ORCID Profile
0000-0002-4443-7963
Current Organisation
The University of Auckland
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Publisher: Elsevier BV
Date: 12-2013
DOI: 10.1016/J.BMCL.2013.10.046
Abstract: A number of structural analogues of the known toxicant para-aminopropiophenone (PAPP) have been prepared and evaluated for their capacity to induce methemoglobinemia--with a view to their possible application as humane pest control agents. It was found that an optimal lipophilicity for the formation of methemoglobin (metHb) in vitro existed for alkyl analogues of PAPP (aminophenones 1-20 compound 6 metHb% = 74.1 ± 2). Besides lipophilicity, this structural sub-class suggested there were certain structural requirements for activity, with both branched (10-16) and cyclic (17-20) alkyl analogues exhibiting inferior in vitro metHb induction. Of the four candidates (compounds 4, 6, 13 and 23) evaluated in vivo, 4 exhibited the greatest toxicity. In parallel, aminophenone bioisosteres, including oximes 30-32, sulfoxide 33, sulfone 34 and sulfonamides 35-36, were found to be inferior metHb inducers to lead ketone 4. Closer examination of Hammett substituent constants suggests that a particular combination of the field and resonance parameters may be significant with respect to the redox mechanisms behind PAPPs metHb toxicity.
Publisher: Elsevier BV
Date: 2009
DOI: 10.1016/J.ETAP.2008.09.007
Abstract: Differences between species in response to norbormide (NRB) may arise through differential pharmacodynamic and/or pharmacokinetic properties. We hypothesise that species-selectivity is at least partly determined by differences in metabolism based on in vitro data generated in liver preparations from rats, mice and guinea pigs. HPLC separation and LC/MS identification revealed that NRB undergoes metabolism primarily to hydroxylated form that was tentatively identified in both rat and non-rat species with NADPH as the preferred cofactor. However, the metabolic profile and the rate are different between species. Gender differences are also reported in the metabolic rate in rats and we postulate that this may be responsible for different toxic sensitivities seen between sexes. Using this knowledge, we aim to develop pharmacological tool(s) for use in designing a new class of drugs that can be targeted in a tissue-selective manner. Further in vivo pharmacokinetic with receptor affinity studies are warranted.
Publisher: Elsevier BV
Date: 04-2014
DOI: 10.1016/J.BMC.2014.02.013
Abstract: A number of isosteres (oxadiazoles, thiadiazoles, tetrazoles and diazines) of benzocaine were prepared and evaluated for their capacity to induce methemoglobinemia-with a view to their possible application as humane pest control agents. It was found that an optimal lipophilicity for the formation of methemoglobin (metHb) in vitro existed within each series, with 1,2,4-oxadiazole 3 (metHb%=61.0±3.6) and 1,3,4-oxadiazole 10 (metHb%=52.4±0.9) demonstrating the greatest activity. Of the 5 candidates (compounds 3, 10, 11, 13 and 23) evaluated in vivo, failure to induce a lethal end-point at doses of 120mg/kg was observed in all cases. Inadequate metabolic stability, particularly towards hepatic enzymes such as the CYPs, was postulated as one reason for their failure.
Publisher: Elsevier BV
Date: 06-2006
DOI: 10.1016/J.JCHROMB.2006.03.063
Abstract: We have developed a specific assay for cisplatin in human plasma ultrafiltrate (PUF) and cell culture medium ultrafiltrate (MUF) using HPLC on-line with inductively coupled plasma mass spectrometry (ICP-MS). Separation of cisplatin (6 min) and monohydrated cisplatin (12 min) was achieved using a muBondapak C(18) column (Waters) and a mobile phase (0.075 mM sodium dodecyl sulfate and 3% methanol, adjusted to pH 2.5 with triflic acid) pumped at a flow rate of 0.5 mL/min. The analytes were detected with little background interference by ICP-MS monitoring of platinum masses (m/z 194/195). Calibration curves were linear over three orders of magnitude (0.05-8 microM) and the limit of quantitation was 0.1 microM. Intra- and inter-assay accuracy (range 91.6-113%) and precision (range 1.00-12.3%) were acceptable for PUF and MUF. The method was applied to determining cisplatin during ex vivo incubation of the drug in whole human blood at 37 degrees C. In conclusion, a specific, sensitive and reliable HPLC-ICP-MS assay has been established for determining intact cisplatin in PUF and MUF.
Publisher: Elsevier BV
Date: 15-10-2003
DOI: 10.1016/S0041-008X(03)00274-6
Abstract: The anti-HIV drug 3'-azido-3'-deoxythymidine (AZT) is the drug of choice for preventing maternal-fetal HIV transmission during pregnancy. Our aim was to assess the cytotoxic effects of AZT on human placenta in vitro. The mechanisms of AZT-induced effects were investigated using JEG-3 choriocarcinoma cells and primary explant cultures from term and first-trimester human placentas. Cytotoxicity measures included trypan blue exclusion, MTT, and reactive oxygen species (ROS) assays. Apoptosis was measured with an antibody specific to cleaved caspase-3 and by rescue of cells by the general caspase inhibitor Boc-D-FMK. The effect of AZT on the activities of glutathione-S-transferase, beta-glucuronidase, UDP-glucuronosyl transferase, cytochrome P450 (CYP) 1A, and CYP reductase (CYPR) in the placenta was assessed using biochemical assays and immunoblotting. AZT increased ROS levels, decreased cellular proliferation rates, was toxic to mitochondria, and initiated cell death by a caspase-dependent mechanism in the human placenta in vitro. In the absence of serum, the effects of AZT were lified in all the models used. AZT also increased the amounts of activity of GST, beta-glucuronidase, and CYP1A, whereas UGT and CYPR were decreased. We conclude that AZT causes apoptosis in the placenta and alters metabolizing enzymes in human placental cells. These findings have implications for the safe administration of AZT in pregnancy with respect to the maintenance of integrity of the maternal-fetal barrier.
Publisher: American Society for Pharmacology & Experimental Therapeutics (ASPET)
Date: 22-03-2011
Publisher: American Society for Pharmacology & Experimental Therapeutics (ASPET)
Date: 16-07-2004
DOI: 10.1124/DMD.32.8.813
Abstract: These studies were performed to characterize the contribution of the uridine diphosphate glucuronosyltransferase (UGT) enzymes to the clearance of 3'-azido-3'-deoxythymidine (AZT) in vivo and to assess the regulation of UGT activity [including the disposition of the cofactor uridine diphosphate glucuronic acid (UDPGA)] in the placenta. Transport of AZT and the cofactor UDPGA across the human placenta and the glucuronidation capacity of the placenta for AZT were assessed using a human placental cell line (JEG-3), primary cultures of villous term placenta, placental subcellular fractions, and a recirculating perfusion model. Glucuronidation of AZT was consistently observed at approximately 2% of the dose administered. High levels of AZT in cultured primary placental cells and lines caused autoinhibition of AZT metabolism. AZT crossed the perfused placenta in a bidirectional fashion and was at equilibrium after 3 h, whereas the AZT-glucuronide metabolite was excreted preferentially into the maternal compartment. In contrast, UDPGA (10 microM) was rapidly transferred from the maternal to the fetal circulation, being complete after 4 h of perfusion. AZT is transported and glucuronidated by the human placenta, but that placental metabolism of the drug is not significant for whole-body clearance. Likewise therapeutic failure of AZT (5-15%) is not due to placental obstruction of drug passage. Finally, the activity of the UGT enzymes in the placenta is not rate-limited by the supply of UDPGA cofactor, whereas the preferential transport of UDPGA toward the fetus observed here may indicate a role in fetal development.
Publisher: Informa UK Limited
Date: 19-06-2019
DOI: 10.1080/00498254.2018.1557760
Abstract: 1. Cytisine, a partial agonist for the α
Publisher: Wiley
Date: 29-10-2008
DOI: 10.1111/J.1440-1681.2008.05017.X
Abstract: 1. Satraplatin is an investigational orally administered platinum-based antitumour drug. The present study compared the plasma protein binding, stability and degradation of satraplatin with that of its active metabolite JM118 and cisplatin. 2. The platinum complexes were incubated in human plasma for up to 2 h at 37 degrees C and quantified in plasma fractions by inductively coupled plasma-mass spectrometry on- or off-line to high-performance liquid chromatography. 3. All three platinum drugs became irreversibly bound to plasma proteins and showed negligible reversible protein binding. They were also unstable in plasma and generated one or more platinum-containing degradation products during their incubation. However, the three platinum complexes differed in the kinetics of their instability and protein binding, as well as in the number of degradation products formed during their incubation. 4. In conclusion, the plasma protein binding, instability and degradation of satraplatin and its active metabolite JM118 are qualitatively similar to that of cisplatin and other clinically approved platinum-based drugs. Quantitative differences in their irreversible protein binding and degradation were related to their respective physiochemical properties and bioactivation mechanisms.
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Malcolm Tingle.