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Item Effect of curcumin supplementation on exercise-induced muscle damage: a narrative review(Springer-Verlag GmbH Germany, part of Springer Nature, 2022-07-13) Nanavati K; Rutherfurd-Markwick K; Lee SJ; Bishop NC; Ali ACurcumin, a natural polyphenol extracted from turmeric, is a potent antioxidant and anti-inflammatory agent. In the past few decades, curcumin's ability to impact chronic inflammatory conditions such as metabolic syndrome, arthritis, and cancer has been widely researched, along with growing interest in understanding its role in exercise-induced muscle damage (EIMD). EIMD impacts individuals differently depending on the type (resistance exercise, high-intensity interval training, and running), intensity, and duration of the exercise. Exercise disrupts the muscles' ultrastructure, raises inflammatory cytokine levels, and can cause swelling in the affected limb, a reduction in range of motion (ROM), and a reduction in muscular force-producing capacity. This review focuses on the metabolism, pharmacokinetics of various brands of curcumin supplements, and the effect of curcumin supplementation on EIMD regarding muscle soreness, activity of creatine kinase (CK), and production of inflammatory markers. Curcumin supplementation in the dose range of 90-5000 mg/day can decrease the subjective perception of muscle pain intensity, increase antioxidant capacity, and reduce CK activity, which reduces muscle damage when consumed close to exercise. Consumption of curcumin also improves muscle performance and has an anti-inflammatory effect, downregulating the production of pro-inflammatory cytokines, including TNF-α, IL-6, and IL-8. Curcumin may also improve oxidative capacity without hampering training adaptations in untrained and recreationally active individuals. The optimal curcumin dose to ameliorate EIMD is challenging to assess as its effect depends on the curcumin concentration in the supplement and its bioavailability.Item Analgesic efficacy and pharmacokinetics of combinations of morphine, dexmedetomidine and maropitant in dogs : a thesis presented in partial fulfilment of the requirement for the degree of Doctor of Philosophy at Massey University, Palmerston North, New Zealand(Massey University, 2020) Karna, Sandeep RajMultimodal analgesia is gaining popularity in veterinary medicine. It is an approach that involves the administration of two or three classes of analgesic drugs with different modes of actions to enhance the analgesic effects and lower the adverse effects associated with high dose of a single drug. In a series of experiments conducted in this thesis, the combinations of morphine, dexmedetomidine and maropitant were evaluated using different pain models with the aim of using them in a multimodal strategy in dogs undergoing ovariohysterectomy or other surgical procedures. Firstly, a pilot study evaluating the efficacy of combinations of the test drugs was performed using a hot-plate test and tail-flick test in rats. The combination of morphine and maropitant showed a significantly higher (p < 0.0001) tail-flick latency compared to all other treatment groups indicating a supra-additive effect of spinal analgesia between morphine and maropitant. A pharmacokinetic study to investigate the disposition of the test drug combinations after intramuscular (IM) administration in dogs under anaesthesia was conducted. The results showed that the elimination half-life of morphine was higher and the clearance rate was lower when combined with dexmedetomidine compared to morphine and maropitant combination or morphine alone at higher doses. This effect may have a clinical advantage of prolonging the dosing interval of morphine. A study to evaluate and compare the analgesic efficacy of the combination of morphine, dexmedetomidine and maropitant in dogs undergoing ovariohysterectomy was conducted. The study showed that dogs receiving the combination of morphine and dexmedetomidine had significantly lower (p < 0.05) pain scores, obtained by the short form of the Glasgow composite measure pain scale and visual analogue pain scale, in the postoperative period. All dogs that received dexmedetomidine showed arrhythmia and second-degree heart block immediately after IM administration. Finally, the efficacy of the test drug combinations was evaluated using changes in electroencephalographic indices of nociception (median frequency, spectral edge frequency and total power) in anaesthetised dogs subjected to a noxious electrical stimulus. The combination of morphine and dexmedetomidine showed a significantly lower change in the post stimulation median and spectral edge frequencies compared to all other treatment groups. The dogs receiving dexmedetomidine also demonstrated arrhythmia and second-degree heart block. In conclusion, the combination of morphine and dexmedetomidine showed a superior analgesic effect compared to morphine alone at higher dose and appeared to be the most effective combination among other combinations of morphine, dexmedetomidine and maropitant. The cardiovascular changes produced by the test drugs may be clinically insignificant in fit and healthy dogs. In future, the efficacy of the combination of morphine, dexmedetomidine and maropitant at other different doses rates and ratios should also be evaluated.Item Pharmacokinetics of nitrate and nitrite following beetroot juice consumption : a thesis presented in partial fulfilment of the requirements for the degree of Master of Science in Nutrition and Dietetics at Massey University, Albany, New Zealand(Massey University, 2019) Jakubcik, Emily MargaretBackground: Nitrate (NO₃⁻) rich beetroot juice (BR) supplementation has been shown to improve cardiovascular function via reduction to nitrite (NO₂⁻) and thus the signalling molecule nitric oxide (NO). However, limited research exists for the role of inorganic NO₂⁻ contained within BR. Objective: To evaluate the individual effects of NO₃⁻ and NO₂⁻ consumed from BR on plasma [NO₃⁻]/[NO₂⁻] and various cardiovascular measures. Design: Eleven adults completed four trials; whereby they consumed 250 mL of BR containing one of the following; i) High-NO₃⁻ (572 mg NO₃⁻, 32 mg NO₂⁻); ii) Med-NO₃⁻/NO₂⁻ (280 mg NO₃⁻, 237 mg NO₂⁻); iii) Med-NO₂⁻ (43 mg NO₃⁻, 262 mg NO₂⁻); iv) Placebo (PL; 8 mg NO₃⁻, 5.8 mg NO₂⁻). Plasma [NO₃⁻]/[NO₂⁻], blood pressure (BP), heart rate (HR), mean arterial pressure (MAP), cardiac output (CO) and stroke volume (SV) were measured at baseline and every hour or second hour for 6 h post BR consumption. Outcomes: Ingestion of the high-NO₃⁻ and med-NO₃⁻/NO₂⁻ BR increased plasma [NO₂⁻] and [NO₃⁻] from 2 h, with both remaining elevated after 6h (p<0.05). Med-NO₂⁻ increased plasma [NO₃⁻] (p<0.05), but did not increase plasma [NO₂⁻] compared to PL (p=0.177). MAP was lower following the consumption of high-NO₃⁻ at 4 h and med-NO₂⁻ at 6 h (p<0.05). However, there were no differences in SBP, DBP, HR, CO and SV between trials. Conclusion: Inorganic NO₃⁻ consumption is the critical factor in elevating plasma [NO₃⁻] or [NO₂⁻], however, both NO₂⁻ and NO₃⁻ show potential to reduce MAP. The known reduction of SBP/DBP following NO₃⁻ supplementation was not observed, making it unclear if NO₂⁻ contributes to a reduction in SBP/DBP alongside NO₃⁻.Item Effect of age on the pharmacokinetics of meloxicam in ISA Brown chickens (Gallus gallus domesticus) : a thesis presented in partial fulfilment of the requirements for the degree of Master of Science in Physiology at Massey University, Palmerston North, New Zealand(Massey University, 2015) Gildersleve, MeganThe Non-Steroidal Anti-Inflammatory drug (NSAID) meloxicam has been deemed a safe and effective treatment for numerous inflammatory conditions and injuries from extensive pharmacokinetic and pharmacodynamic studies in various mammalian species. However, there is a lack of meloxicam pharmacokinetic information in avian species. This leads to pharmacokinetic data being extrapolated from mammals in order to administer and treat birds. This often leads to ineffective pain relief or overdoses that can be fatal for birds. Due to this void in literature this study was designed to increase the basic pharmacokinetic knowledge in birds but to also determine if age affects the pharmacokinetics of meloxicam in ISA Brown chickens. Meloxicam was injected intravenously (IV) at 2 mg/kg in 20 healthy ISA Brown chickens (Gallus gallus domesticus). One group consisted of 10 ISA brown chickens that were 18 weeks old, the second group consisted of 10 ISA Brown chickens that were 24 months old. Serial blood samples were withdrawn from a catheterised vein from each ISA Brown chicken into a heparinised vial at 0, 10, 20, 30 minutes, 1, 4, 8, 10, 12 hours after the administration of meloxicam. The pharmacokinetics for ISA Brown chickens were calculated using the non-compartmental model, which was analysed using the mean data from each group of ISA Brown chickens. The elimination half-life, steady state volume of distribution and mean resident time were significantly higher in the 24 month old ISB Brown chickens compared to the 18 week old ISA Brown chickens. Overall, the results indicate that as an ISA Brown chicken ages the pharmacokinetics of meloxicam show some significant changes in crucial pharmacokinetic parameters. The differences in the pharmacokinetic parameters may ultimately affect the efficacy of meloxicam when treating ‘geriatric’ birds due to possible age-related health issues in the liver and kidneys, which are major organs involved in processing drugs.Item Explorations into the nature of insulin binding to oxidized dextran : this thesis was presented in partial fulfillment of the requirements for the degree of Master of Science in Chemistry at Massey University(Massey University, 1998) Li, YumingThe results reported in this thesis comprise an investigation into the conjugation of insulin to oxidized dextran, various release studies from the conjugates, and an attempt to interpret the binding nature of the conjugates. A model system involving the sustained release from insulin-dextran conjugates has been employed in this study. For insulin, up to 3 potential sites only (A1-Gly. B1-Phe and B29-Lys) were expected to bind to oxidized dextran. The rate of release and the maintenance of activity of the released protein are vital to such systems. Success in the interpretation of the binding nature of the conjugate will allow us to investigate its relationship to the rate of release. The desired rate of release for the sustained release of protein could then be achieved, once the projected binding could be obtained. Activation of dextran was achieved by periodate oxidation to give levels of 8%, 16% and 27% oxidized dextran. Insulin was chosen for its relatively 'uncomplicated' structure and few possible sites available for binding with activated dextran. Insulin was bound to the dextran through imine bonds. Complex formation was examined under a wide range of conditions. Initial studies were begun with the determination of a desirable basic molar ratio. A molar ratio of insulin to 8% activated dextran of 10 : 1 arose from this set of experiments. Insulin was bound to 27% activated dextran at pH 7.4, pH 9 and pH 10. In the cases of pH 9 and pH 10, many more lower MW complexes were formed than at pH 7.4. It seemed that the higher the pH of formation, the more crosslinks occurred between an insulin molecule and dextran molecules in the lower MW range. Approximate physiological pHs (pH 7.1-7.8) were used for complex formation in all subsequent experiments. Release studies were carried out under approximate physiological conditions (pH 7.4, 37°C). Immediate release was observed upon isolation by size exclusion chromatography. The greatest release occurred in the first 24 hours for all three activation levels. The higher the activation level of dextran, the lower the level of release. An equilibrium was established after several days' release and studies at 37°C produced the expected result: greater release relative to ambient. A number of studies were carried out with complex after sodium cyanoborohydride had been used to reduce the imine bonds. The first set of experiments on the reduced complexes was enzymatic cleavage studies, which employed trypsin and α-chvmotrypsin. The results for trypsin digestion of the reduced insulin-27% oxidized dextran complex indicated partial binding had occurred at B29-Lys, in combination with full binding at B1 and/or Al. Amino acid analysis results of the isolated complex after trypsin digestion indicated about 90% binding occurred at B29-Lys for the complex, which formed at pH 7.1. The results of α-chymotrypsin digestion study were shown questionable due to its incomplete cleavage. The reduced complexes were analyzed by amino acid analysis. The insulin-27% activated dextran complexes formed at pH 7.4, pH 9 and pH 10 showed similar extents of binding at B1-Phe, indicating B1 might be the prime binding site. There was more binding at B29 and A1 for the pH 9 than at pH 7.4 case. At pH 10 abnormal values arose. The studies for the complexes of insulin with 16% and 27% activated dextran indicated the more highly activated the dextran, the greater the binding at B29 and A1. Trials with the 2, 4-dinitrophenyl-derivativatization method proved to be a useful way to examine the degree of B1 and B29 binding from the amino acid analysis results of complex. The insulin-16% activated dextran complex formed at pH 7.1 was found to be about 100% binding at B1, 60% at A1 and 50% at B29. Oxidative and reductive cleavage studies of A and B chains of insulin and the complex were carried out to investigate the level of A1 binding. After chemical cleavage of the three disulfide bonds in insulin and subsequent chromatography, the amino acid analysis results for the treated complexes indicated a significant proportion of A chain had bound to dextran, i.e. at A1. An estimation of 60-70% of A1 binding was achieved for this study. This exploratory study has shown that varied complex formation conditions such as the level of activation of dextran, pH, and temperature could alter the extent of binding between insulin and dextran molecules. Amino acid analysis of the reduced complex was a useful method to interpret the binding.Item Dextran enzyme imine complexes : a preliminary study : this thesis was presented in partial fulfilment of the requirements for the degree of Master of Science in Biochemistry at Massey University(Massey University, 1997) Fisher, Louisa JaneA model system involving the formation of protein-dextran complexes has been investigated with a view to improving existing methods of drug administration. Activation of the dextran was achieved by periodate oxidation to give levels of 7%, 21% and 56% activated glucose moieties. The protein-dextran complexes were investigated with the prospect of obtaining sustained release of proteins from the dextran in an unmodified form. Covalent conjugation of proteins to carbohydrate polymers is known to confer stability on the protein. The proteins in this study were bound to the dextran through imine bonds. The proteins investigated were lysozyme, trypsin, amylase, alcohol dehydrogenase and catalase. The selection covered a range of molecular weights and varying enzymatic activities. As might be predicted, the speed of complex formation was shown to be greater at the 21% level of activation compared to the 7% activation of dextran in all cases studied. Lysozyme, the smallest protein, readily formed complexes at all three levels of activation. At the 56% level the resulting complex had an extremely high MW, greater than 1MDa. The extensive binding between the dextran and lysozyme molecules resulted in a complex that was inactive and showed no signs of releasing any lysozyme, active or inactive. At the lower levels of activation, complex was formed with relative ease. Upon conjugation lysozyme exhibited only minimal activity. Release of a lysozyme-like species with normal lytic activity was observed. Precautions were taken to minimise possible autolysis in the trypsin study. Once complexed it was postulated that autolysis would be prevented or minimised. Similarly the 56% level of activation appeared to be too high to obtain a viable complex for facile trypsin release. Sustained release of a trypsin-like protein was observed with complexes at the 7% and 21% levels. SEC and SDS-PAGE, in conjunction with a positive BAPNA assay gave support to the released species being trypsin-like. While complexed to the dextran trypsin showed no signs of activity. Released trypsin-like species and unreacted trypsin showed similar tryptic maps from a synthetic peptide, the peptide was designed to show distinctive fragments. α-Amylase, twice the MW of trypsin and over three times the MW of lysozyme, formed complexes with ease at both 7% and 21% levels of activation. Conjugation to dextran did not effect the activity of α-amylase. Over time the release of an α-amylase-like species from the complex was observed. Alcohol dehydrogenase and catalase are both high MW proteins. Complex formation was observed for each protein. Subsequent experiments showed that upon release the proteins appeared to dissociate, most probably into their subunits. It is also possible that the dimers and monomers bound to the dextran. The main advantage of conjugation in this case appeared to be to confer stability on the proteins. The ADH-complex exhibited enzymatic activity. At 7% and 21% activation levels the lower MW proteins formed complexes with dextran that exhibited release of a protein species. The higher MW proteins were possibly stabilised when conjugated to dextran, but dissociated upon release. Investigations have shown that the level of activation chosen affects the extent of binding and therefore the functions of the resultant complex. Thus activation levels can be manipulated depending on the desired result. While lower dextran activation levels appeared to be more suited for smaller MW proteins, there were indications that the larger MW proteins could form beneficial complexes at higher activation levels. Results indicated that conjugation to periodate activated dextran could be extended to further proteins with the possibility of therapeutic or commercial applications.Item Application of a sedation scoring system in dogs following premedication : thesis is submitted by Deepti Deshpande to fulfil the requirements for the degree of Masters of Veterinary Studies in the Institute of Veterinary, Animal and Biomedical Sciences, College of Sciences, Massey University, Palmerston North, New Zealand(Massey University, 2014) Deshpande, DeeptiPharmacogenetics is the study of how variations in the genome influence drug pharmacokinetics (the body's effect on the drug) and pharmacodynamics (the drug's effect on the body). The MDR1 gene codes for a membrane-bound drug transporter protein, P-glycoprotein (P-gp) that transports drugs across the cell membrane using an energy-dependent mechanism. Anecdotal reports in the literature suggested that dogs with a mutation in the MDR1 gene (MDR1-1Δ) show increased sensitivity to routinely used veterinary sedatives such as acepromazine and butorphanol, resulting in increased duration and depth of sedation. This study has 3 aims. First is to gain experience with a sedation scoring system that can be used to assess the level of sedation. The second aim is to assess the difference in sedation of dogs premedicated with dexmetomidine and acepromazine. The third aim is to investigate the effect of acepromazine (n=29) and a combination of acepromazine and butorphanol (n=12) on MDR1 genotyped rough-coated collies. In the study assessing the sedation of dogs premedicated with dexmadetomidine and acepromazine, 30 dogs scheduled for orchidectomy were divided into two groups; the DEX group (n=15) and the ACE group (n=15). Dogs in the DEX group received dexmedetomidine (125 μg/m2) and morphine (0.5 mg/kg) while the dogs in the ACE group received acepromazine (0.04 mg/kg) and morphine (0.5 mg/kg). The dogs were sedation scored at 0, 10, 20 and 30 minute intervals. The dogs in the DEX group had a statistically higher sedation score at 30 minutes than the dogs in the ACE group (p value =0.0189). Dogs premedicated with dexmedetomidine had a higher sedation score than dog’s premedicated acepromazine at 30 minutes. The heart rate, respiratory rate and mean arterial blood pressure were not different between the DEX and the ACE group at 30 minutes post administration of premedication agent. The second study investigated the effects of acepromazine and a combination of acepromazine and butorphanol in dogs carrying the MDR1-1Δ mutation. Genotyping for the MDR1-1Δ mutation was performed in 31 rough-coated collies. Dogs were considered healthy based on clinical history, physical examination, complete blood count, serum chemistry and urinalysis. Twenty-nine of the 31 rough coated collies were deemed healthy and were enrolled in the sedation trial assessing the effects of acepromazine on the MDR1-1Δ mutants. A subset of the 29 rough coated collies was enrolled in the study assessing the effects of combination of acepromazine and butorphanol. The rough coated collies were divided in 3 groups based on their genotype: homozygous mutants, heterozygous carriers and normal group. After administration of acepromazine (0.04 mg/kg, IV) or a combination of acepromazine (0.04 mg/kg) and butorphanol (0.05 mg/kg), sedation scoring was performed at 0, 30 minutes, 60 minutes, 90 minutes, 2 , 2.5 , 3 , 4 and 6 hour intervals by an observer blinded to the results of the MDR1 genotype. Following administration of acepromazine, homozygous mutant collies (MDR1 -/-) (n = 10) reached a greater level of sedation and remained sedated for a longer duration as compared to the heterozygous carriers (MDR1 +/-) (n =10) and wild-type collies (MDR1 +/+) (n = 9) (p= 0.0176). A subset of 12 dogs was sedated with a combination of acepromazine (0.04 mg/kg) and butorphanol (0.05 mg/kg). Heterozygous carriers (MDR1 -/+) had significantly higher sedation scores than homozygous mutants (MDR1 -/-) and normal groups (MDR1 +/+) when sedated with the combination (p=0.0423). This unexpected result may have been due to the small number of dogs tested. The author recommends lower dosing of acepromazine and butorphanol in dogs that are homozygous mutants to the MDR1-1Δ mutation and recommends the constant monitoring of sedation.Item The disposition of gentamicin in equine plasma, synovial fluid and lymph : a thesis presented in partial fulfilment of the requirements for the degree of Master of Veterinary Science at Massey University(Massey University, 1993) Anderson, BrianAlthough it is easy to monitor blood concentrations of antimicrobials most bacterial infections occur in extravascular sites, more specifically within the interstitial fluid. It is very difficult to sample interstitial fluid and many different methods have been used. Reports of the relationship between blood and interstitial concentrations of antibiotics have varied depending on the tissue/tissue fluid sampling technique used. The sampling of tissue fluid for antimicrobial studies in horses has been limited. Most studies have measured antibiotic concentrations in readily accessible body fluids such as urine, peritoneal fluid and synovial fluid. The relationship between these fluids and interstitial fluid in the horse is not known. The disposition of gentamicin in equine plasma, synovial fluid and in peripheral lymph was studied. A lymph vessel (dorsal digital lymph trunk) on the medial aspect of the distal hindlimb was selected for the disposition study. To better define the relationship between synovial fluid and tissue concentrations of an antimicrobial it was shown that this vessel had a contribution to its lymph derived from the synovium of the fetlock joint. Very high concentrations of gentamicin were retrieved in the lymph collected from the cannulated vessel after intra-articular injection (150mg dose). The mean maximum lymph gentamicin concentration was approximately 50 μg/ml and the time to reach this, approximately 1.7 h after joint injection. The mean synovial fluid concentration 0.25 h following injection was 7244 ± 660 μg/ml and disappearance from the synovial fluid was consistent with first order kinetics with a mean disappearance half-life (harmonic mean) of 0.99 (0.83-1.22) h. A technique for chronic cannulation of the dorsal digital lymph trunk was developed. Two Trials were conducted and in the first (Trial A) the disposition of gentamicin in plasma and lymph was studied after intravenous injection (2.2 mg/kg). In Trial B the disposition of gentamicin in plasma, synovial fluid and lymph was studied. Kinetic parameters were similar to other reported studies. There was no significant difference in kinetic parameters between trials. The disposition curves for all three fluids were similar. Mean maximum lymph concentrations were approximately 4.6 μg/ml and were 40% of the plasma concentrations 15 minutes after injection. These were achieved approximately 1.35 h after injection. The maximum concentration of gentamicin in synovial fluid (2.86 ± 0.45 μg/ml) was significantly less than in lymph. Three hours after injection plasma, synovial fluid and lymph concentrations were very similar and it was concluded that a sample of any one would be a good index of the others at this time. The relationship between synovial fluid and tissue fluid 3-8 h after injection was less clear with marked divergence of the disposition curves. Gentamicin was more slowly eliminated from lymph than plasma but a parallel relationship between the two fluids was observed 3-8 h after injection, with a mean lymph:plasma ratio of approximately 1.6. It was concluded that plasma concentrations were a good index of tissue fluid concentrations. Maximum lymph concentrations of gentamicin after intravenous injection were 10 times less than after intra-articular injection. The presence of very high concentrations in lymph derived from the synovium of a joint after intra-articular injection suggest that subsynovial interstitial fluid concentrations are also this high and therefore that intra-articular injection may have some therapeutic advantage over systemic injection. Lymph cannulation in the horse appears to be a viable technique for antimicrobial disposition studies.