Pharmacology
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Item Metadata only Hypernoradrenergic innervation: Its relationship to functional and hyperplastic changes in the vasculature of the spontaneously hypertensive rat(Karger AG, 1989) Head, R.There is now compelling evidence indicating that there is a greater sympathetic innervation of blood vessels in the spontaneously hypertensive rat (SHR) when compared with the innervation of corresponding vessels in the normotensive genetic control rat (WKY). In selected vascular beds in the SHR, increased sympathetic innervation occurs immediately after birth and prior to the expression of hypertension in the animal. In contrast, the available evidence suggests that the sympathetic innervation of cardiac tissue in SHR and WKY are similar in young and adult rats. The functional significance of the enhanced sympathetic innervation of blood vessels in the SHR with regard to the development or maintenance of hypertension relates in two ways to the well-established phenomena of vascular smooth muscle cell hypertrophy and hyperplasia, which are thought to be the pathophysiological basis for the increased peripheral vascular resistance and elevated blood pressure in this animal model of hypertension. First, the enhanced innervation of blood vessels in the SHR leads to an augmented release of the vasoconstrictor transmitter noradrenaline (NA). The predicted consequences of this augmented release of NA upon vascular contraction are modulated by the presence of a larger number of sites for neuronal inactivation (i.e. reuptake sites) of NA by virtue of the presence of the increased innervation. Second, and of more significance, is the inter-relationship between hypernoradrenergic innervation and vascular smooth muscle hyperplasia, as the early appearance of such changes is a powerful indicator for the subsequent expression of hypertension in the SHR. In view of the substantial evidence that implicates vascular smooth muscle cells in regulating the degree of their sympathetic innervation and confirms the influence of sympathetic nerves upon vascular smooth muscle hyperplastic change, attention is drawn to the role of trophic factors in providing the setting for the development of hypertension in the SHR.Item Metadata only Haemophilia A management in Victorian, New South Wales and South Australian haemophilia centres(Australian Medical Publishing Co., 1995) Ekert, H.; Ekert, N. L.; Street, A. M.; Rickard, K. A.; McPherson, V. J.; Toogood, I. R. G.; Lloyd, J. V.Item Metadata only Treating Hypertension in the Elderly(National Heart Foundation, 1995) Tonkin, Anne L.; School of Medical Sciences : PharmacologyItem Metadata only Experience of once-daily aminoglycoside dosing using a target area under the concentration-time curve(Royal Australasian College of Physicians, 1995) Barclay, Murray L.; Duffull, Stephen B.; Begg, Evan J.; Buttimore, R. C.; School of Medical Sciences : PharmacologyItem Metadata only Formation and reactivity of acyl-glucuronides: The influence of chirality(1995) Hayball, Peter JohnItem Metadata only Neural network based feature extraction scheme for heart rate variability(1995) Nandagopal, D.; Raymond, Ben; Mazumdar, J.; Taverner, DavidItem Metadata only Restriction fragment length polymorphism of the apolipoprotein B gene and response to dietary fat and cholesterol(PULSUS GROUP INC, 1995) Abbey, M.; Chen, G.Z.; Ross, R.; Noakes, M.; Belling, G.; Clifton, P.; Nestel, P.OBJECTIVE: The relationship between response to dietary fat and cholesterol, and the EcoRI restriction fragment length polymorphism (RFLP) of the apolipoprotein B(apoB) gene was examined. DESIGN: Forty-nine free-living subjects took part in a prospective double-blind crossover dietary intervention study. The apoB EcoRI cutting site was present in five women and 18 men (E+) and absent in 15 women and 11 men (E-). INTERVENTION: Subjects consumed a low fat (25% energy), low cholesterol (less than 200 mg/day) diet. After two weeks on this background diet (baseline) subjects were randomly assigned to consume a liquid supplement for three weeks which was either fat and cholesterol free or which contained fat (30 to 36 g) and cholesterol (650 to 780 mg). After the first three-week period subjects switched to the other supplement. Blood samples were collected for plasma lipid analysis after an overnight fast on two consecutive days at the end of baseline and on three consecutive days after each three-week supplement period. RESULTS: There was no significant difference in response to diet between the RFLP groups. Changes in plasma total, low density lipoprotein (LDL), high density lipoprotein(HDL), HDL2 and HDL3 cholesterol or plasma triglyceride were not different between the two RFLP groups. There was a significant difference between RFLP groups for baseline HDL2-cholesterol (0.31 +/- 0.04 and 0.16 +/- 0.02 mmol/L for E- and E+ subjects, respectively) which was independent of sex and apoE genotype (P = 0.032). CONCLUSIONS: These results indicate that the EcoRI RFLP of the apoB gene is not associated with response to dietary fat and cholesterol.Item Metadata only A suggested approach to once-daily aminoglycoside dosing(Blackwell Scientific, 1995) Begg, Evan J.; Barclay, Murray L.; Duffull, Stephen B.Item Metadata only Best Practice in Therapeutic Drug Monitoring(Australian Society of Clinical and Experimental Pharmacologists and Toxicologists, 1995) Tett, Susan Elizabeth; Ray, J.; Morris, R.; School of Medical Sciences : PharmacologyItem Metadata only Improved efficacy with non-simultaneous administration of first doses of gentamicin and ceftazidime in vitro(American Society for Microbiology, 1995) Barclay, Murray L.; Begg, Evan J.; Chalmers, Stephen T.; Boswell, D. Ross; School of Medical Sciences : PharmacologyItem Metadata only Abasic sites stimulate double-stranded DNA cleavage mediated by topoisomerase II(American Society of Biological Chemists, 1995) Kingma, Paul S.; Corbett, Anita H.; Burcham, Philip Cyril; Marnett, Lawrence J.; Osheroff, NeilItem Metadata only Psychotropic drug guidelines(Victorian Medical Postgraduate Foundation, 1995) White, J.Item Metadata only Prescribing in the elderly: Postural hypotension(Australian Medical Publishing Co., 1995) Tonkin, A.Item Metadata only Behavioural effects of caffeine coadministered with nicotine, benzodiazepines and alcohol.(1995) White, Jason MarkItem Metadata only Biosynthesis, characterisation and direct high-performance liquid chromatographic analysis of gemfibrozil 1-O-β-acylglucuronide(Elsevier, 1995) Sallustio, B.; Fairchild, B.Gemfibrozil 1-O-β-acylglucuronide was purified from the urine of a volunteer administered gemfibrozil, and an isocratic reversed-phase HPLC method was developed for its direct measurement. Quantitation of gemfibrozil and gemfibrozil 1-O-β-acylglucuronide was carried out from plasma, following extraction from acidified specimens into ethyl acetate, on a 5-μm CN reversed-phase column with a mobile phase (pH 3.5) containing acetonitrile, tetrabutylammonium sulphate and distilled water, using fluorescence detection at 284 nm excitation and 316 nm emission. Calibration curves were linear for both compounds over a concentration range of 0.1 to 40 mg/l, with intra-assay coefficients of variation <5% at concentrations of 20.0, 2.0 and 0.2 mg/l, and inter-assay coefficients of variation <10%. No degradation of gemfibrozil 1-O-β-acylglucuronide was detected as a result of the analytical procedure. However, a preliminary application of the method indicates that gemfibrozil acylglucuronide is chemically unstable undergoing intra-molecular rearrangement and hydrolysis under physiological conditions.Item Metadata only The renin-angiotensin system and nociception in the spontaneously hypertensive rat(Pergamon Press, 1995) Irvine, R.; White, J.; Head, R.This study investigated the effects of captopril, hydralazine and losartan on the locomotor activity, tailflick and hot plate latencies in spontaneously hypertensive rats (SHR) and their genetic controls the Wistar-Kyoto rat (WKY). The increased hot plate latencies normally exhibited by the spontaneously hypertensive rat were reduced or abolished by captopril ( 95 mg/kg/day p.o.) and losartan (18 mg/kg/day p.o.) treatment, but were unaffected by hydralazine (19 mg/kg/day p.o.). There were no observable effects of any of the drugs on tailflick latencies or locomotor activity. The results highlight a potential role for angiotensin II in analgesia that is independent of blood pressure change.Item Metadata only The influence of the renin angiotensin system on abnormal expression of nerve growth factor in the spontaneously hypertensive rat.(Blackwell, 1995) Jeffreson, S.; Rush, R.; Zettler, C.; Frewin, D.; Head, R.1. The levels of the neurotrophic factor, nerve growth factor (NGF) in the mesenteric vascular bed of the spontaneously hypertensive rat (SHR) were greater than those in the corresponding vascular bed of normotensive Wistar-Kyoto rats (WKY). 2. Administration of angiotensin II (200 ng/kg per min, by minipump) for 2 weeks to juvenile WKY rats increased the levels of NGF in the mesenteric vasculature to those seen in untreated SHR. 3. Administration of the angiotensin II receptor antagonists losartan (30 mg/kg per day, p.o.) or PD144277 (10 mg/kg per day, p.o.) to juvenile SHR for 4 weeks reduced the levels of NGF such that they were indistinguishable from the values obtained for normotensive WKY rats. 4. The results confirm the elevated level of NGF in the mesenteric vasculature of the SHR and suggest that angiotensin II may play a role in regulating the abnormal concentrations of the protein in this tissue.Item Metadata only Lack of effect of gender and oral contraceptive steroids on the pharmacokinetics of (R)-ibuprofen in human.(Blackwell Scientific, 1995) Knights, K.; McLean, C.; Tonkin, A.; Miners, J.The effects of gender and oral contraceptive steroids on the pharmacokinetics of (R)-ibuprofen were studied in groups of healthy adult males, females and oral contraceptive steroid (OCS) using females. The values of AUC, CLpo, t1/2 and Vss, app did not differ significantly between the groups. Similarly, the percentage unbound of (R)-ibuprofen in pooled plasma from the three groups was not statistically different. Since chiral inversion is the major determinant of (R)-ibuprofen clearance in humans, it may be inferred from these data that gender and OCS have little or no effect on conversion of (R)-ibuprofen to the pharmacologically active S-enantiomer. Moreover, it is unlikely that hormonal factors influence the activity of the human hepatic long-chain fatty-acid:CoA ligase, the enzyme mediating the rate limiting step of (R)-ibuprofen inversion.Item Metadata only The relationship between clinical effect and concentrations of temazepam in plasma and cerebrospinal fluid(Academic Press, 1995) Moffat, A.; Osborne, G.; Badcock, N.; Maranucci, P.; Nyman, T.; Russell, W.The clinical pharmacodynamics of temazepam were investigated in patients who received spinal anaesthesia. Total plasma and cerebrospinal fluid temazepam concentrations were measured and correlated with the clinical effects. Sedation was measured by three separate methods. None, including an aggregated score of all three measures, was correlated closely with either the plasma or the cerebrospinal fluid levels (p = 0.86 and 0.12 respectively). Anxiety was measured before and after premedication. The two scores were correlated but the change in anxiety after premedication did not correlate with either the plasma or the cerebrospinal fluid concentrations (p = 0.11 and 0.45 respectively). Short-term memory was measured before and after premedication. The decline in short-term memory ability was moderately well correlated with both the plasma and the cerebrospinal fluid levels (p = 0.0005 and 0.013 respectively). With temazepam, the variation in sedative and anxiolytic effects between subjects is explained not by differences in pharmacokinetics but rather by differences in the pharmacodynamic response. Because sedative and anxiolytic effects are poorly correlated, but the amnesic effect is well correlated with temazepam concentrations, different sites of action for these effects are suggested.Item Metadata only Effects of glyceryl trinitrate tolerance on vascular responsiveness to constrictor agents in bovine isolated coronary artery(BLACKWELL SCIENCE PUBL AUSTR, 1995) Zhang, C.; de la Lande, I.; Horowitz, J.1. Recent clinical studies have raised the possibility that intermittent nitrate dose regimens, while limiting the extent of nitrate tolerance development, may trigger rebound aggravation of ischaemia after abrupt withdrawal of nitrate. To date, only limited studies have been performed to examine the mechanism of this phenomenon. 2. In a bovine isolated coronary artery model, we tested the hypothesis that induction of glyceryl trinitrate (GTN) tolerance might affect large coronary artery responsiveness to a variety of non-catecholamine constrictor agents. Glyceryl trinitrate tolerance was induced by pre-exposure to GTN (10 mumol/L) for 60 min followed by 15 min washout. In some experiments, the effect of prior endothelial removal on putative interactions was also examined. 3. Our results showed that GTN tolerance did not affect responses to KCl, the thromboxane A2 mimetic U46619, endothelin-1 and 5-HT, irrespective of presence or absence of endothelium. None of the constrictor agents tested induced endothelium-dependent constriction. 4. We conclude that in this model of GTN tolerance induction, there is no evidence of 'rebound' vasoconstriction to this group of non-catecholamine vasoconstrictors with GTN withdrawal.