Paul Kubler

A retrospective analysis of mycophenolic acid and cyclosporin concentrations with acute rejection in renal transplant recipients.

OBJECTIVES Although monitoring of cyclosporin (CsA) is standard clinical practice postrenal transplantation, mycophenolic acid (MPA) concentrations are not routinely measured. There is evidence that a relationship exists between MPA area under the concentration-time curve (AUC) and rejection. In this study, a retrospective analysis was undertaken of 27 adult renal transplant recipients. METHODS Patients received CsA and MPA therapy and had a four-point MPA AUC investigation. The relationship between MPA AUC performed in the first week after transplantation, as well as median trough cyclosporin concentrations, and clinical outcomes in the first month posttransplant were evaluated. RESULTS A total of 12 patients experienced biopsy proven rejection (44.4%) and 4 patients had gastrointestinal adverse events (14.8%). A statistically significant relationship was observed between the incidence of biopsy proven rejection and both MPA AUC (p = 0.02) and median trough CsA concentration (p = 0.008). No relationship between trough MPA concentration and rejection was observed (p = 0.21). Only 3 of 11 (27%) patients with an MPA AUC > 30 mg x h/L and a median trough CsA > 175 microg/L experienced acute rejection, compared with a 56% incidence of rejection for the remaining 16 patients. Patients who experienced adverse gastrointestinal events had significantly lower MPA AUC (p = 0.04), but median trough CsA concentrations were not significantly different (p = 0.24). Further, 3 of these 4 patients had rejection episodes. CONCLUSIONS In addition to standard CsA monitoring, we propose further investigation of the use of a 4-point sampling strategy to predict MPA AUC in the first week posttransplant, which may facilitate optimization of mycophenolate mofetil dose at a time when patients are most vulnerable to acute rejection.

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.

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.

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.

Concordance between clopidogrel use and prescribing guidelines

Background: Clopidogrel is an antiplatelet drug increasingly used in the secondary prevention of atherosclerotic vascular events. Compared with aspirin, clopidogrel has marginal additional efficacy and similar safety, but carries a substantial price premium. It remains unclear whether its use is cost‐effective.

Experience with low-dose rituximab in off-label indications at two tertiary hospitals

Rituximab is a monoclonal antibody directed against B cells and is increasingly used to treat a variety of autoimmune conditions. Most published evidence reporting the successful use of rituximab in off‐label indications has empirically used a high‐dose regimen (either 375 mg/m2 weekly for 4 weeks, or 1000 mg × 2), which is the approved course of treatment for lymphoma and rheumatoid arthritis patients.

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

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.

Gentamicin Monitoring Practices in Teaching Hospitals - Time to Undertake the Necessary Randomised Controlled Trial

Objective: To compare the clinical appropriateness of the prescribing and monitoring of gentamicin. Method: A retrospective study was undertaken at two tertiary teaching hospitals in Australia. 161 adult patients administered gentamicin and who had at least one serum concentration taken whilst an inpatient were eligible for analysis. The main outcome measures were adherence to local and national guidelines for dosing and monitoring of gentamicin, and percentage of the recommended measure of adequate gentamicin exposure (Area-Under the concentration-time Curve (AUC)) using a nomogram and a Bayesian calculation. Results: Results were similar in both hospitals. Initial dosing: Adherence to local and national dosing guidelines was poor - approximately 50% of initial doses using less than local and 88% less than national recommendations. Monitoring: Approximately 20% of all gentamicin concentrations were collected outside the required sampling window. Sampling was particularly problematic after the initial dose. Here up with to half of the samples were taken outside the recommended time frame for sampling, therefore making interpretation of the nomogram difficult. Dose adjustment: 15% of doses were adjusted without monitoring and approximately half of all dose adjustments were based on inadequate information or inaccurate nomogram interpretation. Dose evaluation: Approximately half of the AUCs were below the therapeutic range. Conclusion: A large number of issues around appropriate use and monitoring of gentamicin were seen. This is particularly concerning considering both hospitals are large tertiary hospitals with expert clinical pharmacy support. We believe it is time for a randomised controlled trial to be undertaken, comparing Bayesian modelling techniques with standard nomogram, powered for clinical endpoints

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.

Drug utilization evaluation of i.v. paracetamol at a large teaching hospital

Background: I. v. paracetamol has recently become available in Australia for the treatment of pain when the oral or rectal administration route is not accessible. Our primary aim was to assess compliance with prescribing guidelines and our secondary aim to evaluate the safety of i.v. paracetamol use (4 g/day) and the effect of patient comorbidities on drug safety.