Pharmacokinetics of Enteric-Coated Mycophenolate Sodium in Lupus Nephritis (POEMSLUN).

BACKGROUND: Mycophenolate mofetil or enteric-coated mycophenolate sodium (EC-MPS) and steroids are used for induction and maintenance therapy in severe lupus nephritis. Blood concentrations of mycophenolic acid (MPA), the active metabolite of these drugs, vary among patients with lupus nephritis. The objective of this study was to examine whether concentration-controlled (CC) dosing (through therapeutic drug monitoring) of EC-MPS results in a higher proportion of participants achieving target exposure of MPA compared with fixed-dosing (FD). An additional aim of the study was to evaluate the influence of CC dosing on clinical outcomes. METHODS: Nineteen participants were randomly assigned either to the FD or CC group. All the participants were eligible to have free and total measurements of MPA over a period of 8-12 hours on 3 different occasions. Area under the concentration-time curve between 0 and 12 hours (AUC0-12) was calculated using noncompartmental methods. Dose of EC-MPS was titrated according to AUC0-12 in the CC group. RESULTS: Thirty-two AUC0-12 measurements were obtained from 9 FD and 9 CC participants. Large inter-patient variability was observed in both groups but was more pronounced in the FD group. There were no significant differences between FD and CC participants in any pharmacokinetic parameters across the study visits, except for total C0 (FD 2.0 ± 0.3 mg/L versus CC 1.1 ± 0.3; P = 0.01) and dose-normalized C0 (FD 2.9 ± 0.2 mg/L/g versus CC 2.1 ± 0.7 mg/L/g; P = 0.04) at the second visit and total AUC0-12 (FD 66.6 ± 6.0 mg·h/L versus CC 35.2 ± 11.4 mg·h/L; P = 0.03) at the third visit. At the first study visit, 33.3% of the FD and 11.1% of the CC participants achieved the target area under the concentration-time curve (P = 0.58). From the second visit, none of the FD participants, compared with all the CC participants, achieved target AUC0-12 (P = 0.01). More CC participants achieved remission compared with FD participants (absolute difference of -22.2, 95% confidence interval (Equation is included in full-text article.)0.19 to 0.55; P = 0.62). The mean free MPA AUC0-12 was significantly lower in those who had complete remission. CONCLUSIONS: CC participants reached target AUC0-12 quicker. Larger studies are required to test clinical efficacy.

Patterns in use and costs of conventional and biologic disease-modifying anti-rheumatic drugs in Australia.

OBJECTIVES: The aim of this study was to characterise the use and costs of subsidising conventional disease-modifying anti-rheumatic drugs (DMARDs) and biologic DMARDs in Australia from 2004-2014 through pharmaceutical benefits schemes. METHODS: Dispensing and expenditure data on conventional and biologic DMARDs were extracted from Medicare Australia and temporal trends were analysed. Medicine use was standardised in terms of the defined daily dose (DDD) per 1,000 population per day (DDD/1,000 population/day). RESULTS: Conventional and biologic DMARD use increased 74% over the study period (4.86 to 8.46 DDD/1,000 population/day; average annual increase 6.7%). Conventional DMARDs accounted for the vast majority of total use and increased 55% (4.81 to 7.43 DDD/1,000 population/day), while biologic DMARD use increased 1,784% (0.055 to 1.030 DDD/1,000 population/day). The most frequently used conventional DMARD was methotrexate (56% total conventional DMARD use) and use increased 95%. Hydroxychloroquine and leflunomide use increased marginally while sulfasalazine use declined 4.2%. Etanercept was the most commonly used biologic DMARD in 2004 and adalimumab in 2014. Conventional DMARD expenditure decreased 4.2% to AUD$33.3 million but biologic DMARD expenditure increased 2,089% to AUD$585.4 million. CONCLUSIONS: The use of conventional and biologic DMARDs increased substantially over a decade in Australia. Patterns of use of conventional DMARDs have changed, and costs have decreased. In contrast a significant escalation in both the use and cost of biologic DMARDs has occurred. Further research is required to address cost-effectiveness, regulation and quality use of these medicines in clinical practice.

Use and monitoring of low dose rituximab in myasthenia gravis.

BACKGROUND: Myasthenia gravis is an autoimmune disorder of the neuromuscular junction. Rituximab (RTX), a monoclonal antibody to CD20, leads to B lymphocyte depletion and has been used in some autoimmune disorders, including small case series of myasthenia gravis patients. METHODS: A retrospective analysis was performed of all patients with acetylcholine receptor (AChR) (11 subjects) or muscle specific kinase antibody (MuSK) positive myasthenia gravis (three subjects), who had been treated with RTX in Brisbane, Australia. In most patients 1 g of RTX, in two divided doses, was given. Patients were monitored by serial clinical assessments, flow cytometry of peripheral blood B lymphocytes and antibody testing. RESULTS: RTX led to a significant improvement in symptoms in 11 of 14 patients. Doses of immunosuppressive medications were able to be reduced in 12 of 14 patients but medications could be completely ceased in only one patient. A demonstrable reduction of autoantibody levels was found in only three AChR positive patients and one MuSK positive patient, independent of clinical improvement. Peripheral blood B lymphocyte depletion was achieved in 13 out of 14 patients. B lymphocyte recovery occurred between 9 and 30 months post RTX (median 12.3 months) and was consistently associated with worsening of clinical symptoms. CONCLUSION: Rituximab at a dose of 1 g appears to be beneficial in the treatment of patients with severe myasthenia gravis. Serial monitoring of peripheral blood B lymphocytes appears to be useful in guiding the need for further RTX therapy.

A new clinical protocol for the pharmacological management of acute behavioural disturbance.

OBJECTIVE: Psychiatry is awash with pharmacological acute behavioural disturbance protocols which list oral or intramuscular benzodiazepines and antipsychotics with numerous options. This results in frequent over-sedation and occasional profound sedation and death. This paper describes the development of a simplified sedation protocol for the pharmacological management of acute behavioural disturbance. METHOD: Following the wider availability of intramuscular lorazepam in 2008, Metro North Mental Health developed a protocol utilizing only two products - oral or intramuscular lorazepam or olanzapine - which was subsequently developed into a statewide protocol. RESULTS: The advantage of utilizing only two sedating medications is that it greatly reduces the risk of profound sedation and theoretically reduces the risk of other complications including deaths. Clinical staff who have utilized the protocol report a reduction in over-sedation of inpatients. CONCLUSION: A simplified protocol makes the pharmacological management of acute behaviour disturbance safer for both patients and staff.

Recognising skin manifestations of rheumatological disease.

BACKGROUND: An understanding of skin conditions associated with rheumatic diseases ensures accurate diagnosis and management. Cutaneous manifestations of rheumatological disease are legion. OBJECTIVE: The aim of this article is to increase clinician familiarity with the dermatological manifestations of rheumatic conditions to enable accurate diagnosis and effective management. DISCUSSION: This article will address the skin manifestations of lupus erythematosus, rheumatoid arthritis, psoriatic arthritis, dermatomyositis and scleroderma, including their implications in diagnosis, prognosis and treatment.

Multicentre retrospective cohort study assessing the incidence of serious infections in patients with lupus nephritis, compared with non-renal systemic lupus erythematosus.

OBJECTIVES: The incidence of serious infections is poorly defined in patients with lupus nephritis (LN). It is also unclear if LN influences risk of serious infections in a longitudinal analysis. The aim of this study was to determine the incidence of serious infections in patients with SLE and LN, compared with patients with SLE without LN. METHODS: A multicentre retrospective cohort study was conducted. Patients with LN identified at two tertiary centres were matched where possible with age and gender-matched patients with SLE without LN.Any infection requiring inpatient admission, occurring in the 6 months following index clinical visit, was considered serious. Cox regression was employed to investigate the association between risk of serious infection and LN status, and other relevant covariates. RESULTS: A total of 173 patients were included within the analysis (n=87 LN, n=86 SLE only). A total of 9.2% (n=8) of patients with LN experienced at least one serious infection within the study period, compared with 5.8% (n=5) of patients without LN, equivalent to 19.5 and 12.0 infections per 100 patient-years with and without LN, respectively. Univariable and multivariable analyses found no significant increased risk of serious infection in patients with LN versus controls (HR 1.61; 95% CI 0.53 to 4.92 and adjusted HR (aHR) 0.91; 95% CI 0.27 to 3.06, respectively). Increased prednisone dose and modified SLE comorbidity index were strongly associated with serious infection (aHR (per 5 mg) 1.21; 95% CI 1.07 to 1.37; p=0.003 and aHR 1.13; 95% CI 1.02 to 1.25; p=0.018, respectively). CONCLUSIONS: In this cohort, adjusting for cofactors, the presence of LN alone does not appear to increase the risk of serious infections compared with patients with SLE without LN. However, increased prednisone dose at baseline visit and increasing comorbidity were independently associated with the incidence of serious infection.

Aminoglycoside-associated Fanconi syndrome.

The objective is to describe a case of probable aminoglycoside-induced Fanconi syndrome and make clinicians aware of the existence of this underrecognized and underdiagnosed complication in patients treated with a prolonged course of high-dose aminoglycosides. A 53-year-old man admitted for recurrent infective exacerbations of chronic bronchiectasis already colonized with Pseudomonas aeruginosa was treated intermittently with intravenous gentamicin (320 to 560 mg/d) for a total of 4 months to a total cumulative dose of 9.4 g. The patient developed profound hypophosphatemia, hypocalcemia, hyperphosphaturia, and aminoaciduria. Electrolyte disturbances persisted until gentamicin therapy was stopped, recurred with rechallenge, and did not correct with calcium and phosphate supplementation. This case shows that prolonged exposure to high-dose aminoglycoside therapy can be associated with Fanconi syndrome, which is a manifestation of proximal tubular dysfunction. There are only a few case reports to date of Fanconi syndrome as a probable complication of high-dose aminoglycoside therapy. The Naranjo Adverse Drug Reaction probability scale score indicated that this was a probable adverse reaction associated with administration of high-dose aminoglycosides. The differential diagnosis of electrolyte disturbances as a manifestation of proximal tubule dysfunction and type 2 renal tubular acidosis is vast; however, Fanconi syndrome needs to be considered in patients treated with high doses of aminoglycosides for longer than 6 days, after more common causes of hypophosphatemia are excluded.

A vertical mouse and ergonomic mouse pads alter wrist position but do not reduce carpal tunnel pressure in patients with carpal tunnel syndrome.

Non-neutral wrist positions and external pressure leading to increased carpal tunnel pressure during computer use have been associated with a heightened risk of carpal tunnel syndrome (CTS). This study investigated whether commonly used ergonomic devices reduce carpal tunnel pressure in patients with CTS. Carpal tunnel pressure was measured in twenty-one patients with CTS before, during and after a computer mouse task using a standard mouse, a vertical mouse, a gel mouse pad and a gliding palm support. Carpal tunnel pressure increased while operating a computer mouse. Although the vertical mouse significantly reduced ulnar deviation and the gel mouse pad and gliding palm support decreased wrist extension, none of the ergonomic devices reduced carpal tunnel pressure. The findings of this study do therefore not endorse a strong recommendation for or against any of the ergonomic devices commonly recommended for patients with CTS. Selection of ergonomic devices remains dependent on personal preference.

Ferrocenyl-phosphonium ionic liquids - synthesis, characterisation and electrochemistry.

New unsymmetrically substituted ferrocenyl-phosphonium ionic liquids (ILs) [FcPR2R']NTf2 are synthesized by two or three step syntheses starting from ferrocene, Fc = (C5H5)Fe(C5H4); R = Me, (n)Bu, (n)Hex, Ph; R' = Me, (n)Pr, (n)Bu, Ph; NTf2 = N(SO2CF3)2. The selective synthesis of alkyl phosphines FcPR2via a Friedel-Crafts phosphorylation is highlighted as an alternative for the standard protocol commonly used for ferrocenyl arylphosphines involving lithiation of FcH followed by phosphorylation. The influence of the P-substituents on thermal stability, electrochemical potential, chemical shift, and UV-Vis absorption behavior of the ILs is studied. The phosphonium group acts both as an ionic tag and as an electron-withdrawing substituent directly bound at the Cp-ring position. Therefore the title compounds are attractive for further studies to use them as tunable redox mediators for (photo)electrochemical devices such as dye sensitized solar cells (DSSCs) or redox flow batteries.

When conventional treatment fails: the role of intravenous immunoglobulin in recurrent pregnancy loss secondary to antiphospholipid syndrome.

Recurrent pregnancy loss (RPL) is a well-recognized complication of antiphospholipid syndrome (APS). First line therapy consists of low dose aspirin and heparin. Despite conventional therapy some women fail to achieve a successful pregnancy outcome. We describe the case of a patient who had two live births following intravenous immunoglobulin therapy despite previous failure with conventional therapy for RPL in the setting of APS. We will summarize the available literature on intravenous immunoglobulin for this indication.

Off-label use of recombinant factor VIIa in two tertiary hospitals in Queensland.

BACKGROUND: Recombinant factor VIIa (rFVIIa) is used for many off-label indications without high quality evidence to support its efficacy. The aim of this study was to determine indications for use of off-label rFVIIa, efficacy and safety, and adherence to institutional guidelines. METHODS: We performed a retrospective review of off-label rFVIIa at two tertiary hospitals from 2007 to 2010. RESULTS: One hundred forty-five administrations were identified and analysed. Haemorrhage associated with cardiac surgery made up one-third of all rFVIIa usage, with trauma (20%) and other surgery (11%) the next most frequent indications. Compared with all others, cardiac surgery patients were older (60.0 years versus 47.4 years, P < 0.001) and had lower pre-rFVIIa transfusion requirements, a higher subjective response rate (88% versus 46%, P < 0.001) and lower mortality rates (6.1% versus 33%, P < 0.001), but higher rates of arterial thrombormbolic events (16.7% versus 2.1%, P = 0.002). Most patients received only one or two doses (n = 137; 95%), with no subject receiving a third or subsequent dose having an appreciable reduction in bleeding. Only a small number of patients (n = 15; 10.3%) had rFVIIa administered in accordance with our institutions' guidelines. CONCLUSION: Patients administered rFVIIa for haemorrhage not associated with cardiac surgery were severely unwell. Despite lack of evidence, administration of rFVIIa may be justified by the high mortality rate, but more than two doses are unlikely to provide further benefit. The high rate of arterial thromboembolism in cardiac surgical patients raises risk-benefit considerations. Adherence to our institutions' guidelines was poor.

A Protocol for the Pharmacokinetics of Enteric Coated Mycophenolate Sodium in Lupus Nephritis (POEMSLUN): an open-label, randomised controlled trial.

INTRODUCTION: Mycophenolate sodium, an enteric-coated tablet (EC-MPS), is as effective and safe as mycophenolate mofetil (MMF) in preventing transplant rejection. EC-MPS and MMF improve the outcome of severe lupus nephritis (LN) and have fewer side effects than pulsed intravenous cyclophosphamide. Blood concentrations of mycophenolic acid (MPA), the active metabolite of EC-MPS, vary between participants despite fixed dosing. Interpatient variability has been studied in transplantation, but not well documented in LN. The relationship between MPA concentration and its clinical effect on LN has not been described. METHODS AND ANALYSIS: This is a prospective, open-label, randomised controlled trial. -32 participants with LN who meet the inclusion and exclusion criteria will be randomised into two groups: one receiving a fixed dose of EC-MPS and the second, a dosing regimen that is titrated with therapeutic drug monitoring. Included participants will have blood sampled over a period of 8-12 h on three different occasions. Pharmacokinetic parameters will be calculated using non-compartmental methods. ETHICS AND DISSEMINATION: The Human Research and Ethics Committee of the Royal Brisbane Women's Hospital have approved this study. The study is registered with Australian and New Zealand Clinical Trials Registry-ACTRN12611000798965 We planned to present the de-identified information at conferences and publish the results in medical journals. TRIAL REGISTRATION: ACTRN12611000798965.

Description, reliability and validity of a novel method to measure carpal tunnel pressure in patients with carpal tunnel syndrome.

Elevated carpal tunnel pressure is an important pathomechanism in carpal tunnel syndrome (CTS). Several invasive methods have been described for direct measurement of carpal tunnel pressure, but all have two important limitations. The pressure gauge requires sterilisation between uses, which makes time-efficient data collection logistically cumbersome, and more importantly, the reliability of carpal tunnel pressure measurements has not been evaluated for any of the methods in use. This technical note describes a new method to measure carpal tunnel pressure using inexpensive, disposable pressure sensors and reports the within and between session reliability of the pressure recordings in five different wrist positions and during typing and computer mouse operation. Intraclass correlation coefficients (ICC[3,1]) were calculated for recordings within one session for healthy participants (n = 7) and patients with CTS (n = 5), and for recordings between two sessions for patients with CTS (n = 5). Overall, the reliability was high. With the exception of two coefficients, the reliability of the recordings at different wrist angles varied from 0.63 to 0.99. Reliability for typing and mouse operation ranged from 0.86 to 0.99. The new method described in this report is inexpensive and reliable, and data collection can be applied more efficiently as off-site sterilisation of equipment is not required. These advances are likely to promote future research into carpal tunnel pressure, such as investigation of the therapeutic mechanisms of various conservative treatment modalities that are believed to reduce elevated carpal tunnel pressure.

Etoricoxib for arthritis and pain management.

Nonsteroidal antiinflammatory drugs (NSAIDs), including selective cyclooxygenase (COX)-2 inhibitors, have come to play an important role in the pharmacologic management of arthritis and pain. Clinical trials have established the efficacy of etoricoxib in osteoarthritis, rheumatoid arthritis, acute gouty arthritis, ankylosing spondylitis, low back pain, acute postoperative pain, and primary dysmenorrhea. Comparative studies indicate at least similar efficacy with etoricoxib versus traditional NSAIDs. Etoricoxib was generally well tolerated in these studies with no new safety findings during long-term administration. The gastrointestinal, renovascular, and cardiovascular tolerability profiles of etoricoxib have been evaluated in large patient datasets, and further insight into the cardiovascular tolerability of etoricoxib and diclofenac will be gained from a large ongoing cardiovascular outcomes program (MEDAL). The available data suggest that etoricoxib is an efficacious alternative in the management of arthritis and pain, with the potential advantages of convenient once-daily administration and superior gastrointestinal tolerability compared with traditional NSAIDs.

Effect of atorvastatin on cyclosporine pharmacokinetics in liver transplant recipients.

BACKGROUND: The development of hyperlipidemia after liver transplant is frequently treated with hydroxymethylglutaryl coenzyme A reductase inhibitors (statins) such as atorvastatin. As atorvastatin and the primary immunosuppressant drug, cyclosporine, are metabolized by the same pathway, there is the potential for an interaction. OBJECTIVE: To determine the effect of atorvastatin on cyclosporine pharmacokinetics in liver transplant recipients. METHODS: Six stable, long-term adult liver transplant recipients from a single center who developed posttransplant dyslipidemia were recruited to participate in a 14-day, open-label study of atorvastatin 10 mg/d coadministered with standard posttransplant immunosuppression using constant oral doses of cyclosporine and corticosteroids. A 10-point pharmacokinetic profile was performed prior to and on day 14 after commencement of atorvastatin therapy. Cyclosporine concentrations were measured by HPLC-electrospray-tandem mass spectrometry. The AUC was calculated by the linear trapezoidal rule, with other parameters determined by visual inspection. RESULTS: Atorvastatin coadministration increased the cyclosporine AUC by 9% (range 0-20.6%; 3018 vs 3290 ng.h/mL; p = 0.04). No significant change was evident for other cyclosporine pharmacokinetic parameters. Total cholesterol and low-density lipoprotein cholesterol levels were significantly lower on day 14 than at baseline (p < 0.02). One patient developed a twofold increase in transaminases after 2 weeks of atorvastatin therapy, but no other clinical or biochemical adverse events were recorded. CONCLUSIONS: Atorvastatin coadministration increases the cyclosporine AUC by approximately 10% in stable liver transplant recipients. This change in systemic exposure to cyclosporine is of questionable clinical significance. Atorvastatin is effective in reducing cholesterol levels in liver transplant recipients.