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Biomedical subjects

A J McLean

Publications and source records attributed to A J McLean.

At least 37 records · Page 2Linked to original sources
PubMed1999

Cephalosporin clinical concentration-time profile modelling and in-vitro bactericidal effects on Escherichia coli.

We assessed the cephalosporin concentration-time curve area (AUC), peak concentration, maintained concentration and duration of exposure on in-vitro bactericidal effects on Escherichia coli NCTC 10418, using exposures modelling cephazolin clinical profiles after 1 g and 2 g i.m. injection, equal AUC exposures (288 mg x h/L, 576 mg x h/L; 48 h) and constant exposures to 6, 12 and 24 mg/L. Cephalosporin dosage exposures based on maintenance of concentrations at multiples (6-24 times) of the MIC were not as effective in early or sustained (24 h) bactericidal effect as exposures modelling im injection profiles with equal or lower AUC (P<0.05, ANOVA). Similar results applied to i.m. comparisons with equal AUC exposures modelling extremes of concentration and time exposures. These results indicate a need for intermittent dosage to produce optimally effective profiles, and raise the possibility that these optimum dosing profiles may allow an extension of minimum interdose intervals beyond 8 h.

Cephalosporins↗
PubMed1999

Oxidative injury reproduces age-related impairment of oxygen-dependent drug metabolism.

The Oxygen Diffusion Barrier Hypothesis states that aging in the liver is associated with restricted oxygen uptake that explains the age-related impairment of phase I drug clearance observed in vivo with preservation of in vitro phase I enzyme activity and in vivo phase II drug clearance. Aging in the liver may be secondary to oxidative stress. Therefore we examined the effects of oxidative injury on oxygen uptake, and phase I and phase II drug metabolism in the liver. Oxidative stress was induced in the perfused rat liver with hydrogen peroxide. The intrinsic clearances of propranolol and morphine were used as markers of phase I and phase II activity, respectively. Oxidative injury was associated with a 14+/-99% (P=0.03) reduction in oxygen uptake. The decrease in the intrinsic clearance of propranolol was greater than that of morphine (57+/-14% vs 34+/-7% P<0.005). This result supports the concept of a restriction of oxygen supply constraining hepatic drug metabolism following oxidative stress. This has implications for aging and hepatic drug metabolism.

Anesthesia↗
PubMed1999

Visualizing differences in ligand regulation of wild-type and constitutively active mutant beta(2)-adrenoceptor-green fluorescent protein fusion proteins.

Fusion proteins were generated by attachment of green fluorescent protein (GFP) to the C-terminal tail of either the wild-type human beta(2)-adrenoceptor or a form with enhanced constitutive activity. Sustained treatment of HEK293 cells stably expressing the constitutively active mutant (CAM) beta(2)-adrenoceptor-GFP with the inverse agonist betaxolol resulted in a marked up-regulation of the fusion protein that could be monitored by both fluorescence and immunoblotting of membrane fractions. This was not observed for the wild-type beta(2)-adrenoceptor-GFP. Addition of the agonist isoprenaline to CAM beta(2)-adrenoceptor-GFP expressing cells previously treated with betaxolol resulted in rapid internalization of the receptor into punctate intracellular vesicles in a manner similar to wild-type beta(2)-adrenoceptor-GFP. A range of "beta-blockers" replicated the up-regulation of the CAM beta(2)-adrenoceptor-GFP, although pharmacological specificity was maintained, as it was not produced by alpha(1)- and alpha(2)-adrenoceptor-selective antagonists/inverse agonists. Parallel intact cell binding studies with [(3)H]dihydroalprenolol confirmed up-regulation of the CAM beta(2)-adrenoceptor-GFP by betaxolol but failed to predict the optically monitored up-regulation produced by high concentrations of alprenolol. The cellular distribution of the up-regulated CAM beta(2)-adrenoceptor-GFP was not identical after sustained treatment of the cells with different beta-blockers. Inverse agonists, able to reduce basal intracellular cAMP levels, such as betaxolol and ICI118551, resulted in both increased plasma membrane receptor and increased diffuse intracellular staining. In contrast, treatment with labetolol and alprenolol resulted in a significant fraction of the intracellular receptor displaying a punctate distribution pattern. These ligands displayed substantial agonism to stimulate intracellular cAMP levels via the CAM beta(2)-adrenoceptor-GFP.

Cells, Cultured↗
PubMed1999

Carbon monoxide disposition in the perfused rat liver.

A simple method for determining carbon monoxide (CO) disposition in the rat liver perfused with erythrocyte-free buffer was developed. Wash-in experiments were performed with buffer containing tracer quantities of [14C]sucrose and 3H2O and equilibrated with CO. Outflow samples were collected into tubes containing human erythrocytes, which avidly bind CO. Outflow curves were analyzed using compartmental models. Fractional recovery of CO was 1.07 +/- 0. 17, and the apparent volume of distribution was 1.37 +/- 0.30 ml/g of liver (n = 8). A flow-limited model fitted the data most effectively, although estimates of the permeability-to-surface area product were attempted using a barrier-limited model. This technique will facilitate investigation of the effects of disease on gaseous substrate disposition in perfused organs.

Animals↗
PubMed1999

Hepatic artery flow and propranolol metabolism in perfused cirrhotic rat liver.

The oxygen limitation theory states that capillarization of the sinusoidal endothelium in cirrhosis impairs hepatocellular oxygen uptake manifesting as a reduction in oxygen-dependent enzyme activity including phase 1 drug metabolism. The hepatic artery supplies highly oxygenated blood to the liver. Therefore, we tested whether augmentation of hepatic arterial blood flow could improve hepatic oxygenation and function in cirrhosis. Rats were treated with carbon tetrachloride and phenobarbitone to induce hepatic cirrhosis or fibrosis. We used a bivascular rat liver perfusion model to examine the effects of increased hepatic artery flow on propranolol clearance and oxygen consumption. Each liver was perfused at three hepatic artery flow rates, 1 to 3, 4 to 6, and 7 to 9 ml/min with a constant portal venous flow of 7 to 9 ml/min. Increasing the hepatic artery flow led to improvement in propranolol clearance in control (n = 7, P <.001), fibrotic (n = 8, P <.001), and cirrhotic (n = 6, P <.001) livers. Intrinsic clearance of propranolol increased only in the cirrhotic livers (P =.01), indicating an improvement in enzyme activity. Regression analysis indicated that this improvement was mediated by change in oxygen delivery alone (P =.001). The results confirm that propranolol metabolizing enzyme activity in cirrhosis can be improved by increasing oxygen delivery by increasing hepatic arterial blood flow. These findings suggest that increasing hepatic arterial blood flow may be an important therapeutic strategy for improving global liver function in cirrhosis.

Animals↗
PubMed1998

Receptors involved in nerve-mediated vasoconstriction in small arteries of the rat hepatic mesentery.

1. We have investigated the neurotransmitters and receptor subtypes involved in nerve-mediated vasoconstriction in small arteries of the rat hepatic mesentery. 2. A dense sympathetic innervation was demonstrated using catecholamine histochemistry and antibodies against the synaptic vesicle protein synaptophysin. 3. Reverse transcription-polymerase chain reaction (RT-PCR) demonstrated very strong expression of the alpha1A-adrenergic, neuropeptide Y (NPY) Y1, P2X1- and P2X4-purinergic receptors, moderate expression of the alpha2B-adrenergic receptor and the purinergic P2X5- and P2X7-receptors and weak expression of the alpha1B-, alpha1D-, alpha2A- and alpha2C-adrenergic receptors and the P2X2- and P2X3-purinergic receptors. NPY2 and P2X6 receptor expression was absent. 4. Electrical field stimulation (10 Hz, 10 s) produced contractions which were abolished by tetrodotoxin (10(-6) M) and/or guanethidine (GE, 5 x 10(-6) M) and a combination of benextramine (10(-5) M) and alpha,beta-methylene ATP, (alpha,beta-mATP, 3 x 10(-6) M) or PPADS (10(-5) M). Selective alpah1-adrenergic receptor antagonists showed the potency order of prazosin > WB-4101 > 5-methyl-urapidil > BMY 7378. Yohimbine (10(-8) M, 10(-7) M), alpha,beta-mATP (3 x 10(-6) M) and PPADS (10(-5) M) each enhanced the response to nerve stimulation. 5. Some experiments demonstrated a slow neurogenic contraction which was abolished by GE or the selective NPY1 receptor antagonist 1229U91 (6 x 10(-7) M). 6. We conclude that nerve-mediated vasoconstriction results from the activation of postsynaptic alpha,beta-adrenergic and P2X-purinergic receptors and under some conditions, NPY1 receptors. Neurotransmitter release is modulated by presynaptic alpha2-adrenergic receptors and possibly also P2X-purinoceptors. The major postsynaptic subtypes involved were well predicted by mRNA expression as measured by RT-PCR, suggesting that this technique may be a useful adjunct to studies aimed at identifying functional receptor subtypes.

Animals↗
PubMed1998

Changes in MIC alter responses of Pseudomonas aeruginosa to tobramycin exposure.

The pharmacokinetic parameters determining antibiotic efficacy are peak concentrations (Cmax), minimum (trough) concentrations (Cmin), and area under the concentration-time curve (AUC). There is general agreement about the importance of Cmax and AUC for aminoglycosides, but this is not so for maintenance of Cmin. With in vitro exposures modelling in vivo administration, Pseudomonas aeruginosa reference strain ATCC 27853 (MIC, 1 mg/liter) and a higher-MIC (relatively resistant) clinical isolate (MIC, 4 mg/liter) were used to explore bacteriostatic and bactericidal outcomes. With P. aeruginosa ATCC 27853, kill followed a complete bolus profile with a 30-min postdistribution peak (Cpeak30) of 10 mg/liter. The clinical isolate required a Cpeak30 bolus profile of 20 mg/liter for kill, and there was no difference between the efficacies of the bolus and infusion exposures. Bolus profiles that were truncated at 8.5 h and producing sublethal effects were then combined with a wide range of Cmins. With a Cpeak30 profile of 8 mg/liter, P. aeruginosa ATCC 27853 showed a graded bacteriostatic response until a Cmin of > or = 0.8 mg/liter, when complete kill resulted. In contrast, bactericidal effects on the clinical isolate required a Cpeak30 profile of 18 mg/liter with a Cmin of > or = 1.0 mg/liter. Therefore, Cmin also contributes to the bactericidal effect of tobramycin, with requirements showing minor variation with change in MIC. Dosing principles for relatively resistant (higher-MIC) organisms are suggested from the data. Relatively higher aminoglycoside doses via infusion regimens are likely to be needed to generate higher peak concentrations and higher AUC values necessary for bactericidal effect in resistant organisms. Maintenance of trough concentrations on the order of 1.0 mg/liter during the interdose interval will tend to guard against the possibility of inadequate peak and AUC exposures for kill.

Anti-Bacterial Agents↗
PubMed1998

The aging liver. Drug clearance and an oxygen diffusion barrier hypothesis.

A change in drug clearance with age is considered an important factor in determining the high prevalence of adverse drug reactions associated with prescribing medications for the elderly. Despite this, no general principles have been available to guide drug administration in the elderly, although a substantial body of clearance and metabolism data has been generated in humans and experimental animals. A review of age-related change in drug clearances established that patterns of change are not simply explained in terms of hepatic blood flow, hepatic mass and protein binding changes. In particular, the maintained clearance of drugs subject to conjugation processes while oxygen-dependent metabolism declines, and all in vitro tests of enzyme function have been normal, requires new explanations. Reduction in hepatic oxygen diffusion as part of a general change in hepatocyte surface membrane permeability and conformation does provide one explanation for the paradoxical patterns of drug metabolism, and increased hepatocyte volume would also modify oxygen diffusion path lengths (the 'oxygen diffusion barrier' hypothesis). The reduction in clearances of high extraction drugs does correlate with observed reduction in hepatic perfusion. Dosage guidelines emerge from these considerations. The dosage of high clearance drugs should be reduced by approximately 40% in the elderly while the dosage of low clearance drugs should be reduced by approximately 30%, unless the compound is principally subject to conjugation mechanisms. If the hepatocyte diffusion barrier hypothesis is substantiated, this concept may lead to therapeutic (preventative and/or restorative) approaches to increased hepatocyte oxygenation in the elderly. This may lead to approaches for modification of the aging process in the liver.

Aged↗
PubMed1997

Vehicle travel speeds and the incidence of fatal pedestrian crashes.

The aim of this study was to estimate the likely effect of reduced travel speeds on the incidence of pedestrian fatalities in Adelaide, Australia. The study was based on the results of detailed investigations of 176 fatal pedestrian crashes in the Adelaide area between 1983 and 1991. The method developed to estimate the effect of reduced travelling speed is described and supported by references to the published literature. A reduction in the speed limit from 60 to 50 km/h was one of four speed reduction scenarios considered. The smallest estimated reduction in fatal pedestrian collisions in the selection presented was 13%, for a scenario in which all drivers obeyed the existing speed limit. The largest estimated reduction was 48% for a scenario in which all drivers were travelling 10 km/h slower. The estimated reductions in fatalities obtained in this study are compared with those observed in places where the urban area speed limit has been lowered.

Acceleration↗
PubMed1997

Dosing implications of a clinical interaction between grapefruit juice and cyclosporine and metabolite concentrations in patients with autoimmune diseases.

OBJECTIVE: To determine the effect of chronic grapefruit juice administration on steady state blood concentrations of cyclosporine and metabolites in patients with autoimmune diseases. METHODS: 9 patients stabilized on administration of cyclosporine (range 0.7-6.7 mg/kg/day) were given either grapefruit juice or water using randomized crossover design. Whole blood samples were collected before the morning cyclosporine dose and during the 12 h interdose interval. Cyclosporine concentrations were measured using a relatively specific assay (Emit) and total metabolite concentrations were estimated using a nonspecific assay (polyclonal Abbott-TDx). RESULTS: Exposure to grapefruit juice produced significant increases in predose cyclosporine concentrations (p < 0.01) and total metabolite concentrations (p = 0.03) and the area under the cyclosporine and metabolite blood concentration-time curves (p = 0.005, p = 0.001, respectively). One patient developed significant neurological side effects associated with a 68.9 and 214% increase in predose cyclosporine and metabolite concentrations, respectively, during grapefruit juice co-administration. CONCLUSION: Grapefruit juice causes an increase in both parent and metabolite profiles, indicating an alteration in the disposition of cyclosporine and metabolites. This interaction is of potential clinical importance in terms of mechanism, side effects, and dosing.

Adult↗
PubMed1996

Extended hospital stays with increasing age: the impact of an acute geriatric unit.

OBJECTIVES: To examine the association between increasing age and extended length of hospitalisation, and the impact of an acute geriatric unit on this association. DESIGN: Retrospective analysis of concurrently collected data of patients admitted to three general medical units, one of which was an acute geriatric unit. SETTING: Alfred Hospital, Melbourne (a tertiary referral teaching hospital), between 1 July 1993 to 30 June 1994. PATIENTS: Those classified into the same diagnosis-related groups (DRGs) as the 15 most common DRGs of the acute geriatric unit. OUTCOME MEASURE: Incidence of patients with extended lengths of stay ("high outliers"), analysed by age, medical unit and DRG. RESULTS: Of 3499 patients discharged from the hospital with the 15 study DRGs, 303 patients (8.6%) were from the acute geriatric unit, and 274 and 300 patients (7.8% and 8.5%) were from the two other general medical units, respectively. Patients in the acute geriatric unit were significantly older (median age group, 75-79; age range, 18-98) than patients in all other hospital units (median age group, 60-64; age range, 18-97) (P < 0.0001). Analysis of patients with respiratory and cardiovascular DRGs admitted to all general medical units compared with specialty units showed this age discrepancy was even more marked for patients aged over 85. There was an increased likelihood (P < 0.001) of an extended length of stay for patients aged over 55. The incidence of high outliers for comparable DRGs was lower for patients cared for by the acute geriatric unit, compared with general medical units. In the acute geriatric unit, unlike the overall trend, the proportion of high outliers did not increase with age. CONCLUSIONS: The specialised management of acute geriatric medical units can counteract the trend towards increased incidence of high outliers with increasing age, despite significantly older patients.

Acute Disease↗
PubMed1996

Aminoglycoside dosing: one, two or three times a day?

The safety and efficacy of conventional aminoglycoside dosing regimens have been proven in clinical trials. Higher doses at longer intervals may be more effective if they result in higher peak serum levels of the drug, but few trials of "once-a-day" dosing have shown improved clinical outcome. The clinical safety of allowing trough serum levels to fall below the minimum inhibitory concentration is not established. Literal "once-a-day" dosing will result in drug accumulation and toxicity in patients with reduced renal clearance, and in potential lack of efficacy and the emergence of antibiotic-resistant organisms in those with increased renal clearance. However, modified "once-a-day" dosing, with the interval determined by the individual's renal clearance rate (hence avoiding subtherapeutic trough levels), will avoid these problems.

Aminoglycosides↗
PubMed1996

Increased sensitivity of propranolol clearance to reduced oxygen delivery in the isolated perfused cirrhotic rat liver.

BACKGROUND & AIMS: Capillarization of the sinusoids in cirrhosis is proposed to reduce oxygen availability to the hepatocyte, resulting in the patterns of altered drug metabolism observed in cirrhosis. If this were true, drug metabolism in cirrhotic livers would be expected to be more sensitive to reduced oxygen delivery than in noncirrhotic livers. The aim of this study was to compare the sensitivity of propranolol clearance with reduced oxygen delivery in isolated perfused livers from healthy and cirrhotic rats. METHODS: Propranolol clearance was measured at steady state in 5 normal and 5 cirrhotic weight-matched perfused rat livers under single-pass conditions with normal oxygen delivery (mean, 71.5 mumol/min) and with graded reductions in oxygen delivery (range, 58.1-18.8 mumol/min). RESULTS: In noncirrhotic livers, propranolol clearance was independent of oxygen supply for the oxygen delivery range of 73-45 mumol/min but decreased with further reductions in oxygen supply. In cirrhotic livers, propranolol clearance decreased linearly (r2 = 0.92; P < 0.005) for the entire oxygen delivery range (73.4-18.8 mumol/min). CONCLUSIONS: The increased sensitivity of propranolol clearance in perfused cirrhotic livers to reductions in oxygen delivery is consistent with impaired oxygen delivery to hepatocytes in cirrhosis. These novel findings potentially hold implications for clinical management of patients with cirrhosis.

Adrenergic beta-Antagonists↗
PubMed1996

A head impact model of early axonal injury in the sheep.

Axonal injury (AI), one of the principal determinants of clinical outcome after head injury, may evolve over several hours after injury, raising the future possibility of therapeutic intervention during this period. A new head impact model of AI in sheep was developed to examine pathological and physiological changes in the brain resulting from a graded traumatic insult. In this preliminary study 10 anesthetized and ventilated Merino ewes were used. Head injury was produced by impact from a humane stunner to the temporal region of an unrestrained head. Eight sheep were studied for 1, 2, 4, or 6 h after impact. Two sham animals (no impact, 6 h survival) were also examined. Arterial blood pressure, intracranial pressure, and cerebral blood flow were monitored continuously. A physiological index of injury severity was calculated by weighting the percentage shift from preinjury values for each monitored parameter over the first hour after injury. Immunostaining with amyloid precursor protein (APP) was used as a marker of axonal damage and the distribution of APP positive axons was recorded according to a sector scoring method (APPS). Widespread AI was identified in 7 of the 8 impacted animals, around cerebral contusions and in hemispheric white matter, central gray matter, brain stem, and cerebellum, and was detected as early as 1 h after injury. The degree of axonal injury (APPS) correlated well with an index of physiological response to injury (r = 0.83, p = 0.005).

Amyloid beta-Protein Precursor↗
PubMed1996

Kill kinetics and regrowth patterns of Pseudomonas aeruginosa exposed to concentration-time profiles of tobramycin simulating in vivo infusion and bolus dosing.

Pseudomonas aeruginosa ATCC 27853 was exposed to tobramycin concentration-time profiles modelling in vivo bolus and infusion dosing. Dependence of bactericidal and bacteriostatic activity on the initial profile of peak concentration (bolus effect > infusion) and area under the antibiotic concentration-time curve was observed at peak concentration/MIC ratios of 10 or below.

Anti-Bacterial Agents↗
PubMed1996

Minimisation of aminoglycoside toxicity in patients with cystic fibrosis.

BACKGROUND: There is evidence that administration of higher doses of aminoglycosides given less frequently improves the bactericidal effect and reduces the potential to cause side effects. To investigate this, a prospectively randomised open label therapeutic trial was undertaken in stratified groups of patients with cystic fibrosis to examine the efficacy and toxic potential of an aminoglycoside dosing regimen designed to generate high peak drug concentrations at 12 hourly intervals compared with conventional dosing at eight hourly intervals. METHODS: Patients in group A received tobramycin eight hourly using a dose aimed at generating a peak concentration of 10 mg/l with trough concentrations below 2 mg/l, and those in group B received the total daily dose required to achieve eight hourly target concentrations administered as two equal 12 hourly doses. Clinical outcomes measured and assessed included vestibular symptoms, hearing and renal function, length of hospital stay, readmission rate, and mortality. RESULTS: Twenty nine patients were recruited during a six month period, 20 to group A and nine to group B. The average peak tobramycin level was higher in group B (12.5 (2.2) mg/l) than in group A (7.9 (1.9) mg/l), whilst the average trough level was higher in group A (0.8 (0.3) mg/l) than in group B (0.5 (0.2) mg/l). There was a difference in the number of ototoxic events between patients in group A (seven of 18, 38.9%) and group B (none of eight), but no difference was found in other outcome measures assessed. CONCLUSIONS: These results suggest that 12 hourly high peak aminoglycoside dosing may be less toxic than equivalent eight hourly dosing, without any apparent difference in efficacy.

Adult↗