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Background:The sympathetic nervous system regulates energy metabolism via β-adrenoreceptors. Therapeutic exploitation of previous β2-adrenegic agonists for metabolic benefits has been hindered by cross stimulation of cardiac β1-adrenoceptor, causing tachycardia. Formoterol is a novel highly β2-selective adrenergic agonist and holds promise as a β2-agonist that could impart selective beneficial metabolic effects.Objective:To investigate the metabolic effects of formoterol on energy and substrate metabolism.Participants:Healthy volunteers.Design:(1) Dose-finding study, step-wise incremental design of weekly administration of 80, 160 and 320 μg daily of formoterol in four subjects and, (2) metabolic study, an open-label metabolic evaluation of 1-week treatment in eight men using a dose determined from (1).Main outcome:Resting energy expenditure (EE), diet-induced thermogenesis (DIT) and fat oxidation (Fox) using indirect calorimetry, heart rate and plasma non-esterified fatty acid (NEFA) levels.Results:In the dose-finding study, all three doses increased resting EE and Fox with the 320 μg dose significantly increasing heart rate. In the metabolic study, the selected 160 μg daily dose increased resting EE by 13±2% (P<0.001) and Fox by 23±4% (P<0.01), but not DIT. Plasma NEFA levels rose by 16±2% (P<0.01). Heart rate did not change significantly. Out of the eight subjects, six reported tremor and palpitation, two lost appetite and one suffered from insomnia.Conclusions:At a dose of 160 μg per day, formoterol increases resting EE and fat utilization without inducing tachycardia. From this first metabolic evaluation in humans, we conclude that formoterol imparts beneficial metabolic changes that may be exploited for therapy of obesity. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM PUBLISHER]

Objectives: Vancomycin dose recommendations depend on population pharmacokinetic models. These models have not been adequately assessed in critically ill patients, who exhibit large pharmacokinetic variability. This study evaluated model predictive performance in intensive care unit (ICU) patients and identified factors influencing model performance., Methods: Retrospective data from ICU adult patients administered vancomycin were used to evaluate model performance to predict serum concentrations a priori (no observed concentrations included) or with Bayesian forecasting (using concentration data). Predictive performance was determined using relative bias (rBias, bias) and relative root mean squared error (rRMSE, precision). Models were considered clinically acceptable if rBias was between ±20% and 95% confidence intervals included zero. Models were compared with rRMSE; no threshold was used. The influence of clinical factors on model performance was assessed with multiple linear regression., Results: Data from 82 patients were used to evaluate 12 vancomycin models. The Goti model was the only clinically acceptable model with both a priori (rBias 3.4%) and Bayesian forecasting (rBias 1.5%) approaches. Bayesian forecasting was superior to a priori prediction, improving with the use of more recent concentrations. Four models were clinically acceptable with Bayesian forecasting. Renal replacement therapy status (p < 0.001) and sex (p = 0.007) significantly influenced the performance of the Goti model., Conclusions: The Goti, Llopis and Roberts models are clinically appropriate to inform vancomycin dosing in critically ill patients. Implementing the Goti model in dose prediction software could streamline dosing across both ICU and non-ICU patients, considering it is also the most accurate model in non-ICU patients., (Copyright © 2020 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Objectives: Vancomycin is a vital treatment option for patients suffering from critical infections, and therapeutic drug monitoring is recommended. Bayesian forecasting is reported to improve trough concentration monitoring for dose adjustment. However, the predictive performance of pharmacokinetic models that are utilized for Bayesian forecasting has not been systematically evaluated., Method: Thirty-one published population pharmacokinetic models for vancomycin were encoded in NONMEM®7.4. Data from 292 hospitalized patients were used to evaluate the predictive performance (forecasting bias and precision, visual predictive checks) of the models to forecast vancomycin concentrations and area under the curve (AUC) by (a) a priori prediction, i.e., solely by patient characteristics, and (b) also including measured vancomycin concentrations from previous dosing occasions using Bayesian forecasting., Results: A priori prediction varied substantially-relative bias (rBias): -122.7-67.96%, relative root mean squared error (rRMSE) 44.3-136.8%, respectively-and was best for models which included body weight and creatinine clearance as covariates. The model by Goti et al. displayed the best predictive performance with an rBias of -4.41% and an rRMSE of 44.3%, as well as the most accurate visual predictive checks and AUC predictions. Models with less accurate predictive performance provided distorted AUC predictions which may lead to inappropriate dosing decisions., Conclusion: There is a diverse landscape of population pharmacokinetic models for vancomycin with varied predictive performance in Bayesian forecasting. Our study revealed the Goti model as suitable for improving precision dosing in hospitalized patients. Therefore, it should be used to drive vancomycin dosing decisions, and studies to link this finding to clinical outcomes are warranted., (Copyright © 2019 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Introduction: Drug-drug interaction (DDI) alerts are often implemented in the hospital computerized provider order entry (CPOE) systems with limited evaluation. This increases the risk of prescribers experiencing too many irrelevant alerts, resulting in alert fatigue. In this study, we aimed to evaluate clinical relevance of alerts prior to implementation in CPOE using two common approaches: compendia and expert panel review., Methods: After generating a list of hypothetical DDI alerts, that is, alerts that would have been triggered if DDI alerts were operational in the CPOE, we calculated the agreement between multiple drug interaction compendia with regards to the severity of these alerts. A subset of DDI alerts ( n  = 13), with associated patient information, were presented to an expert panel to reach a consensus on whether each alert should be included in the CPOE., Results: There was poor agreement between compendia in their classifications of DDI severity (Krippendorff's α: 0.03; 95% confidence interval: -0.07 to 0.14). Only 10% of DDI alerts were classed as severe by all compendia. On the other hand, the panel reached consensus on 12 of the 13 alerts that were presented to them regarding whether they should be included in the CPOE., Conclusion: Using an expert panel and allowing them to discuss their views openly likely resulted in high agreement on what alerts should be included in a CPOE system. Presenting alerts in the context of patient cases allowed panelists to identify the conditions under which alerts were clinically relevant. The poor agreement between compendia suggests that this methodology may not be ideal for the evaluation of DDI alerts. Performing preimplementation review of DDI alerts before they are enabled provides an opportunity to minimize the risk of alert fatigue before prescribers are exposed to false-positive alerts., Competing Interests: None., (Georg Thieme Verlag KG Stuttgart · New York.)

Background: There is now little doubt that improving antimicrobial use is necessary for the containment of resistance., Objective: To determine whether providing individualised feedback to doctors about their recent compliance with the hospital's antibiotic policy improves compliance with the policy., Methods: This study was conducted at a teaching hospital in Sydney, Australia. Computerised alerts integrated into the electronic prescribing system (ePS) inform prescribers of the local antibiotic policy. We utilised prescribing data extracted from the ePS for 'audit and feedback'. Thirty-six prescribers were sent feedback letters via email. We also interviewed doctors who had received letters to explore their views of the feedback and the policy in general., Results: There was no significant change in compliance with the policy following implementation of the feedback intervention (0% compliant vs 11.9%; p = 0.07). Several problems with the policy and the approval process were identified by researchers during auditing and by prescribers during interviews. Some problems identified made it difficult to accurately assess compliance and for doctors to comply with the policy., Conclusion: Our intervention did not result in improved compliance with the antibiotic policy but revealed practical problems with the policy and approval process that had not been identified prior to the trial. Greater support for the policy by senior doctors and the assignment of more clearly defined roles and responsibilities associated with antibiotic use and approval may result in improved compliance. Harnessing the full potential of technology would streamline the antimicrobial approval process and allow more efficient and reliable monitoring of antibiotic use and compliance. Many of the problems we identified are generic issues of importance to all organisations seeking to integrate antimicrobial stewardship into ePS.

The ideal cyclooxygenase-2-specific inhibitor (coxib) would demonstrate efficacy comparable or superior to the best non-steroidal anti-inflammatory drug (NSAID) and, in addition to being substantially less gastrotoxic than the safest conventional NSAID, would have limited or no cardiovascular or renal toxicity and be generally tolerated as well as placebo. The contribution of the pharmacokinetic properties of a coxib to achieving this goal has been overlooked to some degree for available coxibs. Maximizing synovial compartment exposure while minimizing systemic exposure may deliver tolerability benefits, particularly with respect to rates of hypertension and cardiovascular and thrombotic adverse effects.

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.

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.

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.

1. It is well known that an individual subject often responds preferentially to a particular nonsteroidal anti-inflammatory drug (NSAID) and clinical response to these drugs is characterised by considerable variability between individuals. Variability in response has often been attributed to the episodic nature of musculoskeletal disease. Few studies have studied intrasubject variability in response to these drugs using a multiple crossover design. A major difficulty has been the lack of objective, validated measures of inflammation sensitive to NSAIDs. The primary aim of the present study was to test the utility of urate-crystal induced inflammation as a tool to predict NSAID response in humans. 2. An inflammatory reaction was established in twenty-five healthy subjects with intradermal injection of urate crystals on four separate occasions separated by 1 week. Each subject was randomly assigned to receive either ibuprofen on two of these occasions (800 mg four times over 36 h) or matched placebo on the other two occasions using a double-blind, cross-over design. Decrease in the area under the wheal size-time curve was used to indicate anti-inflammatory response. 3. Peak inflammatory response was observed at about 32 h and had dissipated by 56 h post-urate injection. The logarithmic mean wheal area was significantly lower after ibuprofen (mean +/- s.e. mean; 6.74 +/- 0.09) compared with placebo (6.96 +/- 0.07 mm h); a difference of 20% (95% confidence interval for difference: 1 to 35%; P < 0.05). 4. There was marked intra- and intersubject variability in response to ibuprofen over the four treatment periods.(ABSTRACT TRUNCATED AT 250 WORDS)

1. A sensitive, stereospecific assay using gas chromatography-mass spectrometry (GC/MS) was established to measure the concentrations of the enantiomers of ibuprofen in small volumes (50 microliters) of blister fluid. 2. The concentrations of the enantiomers in blister fluid, assessed in eight patients, were similar to those in synovial fluid, both fluids behaving as peripheral compartments with respect to plasma. 3. The mean rate constants of transfer of R-ibuprofen into (0.14 +/- 0.06 h-1) and out of (0.20 +/- 0.04 h-1) blister fluid were not significantly different from those for synovial fluid (0.19 +/- 0.12 h-1, 0.34 +/- 0.11 h-1, respectively). Similarly, the mean rate constants of transfer of S-ibuprofen into (0.22 +/- 0.07 h-1) and out of (0.27 +/- 0.08 h-1) blister fluid were not significantly different from those for synovial fluid (0.29 +/- 0.10, 0.36 +/- 0.11 h-1). However, the correlations were poor between the transfer constants for each of the enantiomers between plasma, and both blister and synovial fluid (P > 0.2). 4. The complex rate constant of transfer of S-ibuprofen into blister fluid (0.22 +/- 0.07 h-1) was greater than that of R-ibuprofen (0.14 +/- 0.07 h-1), which may be explained by the lesser protein binding of the S-enantiomer.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of pretreatment with cimetidine (1 g day-1, 7 days) and of probenecid (1 g twice daily, 4 days) on the pharmacokinetics of tenoxicam (single oral dose, 20 mg) was studied in six healthy volunteers. Cmax was increased significantly when tenoxicam was given with probenecid (2.8 micrograms ml-1 alone, 3.5 micrograms ml-1 after probenecid; P < 0.005). No other pharmacokinetic parameters were altered significantly by either drug. It is concluded that neither cimetidine nor probenecid affects the pharmacokinetics of tenoxicam in a clinically important way.

1. The aim of this study was to establish a simple and reliable experimental pain model that could distinguish the analgesic effects of non-steroidal anti-inflammatory drug (NSAID) treatment from placebo in human volunteers. 2. The reproducibility and reliability over time of subject pain ratings was compared using cutaneous electrical stimuli applied to either the thenar eminence or the ear lobe at varying intensities and modes. Subjects were asked to respond firstly, when the stimulus became clearly sharp and painful ('first pain') and secondly, when the sensation became deep and burning and no further increase in stimulus intensity could be tolerated ('second pain'). 3. Constant voltage stimuli were found to be more reproducible than constant current stimuli. Both phasic (intermittent) and tonic (continuous) stimulation modalities produced 'first' and 'second pain' sensations. The latter sensation was more reproducible, and was perceived as a burning pain which is akin to clinical pain. 4. Analgesics from the NSAID class were found to attenuate reliably only 'second pain' sensations. The analgesic effects of ibuprofen (ibuprofen vs placebo: 0.12 +/- 0.09 vs 0.02 +/- 0.07 volt h(-1), P = 0.03; 95% confidence interval for differences (CI): 0.03-0.18) and diflunisal (diflunisal vs placebo: 0.29 +/- 0.40 vs 0.005 +/- 0.27 volt h(-1), P = 0.0001; CI: 0.168-0.407), respectively, could be distinguished from placebo.

In eight patients with rheumatoid arthritis receiving racemic hydroxychloroquine, blood and urine concentrations of the enantiomers of hydroxychloroquine and its major metabolites were measured each month over the first 6 months of therapy. Plasma concentrations of hydroxychloroquine enantiomers were measured in five of these patients. In all patients, the blood concentration of (R)-hydroxychloroquine exceeded that of the (S)-enantiomer, the mean (R)/(S) ratio being 2.2 (range 1.6-2.9). A similar excess of (R)-hydroxychloroquine was found in the plasma, the mean (R)/(S) ratio being 1.6 (range 1.2-1.9). The mean enantiomer blood concentration ratio (R)/(S) for the metabolite desethylhydroxychloroquine was 0.45 (range 0.34-0.58) and for desethylchloroquine it was 0.56 (range 0.35-0.86) suggesting stereoselective metabolism of hydroxychloroquine. (S)-hydroxychloroquine had a mean (+/- s.d.) renal clearance from blood of 41 +/- 11 ml min-1, approximately twice that of (R)-hydroxychloroquine. The predicted unbound renal clearance was also higher for (S)-hydroxychloroquine. The clinical implications of enantioselective disposition of hydroxychloroquine are currently not known.

The urinary 1-methyluric acid (1MU) to 1-methylxanthine (1MX) ratio has been assessed as a biochemical index of oxipurinol effect in vivo in man. Dosing with theophylline was used to produce 1MX as an intermediate metabolite in six healthy volunteers. A sigmoid Emax model was fitted to the data and gave a mean plasma oxipurinol IC50 of 3.0 +/- 1.1 mg l-1, a mean exponent n of 3.4 +/- 2.1 and a mean IC90 of 8.5 +/- 5.9 mg l-1. There was marked interindividual variability in the steepness of the plasma oxipurinol concentration response relationship, and in the plasma oxipurinol IC90 values. The study has confirmed the feasibility of using single doses of allopurinol to construct individual plasma oxipurinol concentration-response curves.

1. The plasma pharmacokinetics of D-penicillamine (D-pen) and D-penicillamine-albumin disulphide (D-pen-alb) were examined over a dosage interval in six patients with rheumatoid arthritis. In two of these, 24 h synovial fluid profiles of D-pen and D-pen-alb were also obtained. 2. D-pen was undetectable in plasma at the beginning of the study. The peak concentration (5.4 +/- 1.2 microM) occurred at between 45 min and 2 h and the mean elimination half-life was 0.6 h. D-pen-alb, however, was present at a mean plasma concentration of 19.1 microM prior to dosage, peaked at 26.2 microM and was eliminated with a half-life of 40 h. 3. D-pen concentrations in synovial fluid rose more slowly and peaked lower than in plasma. D-pen-alb was present in synovial fluid of the patients at 50.1% and 83.6%, respectively, of the simultaneous plasma concentration prior to dosage. Concentrations varied during the study interval, corresponding to changes in plasma concentrations. 4. These results demonstrate that D-pen forms stable conjugates with protein in treated patients. The presence of D-pen-alb in relatively high concentrations throughout the dosage interval contrasts with the low concentrations and rapid elimination of D-pen. Both D-pen and D-pen-alb were also shown to be present at the putative site of drug action (the inflamed synovial joint) in concentrations lower than those in plasma.

1. Ototoxicity is a common and troublesome side-effect of high-dose aspirin treatment but there has been little previous study of the relationships between the degree of ototoxicity and the plasma concentrations of salicylate. 2. In order to investigate the relationships between aspirin dose, total and unbound plasma salicylate concentrations and ototoxicity, eight normal volunteers were dosed with aspirin 1.95, 3.25, 4.55 and 5.85 g day-1 for 1 week at each dose level, the doses being administered in random order and double-blind, 2 weeks apart. 3. Ototoxic effects measured were hearing loss in decibels (dB) over six frequencies and tinnitus intensity, estimated both by electronic matching and a fixed interval scale (FIS). Measurements were taken after steady-state concentrations of salicylate had been achieved. 4. Total and unbound plasma salicylate concentrations increased disproportionately with increasing daily doses of aspirin. The increase in the unbound salicylate was relatively greater since the percentage of salicylate unbound in plasma increased over the dose range investigated from a mean of 3.9% to 10.4%. 5. Hearing loss and tinnitus intensity increased progressively with the aspirin dosage and increasing concentrations of total and unbound plasma salicylate concentrations. These ototoxic symptoms were observed at lower concentrations of total salicylate than previously reported. 6. There was a linear relationship between hearing loss and unbound salicylate concentrations. 7. Further work is required to test the hypothesis that unbound plasma salicylate concentration is a better predictor of salicylate-induced ototoxicity than total plasma salicylate concentration.

1. Allopurinol usage in 50 patients of a city teaching hospital was surveyed. 2. The plasma concentrations of oxipurinol and uric acid and the urinary production of uric acid were examined. 3. The daily doses of allopurinol ranged from 50 to 1200 mg but 83% of patients were taking 300 mg daily. 4. A wide range of plasma oxipurinol concentrations was observed from 2.8 to 55.8 mg l-1 with a mean +/- s.d. of 15.2 +/- 11.7 mg l-1. 5. The population studied included a high proportion of patients with renal impairment and creatinine clearance was a significant determinant of oxipurinol concentrations (P less than 0.005). 6. There was no significant correlation between plasma urate and plasma oxipurinol concentrations and only a few plasma urates were above the upper limit of the reference range of the laboratory. 7. It was apparent that many patients were taking unnecessarily high daily doses of allopurinol and that renal status was not always considered when deciding dosage regimens of allopurinol.