Kieran Scott - Academia.edu (original) (raw)

Papers by Kieran Scott

Australian Prescriber, 2004

There are concerns that therapeutic doses of paracetamol may be hepatotoxic in patients who regul... more There are concerns that therapeutic doses of paracetamol may be hepatotoxic in patients who regularly drink moderate to large amounts of alcohol. Critical examination of case histories reveals that overdoses of paracetamol were responsible for the hepatotoxicity in many cases. Experimental studies in which paracetamol was taken for short periods also show no interaction. Paracetamol is therefore a suitable analgesic for patients who regularly drink moderate to large amounts of alcohol but, as with all patients, care should be taken to minimise the chances of overdose.

Biochimica and Biophysica Acta Molecular and Cell Biology of Lipids, 2008

Antibacterial properties of secreted phospholipases A 2 (PLA 2 ) have emerged gradually. Group (G... more Antibacterial properties of secreted phospholipases A 2 (PLA 2 ) have emerged gradually. Group (G) IIA PLA 2 is the most potent among mammalian secreted (s) PLA 2 s against Gram-positive bacteria, but additional antibacterial compounds, e.g. the bactericidal/permeabilityincreasing protein, are needed to kill Gram-negative bacteria. The mechanisms of binding to the bacterial surface and the killing of bacteria by sPLA 2 s are based on the positive charge of the PLA 2 protein and its phospholipolytic enzymatic activity, respectively. The concentration of GIIA PLA 2 is highly elevated in serum of patients with bacterial sepsis, and overexpression of GIIA PLA 2 protects transgenic mice against experimental Gram-positive infection. The synthesis and secretion of GIIA PLA 2 are stimulated by the cytokines TNF-α, IL-1 and IL-6. Secreted PLA 2 s may be potentially useful new endogenous antibiotics to combat infections including those caused by antibiotic-resistant bacteria such as methicillinresistant staphylococci and vancomysin-resistant enterococci.

Expert Opin Ther Targets, 2003

Amphibia Reptilia, 2009

The catalytic activity of phospholipase A 2 (PLA 2 ) was measured in serum samples from 32 crocod... more The catalytic activity of phospholipase A 2 (PLA 2 ) was measured in serum samples from 32 crocodiles in Thailand and Australia by a method using 14 C-oleic acid-labelled autoclaved Escherichia coli membranes as a substrate. The highest PLA 2 activity was measured in the serum of Crocodylus siamensis (n = 9, mean ± SD), 13.3 ± 3.1 U/l followed by hybrid C. siamensis × C. porosus (n = 6), 10.4 ± 8.7 U/l and Crocodylus porosus (n = 17), 4.3 ± 3.0 U/l. The difference between C. siamensis and C. porosus was highly significant (P < 0.001). The gender of the animals and the geographical location of the crocodile farms were not significant variables affecting serum PLA 2 levels. It was concluded that PLA 2 is present in crocodilian serum and may have an antimicrobial role.

Free Radical Biol Med, 2010

The heme peroxidase enzyme myeloperoxidase (MPO) is released by activated neutrophils and monocyt... more The heme peroxidase enzyme myeloperoxidase (MPO) is released by activated neutrophils and monocytes, where it uses hydrogen peroxide (H 2 O 2 ) to catalyze the production of the potent oxidants hypochlorous acid (HOCl), hypobromous acid (HOBr) and hypothiocyanous acid (HOSCN) from halide and pseudohalide (SCN À ) ions. These oxidants have been implicated as key mediators of tissue damage in many human inflammatory diseases including atherosclerosis, asthma, rheumatoid arthritis, cystic fibrosis and some cancers. It is shown here that acetaminophen (paracetamol), a phenol-based drug with analgesic and antipyretic actions, is an efficient inhibitor of HOCl and HOBr generation by isolated MPO-H 2 O 2 -halide systems. With physiological halide concentrations, acetaminophen concentrations required for 50% inhibition of oxidant formation (IC 50 ) were 77 AE 6 mM (100 mM Cl À ) and 92 AE 2 mM (100 mM Cl À plus 100 mM Br À ), as measured by trapping of oxidants with taurine. The IC 50 for inhibition of HOCl generation by human neutrophils was ca. 100 mM. These values are lower than the maximal therapeutic plasma concentrations of acetaminophen ( 150 mM) resulting from typical dosing regimes.

Biochemistry Usa, 1998

ABSTRACT

Biochemical Pharmacology, Apr 15, 2010

Inflammation, 1991

Page 1. Inflammation, VoL 15, No. 5, 1991 CIRCULATING PHOSPHOLIPASE A 2 ACTIVITY ASSOCIATED WITH ... more Page 1. Inflammation, VoL 15, No. 5, 1991 CIRCULATING PHOSPHOLIPASE A 2 ACTIVITY ASSOCIATED WITH SEPSIS AND SEPTIC SHOCK IS INDISTINGUISHABLE FROM THAT ASSOCIATED WITH RHEUMATOID ARTHRITIS ...

Inflammation, 1992

Synovial fluid PLA2 concentration was measured by an ELISA technique using monoclonal antibodies ... more Synovial fluid PLA2 concentration was measured by an ELISA technique using monoclonal antibodies raised against human recombinant "synovial-type" group II phospholipase A2. This ELISA was specific for synovial-type PLAz and did not detect pancreatic (group I) PLA 2. In all synovial fluids examined, including rheumatoid, osteoarthfitic, Izsoriatic, and gouty fluids, synovial fluid PLA 2 enzyme activity significantly correlated with PLA2 immunoreactivity (P < 0.001). Within the limits of the ELISA technique, there was no evidence for the presence of specific or nonspecific modulation of PLA2 activity by either putative PLA 2 activating or inhibitory proteins.

J Biol Chem, 1996

The binding of low molecular weight type II phospholipase A2 (EC) to membrane surfaces and hydrol... more The binding of low molecular weight type II phospholipase A2 (EC) to membrane surfaces and hydrolysis of phospholipid are thought to involve the formation of a hydrophobic channel into which a single substrate molecule diffuses before cleavage. The floor and right side of the channel are provided by hydrophobic residues 2, 5, and 9 of an amphipathic amino-terminal helix. The channel is postulated to form via a conformational change in this helix and inward movement of a hydrophobic flap (residue 69 side chain). We show that the amino-terminal tryptic peptide of human type II phospholipase A2 forms a noncovalent complex with the tryptic peptide from residues 70-74 of the enzyme. Further, the 70-74-peptide sequence (FLSYK) dose-dependently inhibits phospholipid hydrolysis in a mixed micelle assay. This native peptide inhibition also occurred with type II enzymes from Crotalus durissus and Crotalus atrox, which have different amino acid sequences at the amino terminus as well as different 70-74 regions of the molecules. Despite significant conservation of tertiary structure among the enzymes, inhibition by each peptide is specific to the enzyme from which the peptide sequence is derived. We propose that these native peptides inhibit enzyme activity via a sequence-specific, noncovalent interaction with the amino-terminal residues of the enzyme, thereby preventing the conformational change on binding to the micelle interface. These experiments demonstrate a new method for specific inhibition of phospholipase A2 which, in principle, would be applicable to other biologically active polypeptides and proteins.

American Journal of Therapeutics, 2005

Paracetamol (acetaminophen) is generally considered to be a weak inhibitor of the synthesis of pr... more Paracetamol (acetaminophen) is generally considered to be a weak inhibitor of the synthesis of prostaglandins (PGs). However, the in vivo effects of paracetamol are similar to those of the selective cyclooxygenase-2 (COX-2) inhibitors. Paracetamol also decreases PG concentrations in vivo, but, unlike the selective COX-2 inhibitors, paracetamol does not suppress the inflammation of rheumatoid arthritis. It does, however, decrease swelling after oral surgery in humans and suppresses inflammation in rats and mice. Paracetamol is a weak inhibitor of PG synthesis of COX-1 and COX-2 in broken cell systems, but, by contrast, therapeutic concentrations of paracetamol inhibit PG synthesis in intact cells in vitro when the levels of the substrate arachidonic acid are low (less than about 5 mumol/L). When the levels of arachidonic acid are low, PGs are synthesized largely by COX-2 in cells that contain both COX-1 and COX-2. Thus, the apparent selectivity of paracetamol may be due to inhibition of COX-2-dependent pathways that are proceeding at low rates. This hypothesis is consistent with the similar pharmacological effects of paracetamol and the selective COX-2 inhibitors. COX-3, a splice variant of COX-1, has been suggested to be the site of action of paracetamol, but genomic and kinetic analysis indicates that this selective interaction is unlikely to be clinically relevant. There is considerable evidence that the analgesic effect of paracetamol is central and is due to activation of descending serotonergic pathways, but its primary site of action may still be inhibition of PG synthesis. The action of paracetamol at a molecular level is unclear but could be related to the production of reactive metabolites by the peroxidase function of COX-2, which could deplete glutathione, a cofactor of enzymes such as PGE synthase.

Eicosanoids

Peripheral plasma concentrations of immunoreactive phospholipase A2 (irPLA2) (Type II, non-pancre... more Peripheral plasma concentrations of immunoreactive phospholipase A2 (irPLA2) (Type II, non-pancreatic) were determined in 110 women during pregnancy. The concentration of irPLA2 did not significantly change during pregnancy (5.7 +/- 0.6 ng/ml, n = 72) until the onset of labour. When compared with non-labouring women, irPLA2 concentrations were significantly elevated in association with both preterm labour (13.3 +/- 2.4 ng/ml, n = 15, p less than 0.02) and labour at term (10.4 +/- 1.7, n = 23, p less than 0.02). These data suggest that maternal plasma irPLA2 may be reflective of the mechanism(s) underlying the labour-associated increase in human gestational tissue eicosanoid formation.

Drugs

Tolerability of ParacetamolParacetamol (acetaminophen) is a well-tolerated drug at therapeutic do... more Tolerability of ParacetamolParacetamol (acetaminophen) is a well-tolerated drug at therapeutic doses and this safety profile is a major factor in the very wide use of the drug. It is well known that paracetamol is converted by the hepatic cytochrome P450 system to reactive compounds. Less well known is that paracetamol is also metabolized to the same reactive compounds by myeloperoxidase and the peroxidase function of cyclo-oxygenase (COX)-1. The reactive metabolites lead to hepatotoxicity following overdosage. Similar hepatotoxicity has been reported after therapeutic doses, but critical analysis indicates that most patients with alleged toxicity from therapeutic doses have taken overdoses.Associations between the use of paracetamol and chronic renal diseases, gastrointestinal toxicity and asthma may be due to biases in case--control studies. In particular, biases may be caused by the perceived safety of paracetamol in these diseases. Selective inhibition of the delayed pathway of ...

Cancer metastasis reviews, 2014

Circulating tumour cells (CTCs) are emerging as important prognostic markers and have potential c... more Circulating tumour cells (CTCs) are emerging as important prognostic markers and have potential clinical utility as tumour biomarkers for targeted cancer therapy. Although CTCs were proposed more than 100 years ago as potential precursors that may form metastatic lesions, formal evidence that CTCs are indeed capable of initiating metastases is limited. Moreover, the process of CTCs shedding into the circulation, relocating to distant organ sites and initiating metastatic foci is complex and intrinsically inefficient. To partially explain the metastatic process, the concepts of CTCs as metastatic precursors or pre-metastatic conditioners have been proposed; however, it is questionable as to whether these are both variable pathways to metastasis or just markers of metastatic burden. This review explores the evidence for CTCs in the initiation and progression of metastatic cancer and the data supporting these different concepts in an attempt to better understand the role of CTCs in met...

Journal of leukocyte biology, 1999

Prostaglandins generated by the phospholipase A2 (PLA2)/cyclooxygenase (COX) pathway are well kno... more Prostaglandins generated by the phospholipase A2 (PLA2)/cyclooxygenase (COX) pathway are well known to mediate diverse intracellular and extracellular effects that regulate mammalian development, vascular function, renal physiology, parturition, and immune responses to infection or wounding. In immune-mediated diseases and in certain cancers, this pathway is aberrantly up-regulated and excessive prostaglandin production contributes to the pathology. It is now known that there are two isoforms of COX and multiple secreted and intracellular PLA2 enzymes. The use of isoform-specific inhibitors, coupled with antisense and in vivo gene deletion experiments, has identified independent pathways of arachidonic acid metabolism, which are differentially regulated at the levels of gene expression, protein phosphorylation, and cellular localization. There is cross-talk between the pathways at the level of PLA2 and substrate supply to the two isoforms of COX is apparently compartmentalized. Knoc...

Life sciences, 1992

Massive elevations of serum phospholipase A2 activity have been documented in patients with septi... more Massive elevations of serum phospholipase A2 activity have been documented in patients with septic shock. Serum PLA2 activity correlated to the degree and duration of circulatory collapse, while purified native PLA2 reproduced hypotension in experimental animals. In a prospective study of patients with septic shock, we have determined the relationship of PLA2 enzyme activity to PLA2 immunoreactivity using radiolabelled E. coli phospholipid substrate and an ELISA specific for group II human nonpancreatic PLA2. In all patients, there was a clear concordance of the two assays. Maximal PLA2 concentration was increased a mean of 554-fold over normal levels. We found no evidence to support the presence of activating or inhibitory proteins. These data confirm that the observed increase in serum PLA2 activity in septic shock is due to intravascular release of group II nonpancreatic PLA2.

Prostate Cancer, 2012

Tumour necrosis factor (TNF) is a pleiotropic cytokine with dual roles in cancer biology includin... more Tumour necrosis factor (TNF) is a pleiotropic cytokine with dual roles in cancer biology including prostate cancer (PCa). On the one hand, there is evidence that it stimulates tumour angiogenesis, is involved in the initiation of PCa from an androgen-dependent to a castrate resistant state, plays a role in epithelial to mesenchymal plasticity, and may contribute to the aberrant regulation of eicosanoid pathways. On the other hand, TNF has also been reported to inhibit neovascularisation, induce apoptosis of PCa cells, and stimulate antitumour immunity. Much of the confusion surrounding its seemingly paradoxical roles in cancer biology stems from the dependence of its effects on the biological model within which TNF is investigated. This paper will address some of these issues and also discuss the therapeutic implications.