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Biomedical subjects

R O Day

Publications and source records attributed to R O Day.

At least 19 recordsLinked to original sources
PubMed1998

The death of a healthy volunteer in a human research project: implications for Australian clinical research.

A healthy 19-year-old United States college student volunteer in a clinical research program underwent a bronchoscopy and died as a result of acute lignocaine toxicity. The major contributing factor in the tragedy was that the research protocol failed to specify an upper dose limit for lignocaine spray, although previous versions of the protocol had done so. We look at the implications of this case for Australian institutional ethics committees.

Adult↗
PubMed1998

Indicators for drug and therapeutics committees.

AIMS: This study describes development and field testing of a set of indicators for drug and therapeutics committees (DTCs) in hospitals. It was intended that these indicators should be accessible, useful and relevant in the Australian setting. METHODS: Candidate indicators were written following consultation and data collection. A framework of outcome, impact and process indicators was based on DTC goals, objectives and strategies. The candidate indicators were field tested over a 2 month period in teaching, city non-teaching, rural and private hospitals. The field tests provided response data for each indicator and evaluation of the indicators against criteria for accessibility, relevance, usefulness, clarity and resource utilisation. Consensus on which indicators to accept, modify or reject was reached at a workshop of stakeholders and experts, taking account of the field test results. RESULTS: Thirty-five candidate indicators were tested in 16 hospitals. Twenty-two had a response from >80% of sites, 23 had a mean relevance rating >3.5, 19 had a mean usefulness rating >3.5, 27 were correctly interpreted by > 90% of sites and 25 could be collected in an acceptable time. The most acceptable indicators required least data collection or provided data deemed useful for purposes other than the field test. At the consensus workshop 13 indicators were accepted with no or minor change, nine were accepted after major modification and eight were discarded. It was recommended that a further five indicators should be merged or subsumed into one indicator. CONCLUSIONS: This study has developed and field tested a set of indicators for DTCs in Australia. The indicators have been taken up enthusiastically as a first attempt to monitor DTC performance but require ongoing validation and development to ensure continuing relevance and usefulness.

Australia↗
PubMed1998

The application of adverse drug reaction data to drug choice decisions made by pharmacy and therapeutics committees. An Australian perspective.

Pharmacy and Therapeutics (P&T) committees undertake policy, regulatory and educational activities to promote rational use of medicines in their institutions with the aim of improving the quality of health and economic outcomes at these institutions. Formulary management is an important part of the P&T committees' activities and making drug choices is one of the committees' most difficult tasks. The 3 types of information most commonly identified by P&T committees as necessary for making drug choices are effectiveness, safety and cost data; usually in this order of importance. There is some evidence, however, that safety data are not considered by all committees when they make decisions about adding a new drug to a formulary. The role of adverse drug reaction (ADR) data in formulary decision-making (for registered drugs) occurs at several levels. First, ADR data obtained from pre-marketing studies of the drug are important and enable the committee to make an assessment of the risk of toxicity that should be anticipated for the drug. However, the limited nature of this information makes an absolute assessment impossible. Secondly, comparative safety information is necessary when deciding the place in therapy of a particular drug. Weighing up the comparative risks and benefits is a complex task which is a routine activity for most P&T committees whatever level of sophistication is applied. Thirdly, ADR data are an important ingredient of any economic assessment considered by a P&T committee. Calculation of the costs and consequences associated with the adverse effects of treatment demand careful assessment. Finally, aggregated adverse drug event reports which collate not only the consequences of adverse drug reactions but also medication incidents (medication errors) and which have been reported locally can be a useful quality assurance process for a P&T committee. This information will contribute to the identification of drugs for deletion from the formulary and less commonly in making decisions about additions to the formulary. As formulary management forms only part of a P&T committee's work, so the committee's interest in ADR is broader than the use of these data in making drug choices. The P&T committee may also be involved in promoting ADR reporting to either a central database or primary carers. Although often of limited availability, ADR information has an important role in the formulary management process of P&T committees.

Adverse Drug Reaction Reporting Systems↗
PubMed1998

Effect of clofibrate on the chiral disposition of ibuprofen in rats.

A potentially clinically important interaction has been described between clofibrate and ibuprofen in vitro. To determine whether this in vitro interaction is paralleled by a change in pharmacokinetics of ibuprofen in vivo two groups of rats were treated orally with clofibrate (n = 8, 280 mg/kg/day) or vehicle (n = 7) for 3 days. On day 3, 2 hr after the last dose of clofibrate, the rats were given an i.v. dose of pseudoracemic ibuprofen (20 mg/kg, 10 mg R-ibuprofen, 10 mg 13C-S-ibuprofen). Plasma concentrations of the enantiomers were monitored by a stereospecific gas chromatography mass spectrometry assay. The clearance of R-ibuprofen more than doubled in the clofibrate-treated group (mean +/- S.E.M.; 29.4 +/- 4.0 ml/min) as compared to control rats (13.0 +/- 1.4 ml/min; P = .003). This increase was similarly reflected in the clearance by inversion (treated, 23.2 +/- 3.2 ml/min, untreated, 10.0 +/- 1.2 ml/min; P = .003) and there was also an increase in the rate of inversion (treated, t1/2 inversion, 8.3 +/- 1.6 min; untreated, 13.9 +/- 1.4 min; P = .029). By contrast, the estimates of fractional chiral inversion were not affected by clofibrate and were in close agreement whether estimated by the area under the plasma concentration-time curve approach (treated, 0.79 +/- 0.02; untreated, 0.72 +/- 0.02) or by deconvolution (treated, 0.78 +/- 0.02; untreated, 0.73 +/- 0.02). There was a significant increase in volume of distribution at steady-state (treated, 4.42 +/- 1.12 liter/kg; untreated, 1.03 +/- 0.30 liter/kg; P = .017) observed for the R-enantiomer but not the S-enantiomer (treated, 1.04 +/- 0.13 liter/kg; untreated, 1.10 +/- 0.21 liter/kg). Pretreatment of rats with clofibrate significantly increased the concentrations of ibuprofen in fat, lung, brain and liver tissue. With respect to the protein levels of two key enzymes involved in chiral inversion, clofibrate pretreatment significantly induced expression of long chain acyl-coenzyme A synthetase, although the expression of the epimerase was unaltered. It is concluded, that clofibrate may increase the proportion of R-ibuprofen incorporated into long-lived lipid ("hybrid" lipid) stores.

Animals↗
PubMed1997

Copper-salicylate gel for pain relief in osteoarthritis: a randomised controlled trial.

OBJECTIVE: To assess the efficacy and safety of a copper-salicylate gel in osteoarthritis of the hip and knee. DESIGN: Randomised, double-blind, placebo-controlled study. SETTING: Rheumatology Clinic of St Vincent's Hospital, Sydney, New South Wales (a tertiary referral hospital), June 1993 to October 1994. PATIENTS: 116 patients with pain associated with osteoarthritis of the hip and/or knee (diagnosed by criteria of the European League against Rheumatism), drawn from patients attending the Clinic or self-referred after newspaper advertisements. INTERVENTION: Copper-salicylate or placebo gel (1.5 g) applied twice daily to the forearm for four weeks. OUTCOME MEASURES: Self-assessment of pain before the trial and after two and four weeks of treatment; patient and investigator assessments of efficacy; additional analgesia required; adverse reactions; and withdrawal rates. RESULTS: Pain scores at rest and on movement decreased in both the copper-salicylate and placebo groups by 13%-20%. There was no significant difference between the two groups for decrease in pain score, patient and investigator efficacy ratings, number of patients requiring paracetamol for extra analgesia (active, 77%; placebo, 71%) and average dose of paracetamol (active, 555 mg/day; placebo, 600 mg/day). Significantly more patients in the copper-salicylate group reported adverse reactions (83% versus 52% of the placebo group), most commonly skin reactions, and withdrew from the trial because of these reactions (17% versus 1.7% of the placebo group). CONCLUSION: Copper-salicylate gel applied to the forearm was no better than placebo gel as pain relief for patients with osteoarthritis of the hip or knee, but produced significantly more skin rashes.

Administration, Cutaneous↗
PubMed1997

Nonsteroidal antiinflammatory drugs in rheumatoid arthritis and osteoarthritis: support for the concept of "responders" and "nonresponders".

OBJECTIVE: A range of functional, biochemical, and psychological indicators was used to test the concept of "responders"/"nonresponders" and to seek predictors of response to 2 nonsteroidal antiinflammatory drugs in 9 patients with rheumatoid arthritis (RA) and 11 with osteoarthritis (OA). METHODS: In a balanced, randomized, double-blind, latin-square study design that involved four 4-week treatment periods, patients received ketoprofen or piroxicam (each for 2 of the 4 periods). Clinical and laboratory responses (pain, tenderness, swelling, patient and physician global assessments, acute-phase protein levels, and disability) were assessed in the last 2 weeks of each period. Responders were those who showed >30% improvement in at least 5 of 7 measures of disease activity. Mood was also assessed. RESULTS: At baseline, variables were higher in RA than in OA patients. The drugs produced clear improvements in patients' visual analog scale scores, physicians' overall assessments, and patients' responses to the McGill Pain Questionnaire, as well as plasma prostaglandin concentrations. In patients with either RA or OA, responders could be distinguished from nonresponders; about one-third of patients were unambiguous responders. In RA, there were responder/nonresponder differences in lymphocyte counts, erythrocyte sedimentation rate (ESR), and levels of tumor necrosis factor alpha, but no differences were seen in OA patients. However, caution in interpretation of the data is necessary because of the small number of patients. Responders had improved mood scores compared with nonresponders in both disease groups. Baseline ESR and white blood cell counts were correlated with responder status in RA patients. CONCLUSION: This study provides support for the responder/nonresponder concept. It also indicates that in RA, pretreatment ESR and lymphocyte counts are possibly useful indicators of therapeutic response.

Adult↗
PubMed1997

1-Methylxanthine derived from caffeine as a pharmacodynamic probe of oxypurinol effect.

AIMS: In the present study we have investigated the use of caffeine, administered in the form of instant coffee, as a prodrug for 1MX to validate the use of the 1MU:1MX ratio following caffeine administration as a pharmacodynamic measure of oxypurinol effect on xanthine oxidase. METHODS: Five healthy volunteers took caffeine 75 mg 8 hourly administered as instant coffee over a 7 day period. They were given allopurinol 600 mg on day 4. Urine was collected in 8 h aliquots from day 1-day 7. The ratio of 1-methyluric acid (1MU) to 1-methylxanthuric (1MX) was determined. RESULTS: The relationship between the plasma oxypurinol (the active metabolite of allopurinol) concentration at the midpoint of each caffeine dosage interval and the decrement in the urinary 1MX to 1MU ratio fitted well by a sigmoid Emax model. Mean (+/-s.d.) values of the oxypurinol EC50(3.9 +/- 1.4 mg l-1), EC90(8.7 +/- 1.8 mgl-1) and the exponent, n (3.0 +/- 1.2) were similar to those obtained previously following either the direct administration of 1MX or the use of theophylline as a prodrug for 1MX. CONCLUSIONS: These data indicate that the use of caffeine as a source of 1MX could provide a simple and ethically acceptable method for monitoring oxypurinol effect in patients taking allopurinol for the treatment of gout.

Adult↗
PubMed1997

Anti-rheumatic drug-prescribing behaviour of Australasian rheumatologists 1984-1994.

The prescribing behaviour of Australian and New Zealand rheumatologists was studied in 1994 using a questionnaire, and the results compared with a similar questionnaire administered in 1984. Perceived differences in efficacy and toxicity for disease-modifying anti-rheumatic drugs (DMARDs) and cytotoxics were reported. Over the decade, methotrexate and sulphasalazine have become the most commonly used anti-rheumatic agents, and methotrexate is clearly seen as the most effective drug. Wide variations in monitoring practices for DMARDs were reported, highlighting the need for cost-effectiveness studies on monitoring. There was low usage of functional outcome measurements in assessing patients.

Australia↗
PubMed1997

Effects of budesonide and fluticasone on 24-hour plasma cortisol. A dose-response study.

Comparison of the risk-benefit profiles of different inhaled glucocorticoids has been limited by inadequate information about the dose-response relationships for efficacy relative to side effects. Fluticasone propionate (FP) is twice as effective as budesonide (BUD), but the potency ratio of FP:BUD with respect to suppression of cortisol production is unknown. The effects of 5 d of treatment with BUD (800, 1,600, and 3,200 micrograms/d via pMDI) and FP (750, 1,500, and 2,000 micrograms/d via pMDI) on integrated area under the curve of 24-h plasma cortisol profiles (AUC24 h) were compared in a randomized, placebo-controlled, seven-period crossover study in normal male volunteers (n = 28). Plasma cortisol concentrations were measured during the last 24 h of each treatment period. Each treatment (except BUD 800 micrograms) produced significant dose-dependent reductions in AUC24 h compared with placebo; e.g., percent reductions in AUC24 h were 23, 41, and 69% for the three doses of BUD, and, correspondingly, 46, 85, and 93% for the three doses of FP. Model-derived measurements of dose potency ratios showed that FP was 2.9 times more potent than BUD in reducing AUC24 h (95% CI, 2.5 to 3.5) and 3.1 times more potent in reducing 8:00 A.M. plasma cortisol (95% CI, 2.4 to 4.0). Thus, on a microgram-for-microgram notional dose basis, the systemic effects of a given dose of FP on AUC24 h cortisol were equivalent to the effects of three times the dose of BUD.

Administration, Topical↗
PubMed1997

Pharmacokinetic and pharmacodynamic principles of illicit drug use and treatment of illicit drug users.

Many clinicians are confronted by the use of illicit drugs on a daily basis. The unsanctioned use of opioids, psychostimulants, benzodiazepines, alcohol and nicotine is a major cause of morbidity and mortality. Multiple factors have inhibited the scientific study of these agents including prohibition, public denial and lack of commercial interests. In dealing with problems related to these drugs, clinicians need a scientific understanding of their pharmacology, quantifiable effects and potential adverse effects. Illicit drug users select drugs with particular pharmacokinetic parameters and pharmacodynamic properties. Generally, rapid absorption, rapid entry into the central nervous system, high bioavailability, short half-life, small volume of distribution and high free drug clearance are pharmacokinetic characteristics which predict a high potential for harmful use because these factors increase positive reinforcement. Drug users adapt the method and route of drug administration to optimise the delivery of the drug to the brain while attempting to maximise the bioavailability of the drug. Inhalation and smoking are the routes of administration which allow the most rapid delivery of drug to the brain, while intravenous injection maximises the bioavailability of an administered drug. Each route of administration results in attendant complications related to mucosal damage, carcinogenesis and risk of infection. Negative reinforcement or withdrawal is a major drive to recurrent use. Many illicit drugs have pharmacological features that promote dependence, including long half-life, low free drug clearance and sufficient drug exposure to allow development of tolerance. The preventive or reductive pharmacotherapeutics of illicit drug use makes use of several subsets of agents: those which act on the same receptor or system as the illicit drug (such as methadone), those which produce an adverse reaction on consumption of the illicit drug (such as disulfiram) and those which symptomatically attenuate illicit drug withdrawal symptoms (such as clonidine). Many new agents are being trialled as potential preventive or reductive agents. It is important to consider pharmacotherapy as only one potential part of the treatment of illicit drug users. The complications of illicit drug use present many therapeutic challenges. As with all patients consuming multiple drugs, illicit drug users are prone to developing drug interactions. The most common interactions seen in practice are pharmacodynamic in nature, most often due to the additive effects of different drugs on the central nervous system. However, alcohol, cocaine, disulfiram, methadone and tricyclic antidepressants may be involved in important pharmacokinetic interactions. Of these the effect of long term alcohol consumption in increasing the hepatotoxicity of paracetamol and of cytochrome P450 3A microsomal enzyme stimulating drugs in diminishing the efficacy of methadone are the most commonly encountered.

Drug Interactions↗
PubMed1996

Pattern of non-steroidal anti-inflammatory drug use in Australia 1990-1994. A report from the Drug Utilization Sub-Committee of the Pharmaceutical Benefits Advisory Committee.

OBJECTIVE: To determine the pattern of use of non-steroidal anti-inflammatory drugs (NSAIDs) in the Australian community, 1990-1994. DESIGN: Data from the national drug utilisation database were expressed in defined daily doses per 1000 population per day (DDDs/1000 population per day). Temporal trends were assessed and comparisons were made with NSAID use in other countries. Epidemiological data were used to estimate the likely impact of changing NSAID use on peptic ulcer hospitalisation rates. SETTING: Australian community (excluding hospitals). MAIN OUTCOME MEASURES: Estimated consumption of prescription NSAIDs, expressed in DDDs/1000 population per day. RESULTS: NSAID use in the Australian community fell from 50.1 DDDs/1000 population per day in 1990 to 34.6 DDDs/1000 population per day in 1994 (down 31%). From this reduced exposure we estimated that the number of admissions for NSAID-related upper gastrointestinal complications will have fallen by about 400 per year. Market research data for this period show a lower percentage use of NSAIDs for osteoarthritis and a decrease in the proportion of use in age groups over 50 years. CONCLUSIONS: The level of use of non-steroidal anti-inflammatory drugs in Australia has been high in comparison with other countries, but in recent years has fallen markedly. This fall occurred in conjunction with regulatory interventions, educational campaigns and increased concern in the medical and lay press regarding the risks associated with the use of NSAIDs.

Adult↗
PubMed1996

Effect of mu-opioids morphine and buprenorphine on the development of adjuvant arthritis in rats.

OBJECTIVE AND DESIGN: On the basis that endogenous opioids play a role in the physiological response to inflammation, this study tests the anti-arthritic effects of a mu-opioid agonist, morphine and the partial mu-agonist, buprenorphine. MATERIAL: Male Lewis rats were used. TREATMENT: Rats were inoculated subcutaneously with 0.05 ml of Freund's complete adjuvant (5 mg/ml) into the right hind paw to produce adjuvant arthritis. Morphine (either 10 to 60 mg/kg/day s.c. bolus or 60 mg/kg/day s.c. infusion) and buprenorphine (0.65 +/- 0.06 mg/kg/day, orally), respectively, were administered for 3 days during the primary inflammatory phase of adjuvant arthritis. METHODS: The progression of adjuvant arthritis was monitored every three days by body weight change and hind limb oedema (ipsilateral and contralateral). On day 21 the animals were sacrificed and histology and radiography of the contralateral limb were performed. In rats receiving Freund's adjuvant and no drug treatment, the incidence of arthritis was 89%. Effect was expressed as the pooled severity index (PSI) derived from the arithmetic average of the volume, histology and radiography scores in the contralateral hind limb. RESULTS: Buprenorphine had no effect on experimental arthritis (PSI control vs treated: 242 +/- 28 vs 253 +/- 28%). In contrast, morphine by subcutaneous injection twice daily (10 to 60 mg/kg/day) but not by subcutaneous infusion (60 mg/kg/day) was found to attenuate the progression of adjuvant arthritis in a dose-dependent manner. This indicates that the anti-arthritic effects of morphine are opioid receptor mediated (ED50, 58 +/- 9 mg/kg) and suggests that the local concentration reached effective levels only after subcutaneous injection. It is also possible that the high doses of morphine were anti-inflammatory through effects at the kappa receptor. However, these high doses of morphine produced death in one third of the rats, the calculated lethal dose (LD50, 63 +/- 2 mg/kg) being close to the effective dose. CONCLUSION: Anti-arthritic effects of morphine are opioid receptor mediated but morphine use for this indication is restricted by its adverse effects.

Analgesics, Opioid↗
PubMed1996

Pharmacodynamics of oxypurinol after administration of allopurinol to healthy subjects.

1. Eight healthy subjects received 50, 100, 300, 600 and 900 mg allopurinol daily for 1 week each, in random order with 1 week separating each treatment period. The pre-dose plasma concentration of oxypurinol, the extent of inhibition of xanthine oxidase, plasma urate concentration and urine urate excretion rate were assessed on the last 2 days of each treatment week. 2. The ratio of 1-methyluric acid (1MU) over 1-methylxanthine (1MX) in the urine, following a dose of 50 mg 1MX infused intravenously over 20 min, was used to measure the inhibition of xanthine oxidase. 3. The steady-state plasma concentration of oxypurinol increased linearly with increasing dose of allopurinol between 50 mg to 600 mg day-1, with a weak indication of saturation at the higher 900 mg day-1 dose rate. 4. The relationships between plasma oxypurinol concentration and xanthine oxidase inhibition (1MU/1MX ratio), plasma urate concentration and urine urate excretion rate were fitted to an inhibition sigmoid Emax model and the C50 values for oxypurinol were 26.38 +/- 4.87, (mean +/- s.d.) 36.58 +/- 8.36 and 24.61 +/- 9.08 microM, respectively. 5. 1MU/1MX ratio appeared to be a reliable index of xanthine oxidase activity in vivo as the C50 for oxypurinol observed for 1MU/1MX ratio, plasma urate concentration and urine urate excretion rate were similar. 6. The concentration of oxypurinol required for inhibition of xanthine oxidase, as indicated by C50, was lower than those often observed in clinical practice.

Adult↗
PubMed1996

Potential mechanisms by which nonsteroidal anti-inflammatory drugs elevate blood pressure: the role of endothelin-1.

To determine whether endothelin-1 (ET-1) contributes to hypertension associated with non-steroidal anti-inflammatory drug (NSAID) usage in healthy, elderly, normotensive individuals a randomised, double-blind, placebo-controlled, crossover trial of indomethacin was undertaken in 41 healthy, elderly individuals with stable normotension or controlled hypertension (blood pressure (BP) < or = 160/90 mm Hg). The main outcome measures were systolic and diastolic BP, heart rate, cardiac output, weight, creatinine clearance, plasma renin activity, aldosterone, endothelin-1 and arginine vasopressin concentrations and 24 h urinary endothelin-1 and 6 keto prostaglandin F1 alpha outputs. Analysis of covariance was used to evaluate the effect of indomethacin on BP and related parameters. Indomethacin treatment for 1 month increased systolic (+/- s.e.m.: 4.1 +/- 2.2 mm Hg; 95% confidence interval 0 to 8.3 mm Hg) and diastolic BP (2.7 +/- 1.1 mm Hg; 0.4 to 4.9 mm Hg) without altering cardiac output (P = 0.59), implying an increase in total peripheral resistance. Indomethacin treatment produced a small increase in weight (1.4 +/- 0.4 kg; 0.6 to 2.2 kg), a small reduction in renal function (creatinine clearance: 6.8 +/- 1.8 mis/min; 3.3 to 10.3 mis/min) but a significant (83%) increase in daily urinary endothelin-1 production (13.1 +/- 3.4 ng/ml; 6.4 to 19.8 ng/ml) without altering plasma ET-1 concentration, suggesting increased renal synthesis. In conclusion, renal paracrine effects of ET-1 may contribute to NSAID-induced blood pressure elevation in humans.

Aged↗