from the Mayo Nephrology Clinic (Model 1). A second data set was obtained from healthy controls and hypercalciuric stone formers in the literature who had been treated with sodium thiosulfate (STS) (Model 2). The Joint Expert Speciation System (JESS) was used to calculate iCa and SS. In Model 1, these parameters were calculated as a function of sulfate and thiosulfate concentrations. In Model 2, data from pre- and post STS urines were analyzed. ULM and iCa were determined in human urine as a function of sulfate and thiosulfate concentrations. RESULTS: Calculated iCa and SS values for all calcium salts decreased with increasing sulfate concentration. Thiosulfate had no effect on these parameters. In Model 2, calculated iCa and CaOx SS increased after STS treatment, but CaP SS decreased, perhaps due to a decrease in pH after STS treatment. In confirmatory in vitro experiments supplemental sulfate, but not thiosulfate, significantly increased the calcium needed to achieve the ULM of CaP and tended to increase the oxalate needed to reach the ULM of CaOx. Sulfate also significantly decreased iCa in human urine, while thiosulfate had no effect. CONCLUSION: Increasing urinary sulfate could theoretically reduce CaOx and CaP stone risk. Although STS may reduce CaP stone risk by decreasing urinary pH, it might also paradoxically increase iCa and CaOx SS. As such, STS may not be a viable treatment option for stone disease.
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    Synthesis and design of ligand copper complexes as anti-inflammatory drugs
    (2015) Elmagbari, Fatin M Ali; Jackson, Graham
    Rheumatoid arthritis is a debilitating disease for which there is no cure. Copper has been used for centuries to alleviate the inflammation associated with the disease. The aim of this research was to design and test new ligands which are able to promote the percutaneous absorption of copper and/or mobilize endogenous copper reserves. Formation constants of H+, Cu(II), Ni(II) and Zn(II) with five low molecular ligands 2-((2-aminoethyl)amino)-N-(pyridin-2- ylmethyl)acetamide) [H(555)NH2], 2-((2-dimethyl-amino)ethyl)amino)-N-(pyridin-2-ylmethyl) acetamide [H(555)NMe2], N-(2-aminoethyl)-N'-(pyridin-2-ylmethyl)ethanediamide [H2(555)NH2], 3-(2-aminoacetamido)-N-(pyridin-2-ylmethyl)propanamide [H2(565)NH2], 3-amino-N-(pyridin-2-lmethyl)-propanamide [H(56)NH2] were measured at 25±0.01oC and at an ionic strength of 0.15M (NaCl) using glass electrode potentiometry. The structures of the different Cu(II) species formed with these ligands were investigated using ultraviolet-visible (Uv-visible), nuclear magnetic resonance (NMR) spectroscopy and X-ray crystallography as well as molecular mechanics calculations. The Uv-visible spectra obtained for the different species in solution were typical of tetragonally distorted Cu(II) complexes. The active binding sites were identified as the pyridine nitrogen, the amide nitrogen and the terminal amino group. The pyridine nitrogen was involved in coordination first, followed by the amide and then the terminal amine groups. The X-ray crystal structure of two of the Cu(II) complexes were solved; one formed a rectangular pyramidal geometry and the other a distorted square planar geometry. Molecular mechanics was used to determine the lowest energy conformation of different possible geometries. Since the preferred route of administration is through the skin, the rate of dermal absorption and the bioavailability of copper are important. For this reason, the drugs were designed so that they could be administered dermally and be selective for Cu(II) so that they do not affect the speciation of other metal ions in blood plasma. Speciation calculations using a blood plasma model were used to estimate the complexing ability of the ligands in vivo. This result showed that [H(555)NH2] was the best at mobilising copper in vivo.
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    The chemical speciation of potential dermally-absorbed copper-based antiinflamatory drugs
    (1999) Mkhonta-Gama, Lomkhosi; Jackson, Graham
    It has been shown that increasing the amount of copper associated with low molecular weight ligands in plasma helps to alleviate the symptoms of rheumatoid arthritis (RA). Four low molecular weight ligands 1, 13-bis(N,N-dimethyl)-5,9-dioxo-7-(N-benzyl)- 1,4, 7,10, 13-pentaazatridecane (BID), its de-N-benzylated derivative (IDA), 1,13- bis(N,N-dimethyl)-5,9-dioxo-7-(N-phenethyl)-1,4, 7, 10, 13-pentaazatridecane (D1VIE) and its non-methylated derivative (EDA) were synthesised and characterised. The stability constants of their complexes with divalent copper, zinc and calcium complexes were determined at 25 °C in 0. 15 mo] dm·3 (Na)[CIJ by glass electrode potentiometry. The stability constants found for the copper complexes indicated that in vitro mobilisation of this metal ion was quite appreciable. UVMS spectroscopy was used to investigate the structures of the different copper (II) solution species. Even though the degree of coordination of the different ligands varied, the coordination trend of the different species of the chemical models was similar as pH was increased from 2 to 11. Molecular mechanics calculations were used to propose the geometry of the solution species based on the strain energy of each of the possible geometries. Out of four possible coordination geometries found, the one with the lowest strain energy was accepted as best representing the chemical systems at hand. To investigate the feasibility of dermal absorption of the copper complexes of these ligands, octanol/water distribution coefficient experiments were performed the pH range 2 to 10.5. The results confirm that charge neutrality of a species is important for tissue solubility. The superoxide radical the superoxide dismutase (SOD)-like activity of the copper complexes of these ligands was investigated. The results showed that the SOD-like activity of the present complex systems was too negligible for them to be considered as plausible SOD mimics.