Current fluconazole treatment regimens result in under-dosing of critically ill adults during early therapy.

PURPOSE: To evaluate current fluconazole treatment regimens in critically ill adults over the typical treatment course. METHODS: Data from critically ill adults treated with fluconazole (n=30) were used to develop a population pharmacokinetic model. Probability of target attainment (PTA) (fAUC24/MIC >100) was determined from simulations for four previously proposed treatment regimens: (i) 400 mg once daily, (ii) an 800 mg loading dose followed by 400 mg once daily, (iii) 400 mg twice daily, and (iv) a 12 mg/kg loading dose followed by 6 mg/kg once daily. The effect of body weight (40, 70, 120 kg) and renal function (continuous renal replacement therapy (CRRT); 20, 60, 120, 180 mL/min creatinine clearance) on PTA was assessed. RESULTS: Early (0-48 h) fluconazole target attainment for infections with a minimum inhibitory concentration (MIC) of 2 mg/L was highly variable. PTA was highest with an 800 mg loading dose for underweight (40 kg) patients and with a 12 mg/kg loading dose for the remainder. End-of-treatment PTA was highest with the 400 mg twice daily maintenance dosing for patients who were under- or normal weight and 6 mg/kg maintenance dosing for overweight (120 kg) patients. None of the fluconazole regimens reliably attained early targets for MICs of ≥4 mg/L. CONCLUSION: Current fluconazole dosing regimens do not achieve adequate early target attainment in critically ill adults, particularly in those who are overweight, have higher creatinine clearance, or are undergoing CRRT. Current fluconazole dosing strategies are generally inadequate to treat organisms with an MIC of ≥4 mg/L.

A profile of health status and demographics of aged care facility residents with gout.

OBJECTIVE: To estimate gout prevalence and examine associated factors in residential aged care facilities. METHODS: Electronic data from 11 548 residents aged 65+ during 2014-2017 from 68 residential aged care facilities in Australia were analysed. Gout prevalence was estimated, and regression was used to assess differences in comorbidities, sociodemographic factors and health status between residents with and without gout. RESULTS: Over 10% of residents had gout. Most common comorbidities in these residents were hypertension (71.3%), heart disease (37.9%) and diabetes (33.0%) and they were more likely to have renal disease and historical myocardial infarction. The interaction between comorbid gout had complex interactions between age, sex and comorbidities for diabetes and depression was complex. CONCLUSIONS: Gout is common among older people in residential care but may be under-recognised. Holistic management of gout is needed in this population, with careful consideration of chronic comorbidities and treatments.

Understanding the dose-response relationship of allopurinol: predicting the optimal dosage.

AIMS: The aim of the study was to identify and quantify factors that control the plasma concentrations of urate during allopurinol treatment and to predict optimal doses of allopurinol. METHODS: Plasma concentrations of urate and creatinine (112 samples, 46 patients) before and during treatment with various doses of allopurinol (50-600 mg daily) were monitored. Non-linear and multiple linear regression equations were used to examine the relationships between allopurinol dose (D), creatinine clearance (CLcr) and plasma concentrations of urate before (UP) and during treatment with allopurinol (UT). RESULTS: Plasma concentrations of urate achieved during allopurinol therapy were dependent on the daily dose of allopurinol and the plasma concentration of urate pre-treatment. The non-linear equation: UT = (1 - D/(ID50 + D)) × (UP - UR) + UR , fitted the data well (r(2) = 0.74, P < 0.0001). The parameters and their best fit values were: daily dose of allopurinol reducing the inhibitable plasma urate by 50% (ID50 = 226 mg, 95% CI 167, 303 mg), apparent resistant plasma urate (UR = 0.20 mmol l(-1), 95 % CI 0.14, 0.25 mmol l(-1)). Incorporation of CLcr did not significantly improve the fit (P = 0.09). CONCLUSIONS: A high baseline plasma urate concentration requires a high dose of allopurinol to reduce plasma urate below recommended concentrations. This dose is dependent on only the pre-treatment plasma urate concentration and is not influenced by CLcr .

Saving money on the PBS: ranibizumab or bevacizumab for neovascular macular degeneration?

The cost differential between these two drugs is no longer defensible.

"It looks after me": how older patients make decisions about analgesics for osteoarthritis.

OBJECTIVE: To explore the key motivators behind selection of analgesics (nonsteroidal antiinflammatory drugs [NSAIDs], acetaminophen, and complementary medications [CMs]) by patients with osteoarthritis (OA). METHODS: We performed a qualitative study in which in-depth semistructured interviews were conducted with 15 OA patients recruited from 4 general practices in Sydney, Australia. Patients were ages ≥65 years, and were currently taking or had recently taken an NSAID for OA. RESULTS: Three key themes emerged from the data: reliance, routine, and pill load. Patients were strongly reliant upon NSAIDs because they consistently satisfied their needs. By contrast, they were much less reliant upon acetaminophen because of uncertainty or skepticism about its effectiveness. They were not reliant upon CMs but were willing to take them indefinitely because they were perceived as being without risk. Many patients took an NSAID as well as CMs as part of a "daily routine." By contrast, patients had difficulty developing a routine around using acetaminophen at the recommended maximum dose because of the implicit frequency of dosing required and an aversion to the associated "pill load." CONCLUSION: The results highlight the importance of exploring the perceptions and preferences of patients with regard to analgesics for OA. Clinician advice regarding analgesia for OA should take account of the possible reliance of the patient upon an NSAID, their medicine routines, and their potential concern about the pill load associated, in particular, with acetaminophen.

Pharmacokinetic and pharmacodynamic interactions of echinacea and policosanol with warfarin in healthy subjects.

AIMS: This study investigated the pharmacokinetic and pharmacodynamic interactions of echinacea and policosanol with warfarin in healthy subjects. METHODS: This was an open-label, randomized, three-treatment, cross-over, clinical trial in healthy male subjects (n= 12) of known CYP2C9 and VKORC1 genotype who received a single oral dose of warfarin alone or after 2 weeks of pre-treatment with each herbal medicine at recommended doses. Pharmacodynamic (INR, platelet activity) and pharmacokinetic (warfarin enantiomer concentrations) end points were evaluated. RESULTS: The apparent clearance of (S)-warfarin (90% CI of ratio; 1.01, 1.18) was significantly higher during concomitant treatment with echinacea but this did not lead to a clinically significant change in INR (90% CI of AUC of INR; 0.91, 1.31). Policosanol did not significantly affect warfarin enantiomer pharmacokinetics or warfarin response. Neither echinacea nor policosanol had a significant effect on platelet aggregation after 2 weeks of pre-treatment with the respective herbal medicines. CONCLUSION: Echinacea significantly reduced plasma concentrations of S-warfarin. However, neither echinacea nor policosanol significantly affected warfarin pharmacodynamics, platelet aggregation or baseline clotting status in healthy subjects.

A double-blind, placebo-controlled study of the short term effects of a spring water supplemented with magnesium bicarbonate on acid/base balance, bone metabolism and cardiovascular risk factors in postmenopausal women.

BACKGROUND: A number of health benefits including improvements in acid/base balance, bone metabolism, and cardiovascular risk factors have been attributed to the intake of magnesium rich alkaline mineral water. This study was designed to investigate the effects of the regular consumption of magnesium bicarbonate supplemented spring water on pH, biochemical parameters of bone metabolism, lipid profile and blood pressure in postmenopausal women. FINDINGS: In this double-blind, placebo-controlled, parallel-group, study, 67 postmenopausal women were randomised to receive between 1500 mL and 1800 mL daily of magnesium bicarbonate supplemented spring water (650 mg/L bicarbonate, 120 mg/L magnesium, pH 8.3-8.5) (supplemented water group) or spring water without supplements (control water group) over 84 days. Over this period biomarkers of bone turnover (serum parathyroid hormone (PTH), 1,25-dihydroxyvitamin D, osteocalcin, urinary telopeptides and hydroxyproline), serum lipids (total cholesterol, HDL-cholesterol, LDL-cholesterol and triglycerides), venous and urinary pH were measured together with measurements of standard biochemistry, haematology and urine examinations.Serum magnesium concentrations and urinary pH in subjects consuming the magnesium bicarbonate supplemented water increased significantly at Day 84 compared to subjects consuming the spring water control (magnesium - p = 0.03; pH - p = 0.018). The consumption of spring water led to a trend for an increase in parathyroid hormone (PTH) concentrations while the PTH concentrations remained stable with the intake of the supplemented spring water. However there were no significant effects of magnesium bicarbonate supplementation in changes to biomarkers of bone mineral metabolism (n-telopeptides, hydroxyproline, osteocalcin and 1,25-dihydroxyvitamin D) or serum lipids or blood pressure in postmenopausal women from Day 0 to Day 84. CONCLUSIONS: Short term regular ingestion of magnesium bicarbonate supplemented water provides a source of orally available magnesium. Long term clinical studies are required to investigate any health benefits. TRIAL REGISTRATION: ACTRN12609000863235.

A benefit-risk assessment of benzbromarone in the treatment of gout. Was its withdrawal from the market in the best interest of patients?

Benzbromarone, a potent uricosuric drug, was introduced in the 1970s and was viewed as having few associated serious adverse reactions. It was registered in about 20 countries throughout Asia, South America and Europe. In 2003, the drug was withdrawn by Sanofi-Synthélabo, after reports of serious hepatotoxicity, although it is still marketed in several countries by other drug companies. The withdrawal has greatly limited its availability around the world, and increased difficulty in accessing it in other countries where it has never been available.The overall aim of this paper is to determine if the withdrawal of benzbromarone was in the best interests of gouty patients and to present a benefit-risk assessment of benzbromarone. To determine this, we examined (i) the clinical benefits associated with benzbromarone treatment and compared them with the success of alternative therapies such as allopurinol and probenecid, particularly in patients with renal impairment; (ii) the attribution of the reported cases of hepatotoxicity to treatment with benzbromarone; (iii) the incidence of hepatotoxicity possibly due to benzbromarone; (iv) adverse reactions to allopurinol and probenecid. From these analyses, we present recommendations on the use of benzbromarone.Large reductions in plasma urate concentrations in patients with hyperuricaemia are achieved with benzbromarone and most patients normalize their plasma urate. The half-life of benzbromarone is generally short (about 3 hours); however, a uricosuric metabolite, 6-hydroxybenzbromarone, has a much longer half-life (up to 30 hours) and is the major species responsible for the uricosuric activity of benzbromarone, although its metabolism by cytochrome P450 (CYP) 2C9 in the liver may vary between patients as a result of polymorphisms in this enzyme. It is effective in patients with moderate renal impairment. Standard dosages of benzbromarone (100 mg/day) tend to produce greater hypouricaemic effects than standard doses of allopourinol (300 mg/day) or probenecid (1000 mg/day).Adverse effects associated with benzbromarone are relatively infrequent, but potentially severe. Four cases of benzbromarone-induced hepatotoxicity were identified from the literature. Eleven cases have been reported by Sanofi-Synthélabo, but details are not available in the public domain. Only one of the four published cases demonstrated a clear relationship between the drug and liver injury as demonstrated by rechallenge. The other three cases lacked incontrovertible evidence to support a diagnosis of benzbromarone-induced hepatotoxicity. If all the reported cases are assumed to be due to benzbromarone, the estimated risk of hepatotoxicity in Europe was approximately 1 in 17 000 patients but may be higher in Japan.Benzbromarone is also an inhibitor of CYP2C9 and so may be involved in drug interactions with drugs dependent on this enzyme for clearance, such as warfarin. Alternative drugs to benzbromarone have significant adverse reactions. Allopurinol is associated with rare life-threatening hypersensitivity syndromes; the risk of these reactions is approximately 1 in 56 000. Rash occurs in approximately 2% of patients taking allopurinol and usually leads to cessation of prescription of the drug. Probenecid has also been associated with life-threatening reactions in a very small number of case reports, but it frequently interacts with many renally excreted drugs. Febuxostat is a new xanthine oxidoreductase inhibitor, which is still in clinical trials, but abnormal liver function is the most commonly reported adverse reaction.Even assuming a causal relationship between benzbromarone and hepatotoxicity in the identified cases, benefit-risk assessment based on total exposure to the drug does not support the decision by the drug company to withdraw benzbromarone from the market given the paucity of alternative options. It is likely that the risks of hepatotoxicity could be ameliorated by employing a graded dosage increase, together with regular monitoring of liver function. Determination of CYP2C9 status and consideration of potential interactions through inhibition of this enzyme should be considered. The case for wider and easier availability of benzbromarone for treating selected cases of gout is compelling, particularly for patients in whom allopurinol produces insufficient response or toxicity.We conclude that the withdrawal of benzbromarone was not in the best interest of patients with gout.

Non-steroidal anti-inflammatory drugs in general practice: a decision-making dilemma.

OBJECTIVES: To examine the effect of the debate on the safety of non-steroidal anti-inflammatory drugs (NSAIDs) on decision making by Australian general practitioners and patients with osteoarthritis (OA), and to explore issues concerning the use of NSAIDs from both prescriber and consumer perspectives. DESIGN AND SETTING: A qualitative study in which five focus groups (three for GPs, and two for patients with OA) were conducted between 15 May and 4 August 2006 in south-western Sydney. PARTICIPANTS: Five advanced general practice registrars, six experienced GPs, and 20 patients with OA aged 54-85 years. MAIN OUTCOME MEASURES: Key themes and issues identified by content analysis of focus group transcripts. RESULTS: GPs reported adopting a cautious approach to prescribing NSAIDs because of uncertainty about safety and medicolegal concerns. They were sceptical about information provided by the pharmaceutical industry and found the literature about the safety of NSAIDs confusing. Time was identified as a major barrier to adequate discussion with patients, and explaining the risk to patients in a meaningful way was perceived as a challenge. Patients wanted information and sought it from a range of sources, most commonly pharmacists and GPs. Most patients made active decisions about using or not using NSAIDs, with some favouring physical function over safety. Patients were also using other forms of treatment including alternative medicine. CONCLUSION: Our findings reflect the need to provide clear, unbiased information about NSAIDs to help both GPs and patients negotiate this decision-making dilemma.

Accessing health outcome data on high-cost medicines in Australia.

Data on health outcomes resulting from the use of medicines provide important evidence of cost-effectiveness. Currently, clinical information on individual patients, collected by Medicare Australia to assess eligibility for subsidised treatment with high-cost medicines, is inaccessible for research. Comprehensive data on drug use and health outcomes should be made accessible, with appropriate regulation, so that the effectiveness, utility and appropriateness of our systems of access to medicines can be independently analysed. In the interests of continuous improvement in medical care and optimal use of limited resources, we strongly advocate the enhancement of Medicare Australia databases and liberalisation of arrangements for access to administrative and clinical data.

Effect of ginkgo and ginger on the pharmacokinetics and pharmacodynamics of warfarin in healthy subjects.

AIM: The aim of this study was to investigate the effect of two common herbal medicines, ginkgo and ginger, on the pharmacokinetics and pharmacodynamics of warfarin and the independent effect of these herbs on clotting status. METHODS: This was an open label, three-way crossover randomized study in 12 healthy male subjects, who received a single 25 mg dose of warfarin alone or after 7 days pretreatment with recommended doses of ginkgo or ginger from herbal medicine products of known quality. Dosing with ginkgo or ginger was continued for 7 days after administration of the warfarin dose. Platelet aggregation, international normalized ratio (INR) of prothrombin time, warfarin enantiomer protein binding, warfarin enantiomer concentrations in plasma and S-7-hydroxywarfarin concentration in urine were measured. Statistical comparisons were made using anova and the 90% confidence intervals (CIs) of the ratio of log transformed parameters are reported. RESULTS: INR and platelet aggregation were not affected by administration of ginkgo or ginger alone. The mean (95% CI) apparent clearances of S-warfarin after warfarin alone, with ginkgo or ginger were 189 (167-210) ml h(-1), 200 (173-227) ml h(-1) and 201 (171-231) ml h(-1), respectively. The respective apparent clearances of R-warfarin were 127 (106-149) ml h(-1), 126 (111-141) ml h(-1) and 131 (106-156) ml h(-1). The mean ratio (90% CI) of apparent clearance for S-warfarin was 1.05 (0.98-1.21) and for R-warfarin was 1.00 (0.93-1.08) when coadministered with ginkgo. The mean ratio (90% CI) of AUC(0-168) of INR was 0.93 (0.81-1.05) when coadministered with ginkgo. The mean ratio (90% CI) of apparent clearance for S-warfarin was 1.05 (0.97-1.13) and for R-warfarin was 1.02 (0.95-1.10) when coadministered with ginger. The mean ratio (90% CI) of AUC(0-168) of INR was 1.01 (0.93-1.15) when coadministered with ginger. The mean ratio (90% CI) for S-7-hydroxywarfarin urinary excretion rate was 1.07 (0.85-1.32) for ginkgo treatment, and 1.00 (0.81-1.23) for ginger coadministration suggesting these herbs did not affect CYP2C9 activity. Ginkgo and ginger did not affect the apparent volumes of distribution or protein binding of either S-warfarin or R-warfarin. CONCLUSIONS: Ginkgo and ginger at recommended doses do not significantly affect clotting status, the pharmacokinetics or pharmacodynamics of warfarin in healthy subjects.

Effect of St John's wort and ginseng on the pharmacokinetics and pharmacodynamics of warfarin in healthy subjects.

UNLABELLED: M: The aim of this study was to investigate the effect of St John's wort and ginseng on the pharmacokinetics and pharmacodynamics of warfarin. METHODS: This was an open-label, three-way crossover randomized study in 12 healthy male subjects, who received a single 25-mg dose of warfarin alone or after 14 days' pretreatment with St John's wort, or 7 days' pretreatment with ginseng. Dosing with St John's wort or ginseng was continued for 7 days after administration of the warfarin dose. Platelet aggregation, international normalized ratio (INR) of prothrombin time, warfarin enantiomer protein binding, warfarin enantiomer concentrations in plasma and S-7-hydroxywarfarin concentration in urine were measured. Statistical comparisons were made using anova and 90% confidence intervals are reported. RESULTS: INR and platelet aggregation were not affected by treatment with St John's wort or ginseng. The apparent clearances of S-warfarin after warfarin alone or with St John's wort or ginseng were, respectively, 198 +/- 38 ml h(-1), 270 +/- 44 ml h(-1) and 220 +/- 29 ml h(-1). The respective apparent clearances of R-warfarin were 110 +/- 25 ml h(-1), 142 +/- 29 ml h(-1) and 119 +/- 20 ml h(-1) [corrected]. The mean ratio and 90% confidence interval (CI) of apparent clearance for S-warfarin was 1.29 (1.16, 1.46) and for R-warfarin it was 1.23 (1.11, 1.37) when St John's wort was coadministered. The mean ratio and 90% CI of AUC(0-168) of INR was 0.79 (0.70, 0.95) when St John's wort was coadministered. St John's wort and ginseng did not affect the apparent volumes of distribution or protein binding of warfarin enantiomers. CONCLUSIONS: St John's wort significantly induced the apparent clearance of both S-warfarin and R-warfarin, which in turn resulted in a significant reduction in the pharmacological effect of rac-warfarin. Coadministration of warfarin with ginseng did not affect the pharmacokinetics or pharmacodynamics of either S-warfarin or R-warfarin.