Massey Documents by Type

Permanent URI for this communityhttps://mro.massey.ac.nz/handle/10179/294

Browse

Filters

2011 - 201922020 - 20241

Settings

Subject: search.filters.subject.Aspirin

Search Results

Now showing 1 - 3 of 3
  • Thumbnail Image
    Item
    Two genome-wide interaction loci modify the association of nonsteroidal anti-inflammatory drugs with colorectal cancer.
    (American Association for the Advancement of Science, 2024-05-29) Drew DA; Kim AE; Lin Y; Qu C; Morrison J; Lewinger JP; Kawaguchi E; Wang J; Fu Y; Zemlianskaia N; Díez-Obrero V; Bien SA; Dimou N; Albanes D; Baurley JW; Wu AH; Buchanan DD; Potter JD; Prentice RL; Harlid S; Arndt V; Barry EL; Berndt SI; Bouras E; Brenner H; Budiarto A; Burnett-Hartman A; Campbell PT; Carreras-Torres R; Casey G; Chang-Claude J; Conti DV; Devall MAM; Figueiredo JC; Gruber SB; Gsur A; Gunter MJ; Harrison TA; Hidaka A; Hoffmeister M; Huyghe JR; Jenkins MA; Jordahl KM; Kundaje A; Le Marchand L; Li L; Lynch BM; Murphy N; Nassir R; Newcomb PA; Newton CC; Obón-Santacana M; Ogino S; Ose J; Pai RK; Palmer JR; Papadimitriou N; Pardamean B; Pellatt AJ; Peoples AR; Platz EA; Rennert G; Ruiz-Narvaez E; Sakoda LC; Scacheri PC; Schmit SL; Schoen RE; Stern MC; Su Y-R; Thomas DC; Tian Y; Tsilidis KK; Ulrich CM; Um CY; van Duijnhoven FJB; Van Guelpen B; White E; Hsu L; Moreno V; Peters U; Chan AT; Gauderman WJ
    Regular, long-term aspirin use may act synergistically with genetic variants, particularly those in mechanistically relevant pathways, to confer a protective effect on colorectal cancer (CRC) risk. We leveraged pooled data from 52 clinical trial, cohort, and case-control studies that included 30,806 CRC cases and 41,861 controls of European ancestry to conduct a genome-wide interaction scan between regular aspirin/nonsteroidal anti-inflammatory drug (NSAID) use and imputed genetic variants. After adjusting for multiple comparisons, we identified statistically significant interactions between regular aspirin/NSAID use and variants in 6q24.1 (top hit rs72833769), which has evidence of influencing expression of TBC1D7 (a subunit of the TSC1-TSC2 complex, a key regulator of MTOR activity), and variants in 5p13.1 (top hit rs350047), which is associated with expression of PTGER4 (codes a cell surface receptor directly involved in the mode of action of aspirin). Genetic variants with functional impact may modulate the chemopreventive effect of regular aspirin use, and our study identifies putative previously unidentified targets for additional mechanistic interrogation.
  • Thumbnail Image
    Item
    The aspirin augmented standardized lactulose mannitol test as a measure of the 'health' of the gastrointestinal tract : a thesis presented in partial fulfilment of the requirements for the degree of Doctor of Philosophy at Massey University, Palmerston North, New Zealand
    (Massey University, 2015) Sequeira, Ivana Roosevelt
    In this thesis, I studied the ‘classical’ lactulose mannitol test for intestinal permeability that has been used to measure the integrity of the intestinal mucosa and thus to provide an index of recovery from inflammatory bowel disease (IBD) and from autoimmune diseases such as coeliac disease. Perusal of the literature indicates that the protocol for the test has not been standardized and a variety of different test protocols have been used. Hence there are differences in the duration of urinary sampling, the doses of the two test probes, the volumes of fluid consumed during the test and the administration of the test during the fasted or fed state. There is therefore a need for a standardized test. The bulk of the research conducted in this thesis was to develop an optimal protocol with a standardized osmolarity (720 osmol l-1) for the test solution that contained 10 g of lactulose and 5 g of mannitol dissolved in 100 ml of water. Similarly the total fluid intake was standardized to 700 ml. The volumes of fluid consumed over the experimental period were also standardized in order to control for any osmolar effects of the test drink and to hydrate the subjects sufficiently to enable them to produce half-hourly urine samples of a reasonable volume. The rates of excretion and the timings of the peaks in the excretion of mannitol and lactulose were found to vary over time in healthy subjects. Hence the rate of mannitol excretion peaked during the first two hrs whilst the rate of lactulose excretion peaked at four hrs. The correlation between urinary excretion with intestinal transit times were confirmed using a wireless motility capsule. The work with the wireless motility capsule indicated that the probe sugars were in the small intestine from 2½ - 4 hrs and in the proximal colon from 4½ - 6 hrs following dosage with the test solution. Hence a sample collected during the 2½ - 4 hr period is best for assessing permeability of the small intestinal mucosa in healthy subjects. The wireless motility capsule also confirmed that the standardized dose of the lactulose mannitol did not influence gastric transit time or that through the small intestine and large intestine. These findings confirmed that the standardized test was determining absorption during transit of the test sugars through the small and the large intestine. The effect of co-dosage with 600 mg of aspirin in the standardized test was then examined as a means of assessing the effect of a reproducible noxious stimulus on the absorption of the sugar probes. This agent augmented small intestinal permeability to lactulose and decreased its permeability to mannitol. Furthermore dosage with aspirin amplified the effect of a pre-existing adverse stimulus such as smoking. Hence the aspirin augmented test could conceivably be used to ‘unearth’ sub-clinical inflammation. Further work explored the effect of an antioxidant, ascorbic acid, on mucosal permeability. The results showed that, rather than mitigating the adverse effects of aspirin, ascorbic acid augmented intestinal permeability. In summary the work in this thesis has enabled the development of a standardized test that optimizes the ability of the lactulose mannitol test to detect clinical disorders of absorption. Further, augmenting the test with a single dose of aspirin may be useful as an index of gut health or robustness.
  • Thumbnail Image
    Item
    Pharmacology of analgesic drugs in birds : thesis in fulfilment of the degree of Doctor of Philosophy in Animal Science
    (Massey University, 2011) Singh, Preet Mohinder
    Analgesics drugs are widely used to alleviate pain in mammals and birds. However, in the case of birds, there is a scarcity of information on their usage and dosing regimen. A lack of pharmacokinetic knowledge can result in under or over-dosing of drugs with subsequent loss of efficacy or side-effects. Complete understanding of a drug requires knowledge of its pharmacokinetics as well as pharmacodynamics. Considering the various voids in pharmacological research in birds and in an effort to know more about pain and welfare in birds, this study was designed to study the pharmacokinetics of morphine, butorphanol, aspirin and salicylic acid in broiler chickens. Broiler chickens were used as a model for wild and rare birds. Morphine and butorphanol were injected intravenously at 2 mg/kg, while aspirin and salicylic acid were injected intravenously at 50 mg/kg. All the analgesic drugs were well distributed in chickens. The plasma clearance for these drugs was much higher than in mammals, resulting in shorter half-lives. All the drugs remained within the theoretical therapeutic range for 2 hours. For analgesic efficacy testing, all the drugs except aspirin were injected in lame broiler chickens at similar dose rates as in the pharmacokinetics experiment. The results from the efficacy tests suggest that butorphanol and salicylic acid provided adequate analgesia which lasted for less than 2 hours. Morphine at 2 mg/kg intravenously induced sedation and drowsiness in chickens, which might be due to the high dose. It may have analgesic effects at lower dose rates, however this needs to be further evaluated. The approximate therapeutic range in broiler chickens for butorphanol is 50 to 80 ng/mL and for salicylic acid is 50 to 110 ng/mL. The therapeutic range for butorphanol is much higher in birds as compared to mammals while for salicylic acid it is in the mammalian range. The duration of analgesia in birds could be increased by using sustained released formulation or drug delivery systems, which warrants further research. Plasma concentrations after butorphanol given at 4 mg/kg in an injured Northern Royal Albatross under surgical conditions were also evaluated. This is the only pharmacokinetic study of an analgesic drug in a sea bird. The pharmacokinetics of butorphanol in this albatross differed significantly from chickens, with slower clearance and lower tissue distribution, although these were much higher than in mammals. The difference in pharmacokinetic parameters could either be due to species variation or due to the continuous fluid therapy along with butorphanol administration. This albatross was suffering from a major femur fracture, which potentially altered its normal physiology and metabolism. Chickens may be used as a model of drug research for wild and rare avian species, especially for preclinical trials. The dosing regimens can be extrapolated from chicken pharmacokinetics data, but this should be done with extreme caution as pharmacokinetics are highly variable between the species.