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Given their frontline role in Australia and Aotearoa New Zealand (ANZ) healthcare, trainee medical officers (TMOs) will play a crucial role in the development and use of artificial intelligence (AI) for clinical care, ongoing medical education and research. As 'digital natives', particularly those with technical expertise in AI, TMOs should also be leaders in informing the safe uptake and governance of AI within ANZ healthcare as they have a practical understanding of its associated risks and benefits. However, this is only possible if a culture of broad collaboration is instilled while the use of AI in ANZ is still in its initial phase., (© 2024 The Author(s). Internal Medicine Journal published by John Wiley & Sons Australia, Ltd on behalf of Royal Australasian College of Physicians.)

Background: Familial hypercholesterolaemia (FH) is under-diagnosed and under-treated worldwide, including Australia. National registries play a key role in identifying patients with FH, understanding gaps in care and advancing the science of FH to improve care for these patients., Methods: The FH Australasia Network has established a national web-based registry to raise awareness of the condition, facilitate service planning and inform best practice and care services in Australia. We conducted a cross-sectional analysis of 1,528 FH adults enrolled in the registry from 28 lipid clinics., Results: The mean age at enrolment was 53.4±15.1 years, 50.5% were male and 54.3% had undergone FH genetic testing, of which 61.8% had a pathogenic FH-causing gene variant. Only 14.0% of the cohort were family members identified through cascade testing. Coronary artery disease (CAD) was reported in 28.0% of patients (age of onset 49.0±10.5 years) and 64.9% had at least one modifiable cardiovascular risk factor. The mean untreated LDL-cholesterol was 7.4±2.5 mmol/L. 80.8% of patients were on lipid-lowering therapy with a mean treated LDL-cholesterol of 3.3±1.7 mmol/L. Among patients receiving lipid-lowering therapies, 25.6% achieved an LDL-cholesterol target of <2.5 mmol/L without CAD or <1.8 mmol/L with CAD., Conclusion: Patients in the national FH registry are detected later in life, have a high burden of CAD and risk factors, and do not achieve guideline-recommended LDL-cholesterol targets. Genetic and cascade testing are under-utilised. These deficiencies in care need to be addressed as a public health priority., (Copyright © 2020 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). All rights reserved.)

Background and Aims: Familial hypercholesterolaemia (FH) is characterised by a high, but variable risk of premature coronary artery disease (CAD). Cardiac computed tomography angiography (CCTA) can be employed to assess subclinical coronary atherosclerosis. We investigated the features and distribution of coronary artery plaques in asymptomatic patients with and without genetically confirmed heterozygous FH., Methods: We undertook an aged-matched case-control study of asymptomatic phenotypic FH patients with (cases, M+) and without (controls, M-) an FH-causing mutation. Coronary atherosclerosis was assessed by CCTA and calcium scoring. Coronary segments were evaluated for global and vessel-level coronary plaques and degree of stenosis., Results: We studied 104 cases and 104 controls (mean age 49.9 ± 10.4 years), who had a similar spectrum of non-cardiovascular risk factors. Pre-treatment plasma LDL-cholesterol was higher in the M+ than M- group (7.8 ± 2.1 vs 6.2 ± 1.2 mmol/L, p<0.001). There was a greater proportion of patients with mixed and calcified plaque, as well as a higher coronary artery calcium score and segment stenosis score (all p<0.05), in the M+ compared with the M- group. M+ patients also had a significantly higher frequency of coronary artery calcium in the left main and anterior descending and right coronary arteries (all p<0.05), but not in the left circumflex., Conclusions: Among patients with phenotypic FH, those with a genetically confirmed diagnosis had a higher frequency and severity of coronary atherosclerotic plaques, and specifically more advanced calcified plaques., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: GFW has received honoraria for advisory boards and research grants from Amgen, Sanofi and Regeneron. The other authors have nothing to disclose., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Embolic stroke of undetermined source (ESUS) is not uncommon in young patients. Here, we describe two cases of stroke from an unusual aetiology; cerebral embolization from carotid artery injury presumed secondary to hyoid bone impingement. Both patients demonstrated angiographic evidence of hyoid bone impingement. Following resection of the greater cornu of the hyoid bone, neither patient had further strokes., (Copyright © 2019. Published by Elsevier Ltd.)

Aim: The aim of this study was to evaluate the clinical outcome of parent-child testing for familial hypercholesterolaemia (FH) employing genetic testing and the likely additional cost of treating each child., Methods: Parent-child testing for gene variants causative of FH was carried out according to Australian guidelines. The number of new cases detected, the low-density lipoprotein (LDL)-cholesterol that best predicted a mutation and the proportional reduction in LDL-cholesterol following statin treatment was evaluated. Treatment costs were calculated as the cost per mmol/L reduction in LDL-cholesterol., Results: A total of 126 adult patients, known to have a pathogenic mutation causative of FH, and their children were studied. From 244 children identified, 148 (60.7%) were genetically screened; 84 children were identified as mutative positive (M+) and 64 as mutative negative. Six of the M+ children were already on statin treatment; 40 were subsequently treated with low-dose statins, with LDL-cholesterol falling significantly by 38% (P < 0.001). The estimated cost per mmol/L reduction of LDL-cholesterol of a child receiving statins from ages 10 to 18 years is AU$1361, which can potentially be cost-effective. An LDL-cholesterol threshold of 3.5 mmol/L had a sensitivity of 92.8% and specificity of 96.6% for the detection of a mutation., Conclusion: Genetic testing of children of affected parents with FH is an effective means of detecting new cases of FH. Cascade testing can enable early statin therapy with significant reductions in LDL-cholesterol concentration., (© 2018 Paediatrics and Child Health Division (The Royal Australasian College of Physicians).)

Context: The gold standard for diagnosing familial hypercholesterolemia (FH) is identification of a causative pathogenic mutation. However, genetic testing is expensive and not widely available., Objective: To compare the validity of the Dutch Lipid Clinic Network (DLCN), Simon Broome (SB), Make Early Diagnosis to Prevent Early Deaths (MEDPED), and American Heart Association (AHA) criteria in predicting an FH-causing mutation., Design, Setting, and Patients: An adult cohort of unrelated patients referred to a lipid clinic for genetic testing., Main Outcome Measures: Odds ratio (OR), area under the curve (AUC), sensitivity, and specificity., Results: A pathogenic FH-causing mutation was detected in 30% of 885 patients tested. Elevated low-density lipoprotein (LDL) cholesterol and personal or family history of tendon xanthomata were independent predictors of a mutation (OR range 5.3 to 16.1, P < 0.001). Prediction of a mutation for the DLCN and SB definite and MEDPED criteria (ORs 9.4, 11.7, and 10.5, respectively) was higher than with the AHA criteria (OR 4.67). The balance of sensitivity and specificity was in decreasing order DLCN definite (Youden Index 0.487), MEDPED (0.457), SB definite (0.274), and AHA criteria (0.253), AUC being significantly higher with DLCN definite and MEDPED than other criteria (P < 0.05). Pretreatment LDL cholesterol and tendon xanthomata had the highest AUC in predicting a mutation., Conclusions: The DLCN, SB, and MEDPED criteria are valid predictors of an FH-causing mutation in patients referred to a lipid clinic, but concordance between these phenotypic criteria is only moderate. Use of pretreatment LDL cholesterol and tendon xanthomata alone may be particularly useful for deciding who should be genetically tested for FH.

Herpes simplex encephalitis is the most common sporadic viral encephalitis in the western world, HSV-1 (herpes simplex virus) being the mostly commonly implicated serotype. The disease is usually monophasic, although patients may relapse weeks, months or years after initial infection. This chronic granulomatous inflammatory process is almost exclusively described in children and rarely forms discrete enhancing parenchymal nodules. We present the clinical and radiological features of an unusual case of chronic nodular granulomatous herpes encephalitis with enhancing "mass-like" nodules in an adult. To the author's knowledge, this is the first reported case of macroscopic "mass-like" nodular granuloma formation in an adult.

Background and Purpose: Uncertainty exists over whether quality improvement strategies translate into better health-related quality of life (HRQoL) and survival after acute stroke. We aimed to determine the association of best practice recommended interventions and outcomes after stroke., Methods: Data are from the Australian Stroke Clinical Registry during 2010 to 2014. Multivariable regression was used to determine associations between 3 interventions: received acute stroke unit (ASU) care and in various combinations with prescribed antihypertensive medication at discharge, provision of a discharge care plan, and outcomes of survival and HRQoL (EuroQoL 5-dimensional questionnaire visual analogue scale) at 180 days, by stroke type. An assessment was also made of outcomes related to the number of processes patients received., Results: There were 17 585 stroke admissions (median age 77 years, 47% female; 81% managed in ASUs; 80% ischemic stroke) from 42 hospitals (77% metropolitan) assessed. Cumulative benefits on outcomes related to the number of care processes received by patients. ASU care was associated with a reduced likelihood of death (hazard ratio, 0.49; 95% confidence interval, 0.43-0.56) and better HRQoL (coefficient, 21.34; 95% confidence interval, 15.50-27.18) within 180 days. For those discharged from hospital, receiving ASU+antihypertensive medication provided greater 180-day survival (hazard ratio, 0.45; 95% confidence interval, 0.38-0.52) compared with ASU care alone (hazard ratio, 0.64; 95% confidence interval, 0.54-0.76). HRQoL gains were greatest for patients with intracerebral hemorrhage who received care bundles involving discharge processes (range of increase, 11%-19%)., Conclusions: Patients with stroke who receive best practice recommended hospital care have improved long-term survival and HRQoL., (© 2017 American Heart Association, Inc.)

Background: Familial hypercholesterolemia (FH) is characterized by elevated LDL-cholesterol and increased risk of premature coronary artery disease (CAD). Lipoprotein(a) [Lp(a)] increases CAD in FH, although the independence of this association relative to other CAD risk factors remains unclear. In this study, we examined the association between Lp(a) and other cardiovascular risk factors and prevalent CAD in patients with FH., Methods: A cross-sectional study of 390 patients with genetically confirmed FH were studied. Clinical and biochemical parameters of FH patients with and without CAD were compared., Results: FH patients with CAD were older and more often male and had a higher prevalence of hypertension, smoking, diabetes, obesity, reduced eGFR, and elevated plasma Lp(a) and pre-treatment LDL-cholesterol and triglyceride (or low HDL-cholesterol) than FH patients without CAD (P<0.05 for all). In univariate analyses, age, male gender, smoking, hypertension, reduced eGFR, diabetes, obesity, plasma creatinine, Lp(a) and pretreatment LDL-cholesterol, triglycerides and HDL-cholesterol levels were significant predictors of CAD in the FH patients (P<0.05 for all). Elevated LDL-cholesterol, raised Lp(a), hypertension and reduced eGFR remained significant independent predictors of CAD (P<0.05 for all) in FH after adjusting for other modifiable risk factors., Conclusions: Elevated Lp(a), hypertension and renal insufficiency are independent risk factors beyond elevated pretreatment LDL-cholesterol which predict CAD in patients with FH. In spite of the cross-sectional design of our study, we propose the need for identifying and managing these abnormalities to reduce excess CAD risk in FH patients. However, this proposal remains to be formally tested in a prospective study., (Copyright © 2015. Published by Elsevier Ireland Ltd.)

Background: Familial hypercholesterolemia (FH) is the most common dominantly inherited cause of premature coronary artery disease (CAD). However, the diagnosis of FH in patients who have premature CAD in hospital settings is under-recognized, this also represents a missed opportunity for screening their close family members and implementing primary prevention., Objective: To investigate the point prevalence of FH in a coronary care unit (CCU) among patients with early-onset CAD., Methods: The prevalence of FH, based on modified phenotypic Dutch Lipid Clinic Network Criteria, and the spectrum of associated CAD risk factors, were investigated in a CCU setting. Data were collected on 175 coronary care patients with onset of CAD at age <60 years., Results: The prevalence of probable/definite FH was 14.3% (95% confidence interval, 9.0%-19.5%); 46.3% of the patients gave a family history of premature CAD and 20.6% had an untreated low-density lipoprotein cholesterol >5.0 mmol/L. Diabetes, hypertension, obesity, and smoking were common and equally prevalent in patients with and without FH., Conclusions: FH is relatively frequent among patients with a history of early-onset CAD in the CCU. Every effort should be made to detect FH in these patients and to initiate cascade testing of available family members to prevent the development of CAD in those who may be unaware that they also have the condition., (Copyright © 2015 National Lipid Association. Published by Elsevier Inc. All rights reserved.)

Glycogenic hepatopathy (GH) is an under-recognised complication of type 1 diabetes mellitus (T1DM) not controlled to target resulting in hepatomegaly and elevated liver transaminases. We report the case of a 19-year-old man with T1DM not controlled to target who presented with abdominal pain, hepatomegaly and deranged liver transaminases. He was subsequently diagnosed with GH on liver biopsy, with the mainstay of treatment being reduction in caloric intake and insulin., (© 2015 Royal Australasian College of Physicians.)

Background: Familial hypercholesterolaemia (FH) is a co-dominantly inherited disorder of low-density lipoprotein (LDL) catabolism, causing elevated LDL-cholesterol and premature coronary artery disease (CAD). Several guidelines recommend genetic cascade screening relatives of probands (index cases) with genetically proven FH, but experience in a clinical service setting is limited., Methods: Relatives from 100 index cases with genetically confirmed FH underwent genetic and lipid testing via a centralised screening program in Western Australia. The program's effectiveness was evaluated as the number of newly diagnosed relatives with FH per index case and the proportional reduction in LDL-cholesterol after treatment., Results: Of 366 relatives tested for FH, 188 (51.4%) were found to have a pathogenic mutation. On average, 2 cases were detected per index case. Affected relatives were younger and less likely to have physical stigmata of FH and premature CAD than index cases (p < 0.001). Of the new cases, 12.8% had hypertension, 2.7% had diabetes and 16.0% were smokers; 48.4% were already on statin therapy and these were older (p < 0.001) and had more vascular risk factors and CAD (p < 0.01) than those not on therapy. Significant reductions in LDL-cholesterol (-24.3%, p < 0.001) were achieved overall, with previously untreated new cases of FH attaining a maximal average reduction of 42.5% in LDL-cholesterol after drug therapy. Over 90% of subjects were satisfied with screening and care., Conclusion: Genetic cascade screening co-ordinated by a centralised service is an effective and acceptable strategy for detecting FH in an Australian setting. A significant proportion of new cases exhibit other CAD risk factors and are already on statins, but have not received a prior diagnosis of FH., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Introduction: Cardiovascular disease (CVD) remains the leading cause of death in industrialized nations. Despite clear evidence of CVD risk reduction with HMG-CoA reductase inhibitors (statins), the side effects of these medications, particularly myopathy, limit their effectiveness. Studies into the mechanisms, aetiology and management of statin myopathy are limited by lack of an internationally agreed clinical definition and tools for assessing outcomes. Currently there is a paucity of evidence to guide the management of patients affected by statin myopathy; with the exception of dose reduction, there is little evidence that other strategies can improve statin tolerance, and even less evidence to suggest these alternate dosing strategies reduce cardiovascular risk., Areas Covered: This review will cover current definitions, clinical presentations, risk factors, pathogenesis and management. PubMed was searched (English language, to 2014) for key articles pertaining to statin myopathy. This review then briefly describes our experience of managing this condition in a tertiary lipid disorders clinic, in the setting of limited guiding evidence., Expert Opinion: Knowledge gaps in the field of statin myopathy are identified and future research directions are suggested. We urge the need for international attention to address this important, but largely neglected clinical problem, that if unresolved will remain an impediment to the effective prevention and treatment of CVD.

Aim: To determine general practitioners' (GPs') knowledge and practice regarding familial hypercholesterolaemia (FH) in Western Australia., Method: A structured questionnaire was anonymously completed by GPs. Information was sought on awareness and knowledge of FH including, diagnosis, inheritance, prevalence, cardiovascular risk, management practices and opinions on FH screening., Results: 191 GPs completed the survey, 62% were familiar with FH, 80% correctly defined FH and 68% identified the typical lipid profile, but only 33% were aware of national guidelines. There were knowledge deficits in prevalence, inheritance, and clinical features of FH, with correct responses in 27%, 45% and 38%, respectively. Most (84%) GPs considered themselves the most effective health professionals to detect FH, with 90% preferring laboratory interpretative commenting to highlight individuals at risk of FH. GPs identified appropriate cholesterol lowering drugs as mono (95%) or combination therapies (74%)., Conclusion: The majority of GPs considered they were the most effective health practitioners for managing FH and preferred laboratory reports to alert them of possible FH. Although GPs knowledge of cholesterol lowering therapies was good, their awareness of national guidelines, hereditability, prevalence and diagnostic features of FH was suboptimal. Implementing a community model of care for FH requires more extensive GP education., (Crown Copyright © 2013. Published by Elsevier B.V. All rights reserved.)

Background and Purpose: Minocycline, in animal models and 2 small randomized controlled human trials, is a promising neuroprotective agent in acute stroke. We analyzed the efficacy and safety of intravenous minocycline in acute ischemic and hemorrhagic stroke., Methods: A multicenter prospective randomized open-label blinded end point evaluation pilot study of minocycline 100 mg administered intravenously, commenced within 24 hours of onset of stroke, and continued 12 hourly for a total of 5 doses, versus no minocycline. All participants received routine stroke care. Primary end point was survival free of handicap (modified Rankin Scale, ≤2) at day 90., Results: Ninety-five participants were randomized; 47 to minocycline and 48 to no minocycline. In the intention-to-treat population, 29 of 47 (65.9%) allocated minocycline survived free of handicap compared with 33 of 48 (70.2%) allocated no minocycline (rate ratio, 0.94; 95% confidence interval, 0.71-1.25 and odds ratio, 0.73; 95% CI, 0.31-1.71). A meta-analysis of the 3 human trials suggests minocycline may increase the odds of handicap-free survival by 3-fold (odds ratio, 2.99; 95% CI, 1.74-5.16) but there was substantial heterogeneity among the trials., Conclusions: In this pilot study of a small sample of acute stroke patients, intravenous minocycline was safe but not efficacious. The study was not powered to identify reliably or exclude a modest but clinically important treatment effect of minocycline. Larger trials would improve the precision of the estimates of any treatment effect of minocycline., Clinical Trial Registration Url: http://www.anzctr.org.au. Unique identifier: ACTRN12612000237886.

Haemorrhagic transformation (HT) of recently ischaemic brain is a feared complication of thrombolytic therapy that may be caused or compounded by ischaemia-induced activation of matrix metalloproteinases (MMPs). The tetracycline antibiotic minocycline inhibits matrix MMPs and reduces macroscopic HT in rodents with stroke treated with tissue plasminogen activator (tPA). The West Australian Intravenous Minocycline and TPA Stroke Study (WAIMATSS) aims to determine the safety and efficacy of adding minocycline to tPA in acute ischaemic stroke. The WAIMATSS is a multicentre, prospective, and randomised pilot study of intravenous minocycline, 200 mg 12 hourly for 5 doses, compared with standard care, in patients with ischaemic stroke treated with intravenous tPA. The primary endpoint is HT diagnosed by brain CT and MRI. Secondary endpoints include clinical outcome measures. Some illustrative cases from the early recruitment phase of this study will be presented, and future perspectives will be discussed.

Objective: To determine the spectrum of mutations associated with familial hypercholesterolaemia (FH) and their detection rate in the FH Western Australia (FHWA) Program., Methods: Mutation testing of the LDLR gene, plus select regions in APOB and PCSK9, was performed in the first 343 patients considered to be phenotypic index cases of FH and classified on the basis of the Dutch Lipid Clinic Network Criteria (DLCNC) score as "possible", "probable", or "definite" FH., Results: Overall, 86 different pathogenic (or likely pathogenic) mutations were identified in 129 patients, including four compound heterozygotes manifesting a more severe clinical phenotype. Fourteen of these mutations were novel and twelve (9.6%) were large deletions/duplications of the LDLR. The most common mutations were the familial defective apoB-100 mutation APOB p.Arg3527Gln (7.2%) and an LDLR intron 3 splice site mutation c.313 + 1G > A (4.8%). While 70% of 'definite' FH patients were found to carry a mutation, only 29% of 'probable' and 11% of 'possible' FH patients were mutation-positive., Conclusion: This information provides a useful DNA database on which to base ongoing cascade screening for FH and future research into the genetic aetiology of FH in Western Australia. These findings suggest genetic testing should be prioritised to those with high DLCNC scores and offers a cost-effective family screening method from FH index cases, leading to detection of other previously undiagnosed and younger family members, enabling early instigation of intervention and preventative measures for premature coronary heart disease., (Crown Copyright © 2012. Published by Elsevier Ireland Ltd. All rights reserved.)

Urea cycle disorders (UCDs) are rare causes of hyperammonemic encephalopathy in adults. Most UCDs present in childhood and, if unrecognized, are rapidly fatal. Affected individuals who survive to adulthood may remain undiagnosed because of clinicians' unawareness of the condition or atypical presentations. We describe the case of a 49-year-old man who initially presented with a stroke and developed hyperammonemic encephalopathy over a period of 8 months. A diagnosis of carbamoyl phosphate synthetase type 1 deficiency was made, and the patient was referred for liver transplantation. One year after liver transplantation, the patient had normal plasma ammonia concentrations and had returned to work., (Copyright © 2011 American Association for the Study of Liver Diseases.)

Etravirine is a non-nucleoside reverse transcriptase inhibitor (NNRTI) that is active against NNRT-resistant HIV-1. A simple, sensitive, and specific LC-MS/MS method was developed and validated for the analysis of etravirine in rat plasma using itraconazole as the internal standard. The analytes were extracted with ethyl acetate and chromatographed on a reverse-phase XTerra MS C₁₈ column. Elution was achieved with a mobile phase gradient varying the proportion of a 2 mM ammonium acetate aqueous solution containing 0.1% formic acid (solvent A) and a 0.1% formic acid in methanol solution (solvent B) at a flow rate of 300 μL/min. The analytes were monitored by tandem-mass spectrometry with positive electrospray ionization. The precursor/product transitions (m/z) in the positive ion mode were 435.9→163.6 and 706.7→392.6 for etravirine and the internal standard, respectively. Calibration curves were linear over the etravirine rat plasma concentration range of 1-100 ng/mL. The inter- and intra-day accuracy and precision were within ±10%. The assay has been successfully used for pharmacokinetic evaluation of etravirine using the rat as an animal model., (Copyright © 2010 Elsevier B.V. All rights reserved.)

Familial hypercholesterolaemia (FH) is a common genetic disorder that untreated has an almost one hundredfold risk of coronary artery disease (CAD). In an audit of 334 patients with premature CAD admitted to a Department of Cardiology, only 60% of medical records had sufficient clinical information for identifying FH. Of those with sufficient information recorded, 54% of patients had possible to definite FH on recognised clinical criteria. Amongst those with FH, only 38% were on statin therapy and only 22% were treated to National Heart Foundation targets. Detection and treatment of FH represents a major gap in coronary prevention.

A simple, specific, sensitive, and rapid high performance liquid chromatography (HPLC) method for the determination of griseofulvin in small volumes of rat plasma was developed and validated using warfarin as an internal standard. Biological sample preparation involved simple extraction with acetonitrile, followed by dilution with aqueous mobile phase buffer (20 mM sodium dihydrogen phosphate, pH 3.5) to eliminate any chromatographic solvent effects. Griseofulvin and warfarin were baseline separated and quantitated on a C(18) reversed phase column (4.6 x 150 mm, 3.5 microm), using a mobile phase composed of a 20 mM aqueous solution of sodium dihydrogen phosphate-acetonitrile (55:45, v/v, pH 3.5) delivered at a flow rate of 1.0 mL/min, and with fluorescence detection (lambda(excitation) = 300 nm, lambda(emission) = 418 nm). The method was proven to be linear over a plasma griseofulvin concentration range of 10 to 2500 ng/mL with a mean correlation coefficient of 0.9996. The intra-day and inter-day accuracy (relative error) were in the range of 0.89% to 9.26% and 0.71% to 7.68%, respectively. The within-day precision (coefficient of variation) was less than 3.0% and the between-day precision was less than 7.5%. The mean recovery of griseofulvin from rat plasma was found to be 99.2%. The limit of detection (LOD) and the limit of quantification (LOQ) of griseofulvin were determined to be 1 ng/mL and 10 ng/mL, respectively. The developed method was successfully applied to quantitatively assess the pharmacokinetics of griseofulvin in rats following a single 50 mg/kg oral dose of the drug.

A HPLC method with UV detection at 262nm was developed to analyze inositol hexanicotinate in rat plasma. Plasma samples were extracted with an equal volume of acetonitrile, followed by dilution with mobile phase buffer (5mM phosphate buffer, pH 6.0) to eliminate any solvent effects. Inositol hexanicotinate and the internal standard (mebendazole) were separated isocratically using a mobile phase of acetonitrile/phosphate buffer (35:65, v/v, pH 6.0) at a flow rate of 1.0mL/min and a reverse-phase XTerra MS C(18) column (4.6mmx150mm, 3.5microm). The standard curve was linear over a concentration range of 1.5-100.0microg/mL of inositol hexanicotinate in rat plasma. The HPLC method was validated with intra- and inter-day precisions of 1.55-4.30% and 2.69-21.5%, respectively. The intra- and inter-day biases were -0.75 to 19.8% and 2.58-22.0%, respectively. At plasma concentrations of 1.5-100microg/mL, the mean recovery of inositol hexanicotinate was 99.6%. The results of a stability study indicated that inositol hexanicotinate was unstable in rat plasma samples, but was stable in acetonitrile extracts of rat plasma for up to 24h at 4 degrees C. The assay is simple, rapid, specific, sensitive, and reproducible and has been used successfully to analyze inositol hexanicotinate plasma concentrations in a pharmacokinetic study using the rat as an animal model.

Objectives: To estimate the impact of Rx for Change, an 8-h tobacco cessation training program on pharmacy students' perceived counseling skills, confidence for counseling, and future counseling of patients for tobacco cessation., Methods: Unlinked, pre- and post-training surveys were administered to 142 pharmacy students enrolled at Texas Southern University, a primarily minority and historically black educational institution., Results: Post-training counseling abilities were significantly improved over pretraining values for each of the five key components of tobacco cessation counseling (Ask, Advise, Assess, Assist, and Arrange), overall counseling abilities, and confidence for counseling (P < 0.001). Racial/ethnic differences in self-reported overall counseling was observed (P = 0.01). Ninety-one percent of participants believed that the training would increase the number of patients whom they counsel for cessation, and 95% believed that it would improve the quality of counseling that they provide. At least 95% of participants believed that the pharmacy profession should be more active in preventing patients from starting smoking and helping patients to stop smoking., Conclusions: The Rx for Change program had a positive impact on perceived abilities and confidence for providing tobacco cessation counseling to patients. While it is important that all current and future health care providers receive specialized tobacco cessation training, it is particularly important for clinicians of racial/ethnic minority backgrounds, who are more likely to practice in geographic areas with a high density of population subgroups at an elevated risk for tobacco-related mortality. In particular, pharmacists, who are uniquely positioned within the community to provide care to all patients, including the medically underserved, must be equipped with the necessary skills to assist patients with quitting.

Arabidopsis thaliana root hairs grow longer and denser in response to low-phosphorus availability. We tested the hypothesis that wild-type Arabidopsis would acquire more phosphorus under phosphorus-limiting conditions than mutants that do not have the root hair response. The growth and phosphorus acquisition of wild-type Arabidopsis (WS) were compared to two root hair mutants (rhd6 and rhd2) under eight phosphorus treatments ranging from 0.4 mmol/m to 54 mmol/m phosphorus. At the lowest phosphorus treatment, all plants were small and showed severe phosphorus stress symptoms. At 1.5 mmol/m phosphorus, WS plants had greater shoot biomass, absolute growth rate, total phosphorus, and specific phosphorus absorption than the two root hair mutants. At the highest phosphorus treatment, there was no difference between genotypes in any of the parameters measured. We conclude that the response of increased root hair growth under low phosphorus availability in Arabidopsis is important in increasing phosphorus acquisition under phosphorus-limiting conditions.

Arabidopsis thaliana root hairs grow longer and denser in response to low-phosphorus availability. In addition, plants with the root hair response acquire more phosphorus than mutants that have root hairs that do not respond to phosphorus limiting conditions. The purpose of this experiment was to determine the efficiency of root hairs in phosphorus acquisition at high- and low-phosphorus availability. Root hair growth, root growth, root respiration, plant phosphorus uptake, and plant phosphorus content of 3-wk-old wild-type Arabidopsis (WS) were compared to two root hair mutants (rhd6 and rhd2) under high (54 mmol/m) and low (0.4 mmol/m) phosphorus availability. A cost-benefit analysis was constructed from the measurements to determine root hair efficiency. Under high-phosphorus availability, root hairs did not have an effect on any of the parameters measured. Under low-phosphorus availability, wild-type Arabidopsis had greater total root surface area, shoot biomass, phosphorus per root length, and specific phosphorus uptake. The cost-benefit analysis shows that under low phosphorus, wild-type roots acquire more phosphorus for every unit of carbon respired or unit of phosphorus invested into the roots than the mutants. We conclude that the response of root hairs to low-phosphorus availability is an efficient strategy for phosphorus acquisition.

To elucidate the mechanism underlying the reported potentiation of warfarin anticoagulant action after initiation of miconazole therapy, the effects of acute and chronic miconazole administration on warfarin disposition were examined in six adult New Zealand male rabbits. The rabbits received a 3.5 mg/kg iv dose of warfarin either alone, 1 hr after a single 100 mg/kg ip miconazole dose, or on day 5 of a 6-day 50 mg/kg/12 hr ip miconazole dosing regimen. Acute miconazole administration decreased the elimination rate constant of warfarin, but other warfarin disposition parameters were not altered. Chronic miconazole administration caused a 47% increase in warfarin plasma-free fraction (probably caused by competitive or noncompetitive protein binding displacement by miconazole metabolites) and a 42% decrease in warfarin intrinsic clearance (probably caused by a miconazole-induced inhibition in warfarin metabolism). As a consequence of these quantitatively similar but opposite changes, the total body clearance of warfarin (a low clearance drug) was marginally decreased. A significant decrease in the elimination rate constant and an increase in the tissue-free fraction of warfarin were also observed during chronic miconazole treatment. These results suggest that chronic miconazole administration should not significantly affect the steady-state plasma concentrations of total warfarin, but should increase the steady-state plasma concentrations of free warfarin. The expected increases in the steady-state plasma concentrations of free, pharmacologically active warfarin may account for the reported potentiation of the pharmacological action of warfarin when coadministered with chronic miconazole. Measurement of total plasma concentrations, and estimation of total body clearance might be misleading, and inadequate in identifying certain drug interactions involving low clearance drugs.

Using a three-way crossover experimental design, the effects of food and propantheline bromide on the pharmacokinetics of orally administered zidovudine (AZT; 3'-azido-3'-deoxythymidine) were assessed in six adult male Sprague-Dawley rats by the urinary excretion rate method. Accordingly, a single-10 mg/kg oral dose of AZT was administered as an aqueous solution to either fasting (F) rats, nonfasting (NF) rats or fasting rats pretreated with a 5 mg/kg oral dose of propantheline bromide (P; an inhibitor of GI motility). Quantitative urine collections were made at predetermined intervals for 24-32 hr after AZT administration, and each urine specimen was assayed for unmetabolized AZT by a sensitive and specific high-performance liquid chromatographic method. The mean extent of AZT absorption, as reflected by mean total urinary excretion values expressed as % of AZT dose, ranged from 72.9% to 75.2% and was unaffected by study condition. Kinetic interpretation of the terminal linear phase of the urinary excretion rate vs. time data yielded mean (+/- SD) half-lives of 4.35 +/- 2.1 hr for NF and 3.42 +/- 0.86 hr for P, which were significantly greater than the mean 1.58 +/- 0.63 hr half-life observed for F. The reported mean biological half-life of AZT after a 10 mg/kg intravenous dose to the same strain of rats is 0.76 +/- 0.35 hr (n = 6). After intravenous AZT administration, the terminal half-life reflects drug elimination. However, after oral AZT administration, the observed terminal half-lives reflect drug absorption rather than drug elimination (i.e., a flip-flop kinetic model is operable). There is some evidence to suggest that the disappearance of AZT from the blood of orally dosed AIDS patients may also be controlled by drug absorption.

A high-pressure liquid chromatographic method for the sensitive, rapid, and specific determination of sulfapyridine and its N-acetyl derivative in plasma and saliva was developed. A cyano-bonded, reversed-phase, high efficiency column was used. The system detected these sulfonamides in serum to 0.25 mg/liter and within only 6 min. Sulfapyridine was separated from its acetyl derivative with little interference from other drugs. The assay reproducibility was within 3%. The assay was highly useful for routine monitoring of patients receiving sulfasalazine for inflammatory bowel disease.

We used two strains of ampicillin-susceptible Escherichia coli to produce meningitis in rabbits and utilized these models (i) to compare the killing effects of parenteral trimethoprim-sulfamethoxazole (TMP-SMZ) and ampicillin on E. coli in cerebrospinal fluid after 8 h of treatment and (ii) to measure the penetration of TMP-SMZ and ampicillin into cerebrospinal fluid and the brain. At 16 h after intracisternal inoculation with a test strain, rabbits were treated with TMP (6 mg/kg per h) and SMZ (30 mg/kg per h), ampicillin (40 mg/kg per h), or saline intravenously for 8 h. TMP-SMZ levels were measured by high-pressure liquid chromatography, and ampicillin levels were measured by microbiological assay. Mean +/- standard deviation concentrations of TMP, SMZ, and ampicillin in cerebrospinal fluid (mean percent penetration) at the completion of 8 h of therapy were 0.80 +/- 0.41 (18%), 15.7 +/- 21.1 (27.2%), and 2.6 +/- 1.7 (8.9%) microgram/ml, respectively. TMP, SMZ, and ampicillin levels in brain homogenate after 8 h of therapy were 0.23 +/- 0.07 (6.6%), 3.31 +/- 3.3 (5.5%), and 0.6 +/- 4.53 (1.9%) microgram/g, respectively. TMP-SMZ infusion for 8 h produced a significant reduction in mean bacterial counts in cerebrospinal fluid in both models of meningitis compared with saline controls. The decrease in mean bacterial counts with TMP-SMZ therapy was equivalent to that produced by ampicillin.

The time course of free and N4-acetylated sulfapyridine (SP) concentrations in the saliva and whole plasma was determined in a healthy male volunteer after a single 2.0 g oral dose of salicylazosulfapyridine (SASP) as four-500 mg commercial, uncoated tablets. The mean (+/- S.D.) plasma: saliva concentration ratios for free and acetylated SP was 2.04 (+/- 0.24) and 3.12 (+/-0.43), respectively, and were independent of plasma concentration and saliva pH. The elimination half-lives of SP and N4-acetyl SP could be determined from either salivary or plasma concentration-time data. These preliminary results suggest that measurement of saliva concentrations of free and acetylated SP may be a convenient, noninvasive method for monitoring indirectly the plasma concentrations of SP and acetyl SP in patients treated with SASP and for determining acetylator phenotype.

The purposes of this investigation were to determine and to compare the oral absorption characteristics of micronized griseofulvin (500 mg) after its administration to humans in the form of a corn oil-in-water emulsion containing dispersed drug, an aqueous suspension, and two different commercial tablets (A and B). The four dosage forms were administered in a random crossover fashion to five fasting subjects, and drug absorption was assessed from urinary excretion data for the major metabolite of the antibiotic (6-desmethylgriseofulvin). The drug was most rapidly, uniformly, and completely absorbed from the corn oil-in-water emulsion. As compared to either the aqueous suspension, Tablet A, or Tablet B, three- to fourfold increases in the maximum body levels and a twofold enhancement in the bioavailability of the antibiotic were observed after administration of the emulsion dosage form. A mechanism based on the ability of the linoleic and oleic acids liberated during the digestion of corn oil to inhibit GI motility and stimulate gallbladder evacuation may explain the marked enhancing effect of emulsified corn oil on griseofulvin absorption in humans. This new lipid-in-water emulsion dosage form of micronized griseofulvin appears to offer several clinical advantages in the treatment of fungal infections.

A sensitive and specific high-performance liquid chromatographic (HPLC) procedure was developed for determination of propoxyphene and norpropoxyphene in plasma and breast milk. The compounds were isolated from the biological specimen by extraction, the organic phase was evaporated to dryness, and the residue was redissolved in mobile phase [acetonitrile: 0.002 M H2SO4 (1:1)]. The resultant solution was then injected into an HPLC system utilizing a C18 reversed-phase analytical column and a variable-wavelength detector set at 205 nm. Under these conditions the method has a sensitivity of 20 ng/mL using 1 mL of plasma or milk. The within-run coefficient of variation for both compounds varied between 6.2 and 8.9% within the concentration range tested. Applicability of the method was demonstrated in a nursing mother who received multiple oral doses of propoxyphene.

The objective of this study was to compare the pharmacokinetic behavior of erythromycin in normal volunteers with that in subjects with alcoholic liver disease. Six normal volunteers received 500 mg erythromycin as an intravenous infusion or as two 250-mg enteric-coated tablets in a crossover fashion. The pharmacokinetics of erythromycin after intravenous administration was best described as a two-compartment model. The elimination half-life was 1.6 +/- 0.7 hours (mean +/- S.D.) after the intravenous dose and 2.0 +/- 0.7 hours after the oral dose. In patients with alcoholic liver disease the elimination half-life after oral administration of two 250-mg enteric-coated tablets was 3.2 +/- 0.5 hours, significantly different from that in normal subjects, probably due to impaired metabolism. The difference in half-life does not require dosage adjustment in this patient population. The systemic availability of erythromycin was 33.5 per cent (range 10.5 to 79.3 per cent).

The effect of the amount of emulsified corn oil ingested on the gastrointestinal absorption of griseofulvin in man was assessed after oral administration of 5, 10, 15, or 30 gm doses of a corn oil (40% w/w)-in-water emulsion dosage form, each containing 250 mg of microsize griseofulvin. For comparison, griseofulvin absorption from two-125 mg commercial tablets of ultramicrosize drug dispersed in polyethylene glycol 6;000 was also determined. Griseofulvin was almost completely absorbed from the microsize drug emulsions and ultramicrosize drug tablets, whereas 50% of an oral dose is absorbed from commercial microsize griseofulvin tablets. Only 4 gm of emulsified corn oil (as a 10-gm dose of emulsion) is required to maximize the uniformity and extent of griseofulvin absorptions. The emulsion dosage form is uniquely suited for pediatric use.

The bioavailability of an aqueous solution of chlorothiazide and three commercially available chlorothiazide tablets was assessed in adult mongrel dogs. In two crossover urinary excretion studies, six fasting dogs received single 500-mg doses of chlorothiazide as an aqueous solution, one 500-mg originator tablet on two separate occasions (Tablets A-1 and A-2), two 250-mg originator tablets (Tablet B), or one 500-mg generic tablet (Tablet C). 6-Amino-4-chlorobenzene-1,3-disulfonamide )chloraminophenamide), a pharmacologically active hydrolysis product of chlorothiazide was not detected in any urine sample. Urinary recoveries of chlorothiazide after oral administration, expressed as the mean (range) percent of the dose, was only 22.0 (8.41-33.9), 15.7 (10.2-25.0), 20.7 (7.25-31.0), 18.5 (8.72-33.2), and 21.9% (6.69-41.1%) for the aqueous solution and Tablets A-1, A-2, B, and C, respectively. Considerable interindividual variation and some intraindividual variation were observed. No statistically significant difference in bioavailability existed among the aqueous solution and Tablets A-2 and B, between Tablets A-1 and C, and between Tablets A-1 and A-2.

Using a crossover experimental design, the absorption profile of griseofulvin was assessed in human volunteers after oral administration of a 500 mg dose of the antifungal antibiotic as capsules of the anhydrous (nonsolvated)-and monochloroform solvate forms of the drug. The maximum body level of drug and the rate and extent of griseofulvin absorption (or bioavailability) were significantly increased after administration of the chloroform solvate as compared to that observed after administration of the nonsolvated form of the drug. The enhanced absorption of griseofulvin chloroformate correlated well with its enhanced solubility and dissolution rate at 37 degrees C in simulated intestinal fluid (20 mM sodium deoxycholate, pH 7.5). This is the first demonstration of a drug-organic solvate displaying improved gastrointestinal absorption characteristics over the anhydrous form of a drug.