Toenails and agranulocytosis.

The objective of this article was the study of 12 cases of granulocytopenia associated with terbinafine use in Australia, the most recent, with agranulocytosis, which is described in detail. The mean age of the participants was 64 years (range 35-79 years). Sex was reported in 11 patients and all but one was a woman. Time to onset of neutropenia/agranulocytosis was 4-5 weeks in most cases. Neutropenia was typically severe with neutrophil counts < or = 0.3 x 10(3)/mm3 in all but 3 of 11 patients where counts were given. Terbinafine was stopped in all patients, five were hospitalized and one died of septic shock. Six patients received antibiotics and three were given granulocyte colony stimulating factor. Terbinafine, indicated for the treatment of onychomycosis and ringworm, may rarely be associated with granulocytopenia, which is typically severe. It takes approximately 1 month or longer for the development of manifestations of neutropenia, which include fatigue, fever, sore throat and mouth ulceration. Withdrawal of terbinafine and appropriate management of febrile neutropenia will probably result in a favourable outcome. Patients should be warned about this potentially life-threatening adverse reaction and the warning symptoms.

Heparin-induced thrombocytopenia: recent experience in a large teaching hospital.

BACKGROUND: Heparin-induced thrombocytopenia (HIT) is a potentially serious adverse reaction caused by platelet-activating antibodies. AIM: To describe experience with HIT. METHODS: Twenty-two patients identified by laboratory records of heparin-associated antibodies with a 50% or greater decrease in platelet count were reviewed in our 600-bed metropolitan teaching hospital from 1999 to April 2005. RESULTS: There was an increase in the frequency of HIT diagnosed during the review period, which was associated with a rise in the number of requests for HIT antibodies. Thrombotic complications were identified in 14 of 22 patients with HIT. Mean age was 65 years, and 11 patients were men. Seven patients died and HIT was considered contributory in four. One patient required mid-forearm amputation. Unfractionated heparin was used in all cases and five patients also received enoxaparin. Mean time to HIT screen, reflecting when the diagnosis was first suspected, was 14 days. Platelet nadir ranged from 6 x 10(9)/L to 88 x 10(9)/L, with a percentage drop in platelet count of 67-96%. Alternative anticoagulation (danaparoid) was not used in three patients, two of whom died. CONCLUSIONS: HIT is a potentially life-threatening complication of heparin therapy, associated with a fall in platelet count and a high incidence of thromboembolic complications. It is most frequently seen using unfractionated heparin therapy. The increase in frequency of HIT diagnosed in our hospital appears to be associated with a greater awareness of the entity, although detection is often delayed. Platelet count should be monitored in patients on heparin and the presence of antiplatelet antibodies determined if HIT is suspected. Treatment involves both discontinuation of heparin and the use of an alternative anticoagulant such as danaparoid because of the persisting risk of thrombosis.

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. AIMS: (i) To determine concordance between clopidogrel use and the Pharmaceutical Benefits Scheme and local hospital prescribing guidelines and (ii) to determine the intended duration of clopidogrel therapy and ascertain whether this is supported by other published reports. METHODS: Cross-sectional evaluation by patient interview and chart review of appropriateness of clopidogrel prescribing was carried out for 100 consecutive patients attending a 700 bed metropolitan, primary care and tertiary referral hospital. RESULTS: Clopidogrel was predominantly used for secondary prevention of ischaemic heart disease (60%) and following percutaneous coronary intervention (34%). A significant proportion of patients (29%) received clopidogrel outside the prescribing guidelines. Many patients were intended to receive indefinite therapy for secondary prevention of ischaemic vascular events. Concomitant aspirin therapy was not prescribed in 23% of patients, for 78% of whom it was inappropriate. CONCLUSIONS: There is a lack of concordance between clopidogrel use and prescribing guidelines. In the majority of patients (71%), clopidogrel is used for valid indications but there is considerable leakage of use beyond prescribing guidelines. Concomitant aspirin therapy is often not prescribed in the absence of clinically relevant contraindications. Moreover, treatment is continued in many patients beyond what is supported by current published data.

Evaluation of cyclooxygenase 2 inhibitor use in patients admitted to a large teaching hospital.

BACKGROUND: The heavy usage of coxibs in Australia far outstrips the predicted usage that was based on the treatment of patients with risk factors for upper gastro-intestinal adverse events from conventional anti-inflammatory agents. This raises questions regarding the appropriateness of prescribing. AIMS: To determine: (i) the relationship between prescriptions for cyclooxygenase 2 (COX-2) inhibitors and objective evidence of inflammatory arthritis, (ii) prior experience with paracetamol and/or conventional non-steroidal anti-inflammatory drugs (NSAIDs), and (iii) contraindications to the use of NSAIDs. METHODS: Drug utilization evaluation and rheumatological assessment was conducted on 70 consecutive patients admitted on COX-2 inhibitors to a 480-bed metropolitan hospital. The main outcome measures were: the indication for COX-2 inhibitor; objective evidence of inflammatory arthritis; previous trial of paracetamol or conventional NSAIDs; and patient satisfaction. RESULTS: Only 11 patients (16%) had symptoms or signs of an inflammatory arthropathy, and met Pharmaceutical Benefits Schedule criteria for prescribing a COX-2 inhibitor. Fifty-nine patients (84%) had chronic osteoarthritis, degenerative spinal disease, injury or malignancy, without overt active inflammation. Fourteen patients (20%) had trialled regular paracetamol prior to using any NSAID treatment. Conventional NSAIDs had been previously used by 51 patients (73%). Eleven patients (16%) reported previous adverse gastrointestinal effects from conventional NSAIDs. On the basis of significant renal impairment (creatinine clearance <50 mL/min) or cardiac failure, cautions or contraindications applied to the use of any form of NSAID in 49% of patients. Fifteen patients (21%) had demonstrable worsening of their renal function after commencement of a COX-2 inhibitor. Thirty-one percent of patients considered the drug was effective (rated >5/10). CONCLUSIONS: Drug utilization data indicate that COX-2 inhibitors are frequently used first line for degenerative osteoarthritis in the absence of overt inflammation, without prior adequate trial of paracetamol and with disregard for the cautions and contraindications of these agents. These findings may explain the unprecedented Pharmaceutical Benefits Schedule expenditure on COX-2 inhibitors in Australia.

Evaluation of dosage adjustment in patients with renal impairment.

AIMS: To determine whether appropriate dosage adjustments are made in patients with significant renal impairment for drugs with a high fractional renal clearance. METHODS: Evaluation of dosage adjustment was performed in patients who were admitted to a 480-bed metropolitan hospital (Princess Alexandra Hospital, Brisbane, Australia) with an estimated creatinine clearance of < or =40 mL/min. All drugs had a high fractional renal excretion. A prescribed dose within 30% of the calculated dose was considered appropriate. RESULTS: Doses were found to be inappropriately high in 111 (44.8%) of 248 admission prescriptions of the targeted drugs. Doses were appropriately reduced in hospital in 26 patients (23.4%). Seventy-three (29.3%) prescriptions were continued with excessive doses. Only 34 prescriptions for the target drugs were initiated in hospital, of which 88.2% were appropriately dosed. CONCLUSIONS: A significant percentage of patients with renal impairment are admitted to hospital on inappropriately high doses of drugs, with a high fractional renal excretion and low therapeutic index. Doses are appropriately reduced in hospital in some patients but there is still room for improvement [corrected].

Increasing relevance of pharmacogenetics of drug metabolism in clinical practice.

Much of the individual variation in drug response is due to genetic drug metabolic polymorphisms. Clinically relevant examples include acetylator status; cytochrome P450 2D6, 2C9 and 2C19 polymorphisms; and thiopurine methyltransferase deficiency. It is important to be aware of which drugs are subject to pharmacogenetic variability. In the future, population-based pharmacogenetic testing will allow more individualized drug treatment and will avoid the current empiricism.

A detection scheme for paraquat poisoning: validation and a five-year experience in Australia.

We report the validation of a quantitative method for paraquat in plasma and urine using high-performance liquid chromatography (HPLC) with ultraviolet detection (260 nm). Furthermore, we illustrate the use of this method in the clinic (over five years), in conjunction with a qualitative urine paraquat screen. Urine or plasma sample (1 mL) preparation was performed in duplicate using C18 solid-phase extraction. Chromatographic separation was achieved on a Zorbax RX-Silica column (250 x 4.6-mm i.d.). The mobile phase consisted of 96% sodium chloride (5 g/L) and 4% acetonitrile (pH 2.2) pumped at 1.0 mL/min. Using a single-point calibration (1.0 mg/L), the method was found to be linear from 0.1 to 5.0 mg/L. The accuracy and imprecision of the method, over the linear range and for plasma and urine, were 94.7-104.9% and < 12.2%, respectively. The limit of quantitation for both matrices was 0.1 mg/L. The absolute recovery of paraquat from plasma and urine was 79.9 +/- 5.3% and 88.2 +/- 5.3%, respectively. From January 1995 to February 2000, 47 qualitative urine paraquat screens were requested throughout Australia. Nine screens were positive, and eight were confirmed to have paraquat present by our HPLC method. One sample was not analyzed by HPLC because the patient died prior to analysis. Thus, no false-positive results were reported for the qualitative urine screen. An additional 11 samples were referred for patients with positive screens from other sites for HPLC confirmation. The presence of paraquat was confirmed in nine of these samples. In conclusion, a qualitative urine screen combined with our validated HPLC confirmation is an effective protocol for assessing suspected cases of paraquat poisoning.

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.

Evaluation of microparticle enzyme immunoassay against HPLC-mass spectrometry for the determination of whole-blood tacrolimus in heart- and lung-transplant recipients.

OBJECTIVES: Tacrolimus is an immunosuppressant drug with a narrow therapeutic window and thus requires therapeutic drug monitoring. This study evaluates the suitability of the second-generation microparticle enzyme immunoassay (MEIA II) against a specific method, high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS), for the measurement of tacrolimus in both heart- and lung-transplant groups. A secondary objective was to investigate the effect of tacrolimus concentration on MEIA II measurement. METHODS: The HPLC-MS assay was conducted as per our reported method and MEIA II performed according to manufacturer's instructions. Quality-control samples at 5, 11, and 22 microg/L were run in each batch to ensure assay integrity in both methods. Multiple trough samples from 18 heart patients (n = 126) and 17 lung patients (n = 203) were analyzed. RESULTS: The inter-batch imprecision and analytical recovery over the quality-control range by HPLC-MS (n = 12) was <6% and 98.2% to 104%, respectively, and by MEIA II (n = 16) <15% and 92.0% to 99.1%, respectively. The mean overestimation by MEIA II between the two methods for heart- and lung-transplant patient samples was found to be 9.9% (range: -37.4-45.4%) and 13.2% (range: -29.2-64.3%), respectively. Stratification of these data based on the tacrolimus concentration determined by MEIA II, yielded no statistically significant differences in bias between concentration subgroups within the clinically relevant range (p > 0.4). However, a statistically significant difference was detected between the highest concentration subgroup (>20.0 microg/L) and lower concentration subgroups in both transplant populations (p < 0.05). CONCLUSIONS: This study suggests that where HPLC-MS is not available, MEIA II may be suitable for the therapeutic drug monitoring of tacrolimus in heart- and lung-transplant recipients. However, the clinical importance of the observed mean bias, considering the wide range in overestimation in heart- and lung-transplant patient samples, is yet to be determined.

Quantification of free mycophenolic acid by high-performance liquid chromatography-atmospheric pressure chemical ionisation tandem mass spectrometry.

To facilitate the investigation of free mycophenolic acid concentrations we developed a high-performance liquid chromatography tandem mass spectrometry method using indomethacin as an internal standard. Free drug was isolated from plasma samples (500 microl) using ultrafiltration. The analytes were extracted from the ultrafiltrate (200 microl) using C18 solid-phase extraction. Detection was by selected reactant monitoring of mycophenolic acid (m/z 318.9-->190.9) and the internal standard (m/z 356.0-->297.1) with an atmospheric pressure chemical ionisation interface. The total chromatographic analysis time was 12 min. The method was found to be linear over the range investigated, 2.5-200 microg/l (r>0.990, n=6). The relative recovery of the method for the control samples studied (7.5, 40.0 and 150 microg/l) ranged from 95 to 104%. The imprecision of the method, expressed in terms of intra- and inter-day coefficients of variation, was <8 and <9%, respectively. Further, analysis of pooled patient plasma produced an intra-day imprecision of 6.6%. The signal-to-noise ratio at the limit of quantification (2.5 microg/l) was approximately 5:1. The mean absolute recovery (n=6) of mycophenolic acid and the internal standard were 76.0+/-13.5% and 86.0+/-9.1%, respectively. The method reported provides an accurate and precise quantification of free mycophenolic acid over a wide analytical range and thus can be used for routine monitoring and pharmacokinetic studies.

Evaluation of limited sampling strategies for estimation of 12-hour mycophenolic acid area under the plasma concentration-time curve in adult renal transplant patients.

Mycophenolate mofetil, the oral prodrug of mycophenolic acid, is indicated as immunosuppressive therapy after renal transplantation. To aid in the investigation of pharmacokinetic-pharmacodynamic relationships of mycophenolic acid in the clinical setting, limited blood sampling strategies have been proposed, and models from these developed, for the estimation of mycophenolic acid area under the concentration-time curve (AUC). In the current study, the authors investigated the predictive performance of six published models to estimate AUC. A total of 49 profiles from 25 renal transplant patients were used to test each model's performance against a full 14 time-point AUC. A wide range of agreement was found when predicted AUCs were compared with full AUCs using linear regression analysis (range: r2 = 0.499 to 0.836). Model 1, which uses 4 time-points over 6 hours, was found to be superior to all other models. The range of time-points used in this model takes into account patients with variable absorption. This model should be further tested on data sets from other centers. The relatively poor performance of the other models may be caused by their inability to describe the peak concentration in these patients. Caution is warranted when using limited sampling strategies on patients whose absorption of mycophenolic acid is altered, compared with those of the pharmacokinetic profiles from which the model was developed.

Simultaneous quantification of tacrolimus and sirolimus, in human blood, by high-performance liquid chromatography-tandem mass spectrometry.

In this paper the authors present a validated method for the simultaneous analysis of tacrolimus and sirolimus in human blood by high-performance liquid chromatography-electrospray tandem mass spectrometry. Blood samples (500 microL) were prepared by C18 solid-phase extraction. Mass spectrometric detection was by selected reaction monitoring. The assay was linear for both compounds over the range 0.25-100 microg/L (r2 > 0.996, n = 7). At the limit of quantification (0.25 microg/L), for both sirolimus and tacrolimus, the interday imprecision was < 3% and the analytical recovery was between 97.0% and 102%, respectively. The interbatch and intrabatch coefficients of variation of the method for both analytes, at the three quality control concentrations (0.5, 20, and 80 microg/L), were < 16% and < 10%, respectively. The analytical recovery, at the three control concentrations, ranged from 99.2% to 104% of the nominal concentration. The mean absolute recovery (+/- standard deviation) of tacrolimus, sirolimus, and internal standard was 82 +/- 7%, 89 +/- 12%, and 77 +/- 8%, respectively (n = 12). In conclusion, the method presented can be used for simultaneous determination of tacrolimus and sirolimus and will aid in pharmacokinetic studies and therapeutic drug monitoring of these drugs. Furthermore, this method has economic benefits in the clinical setting where these drugs are coadministered.

Stability of sirolimus (rapamycin) in whole blood.

The effects of storage time (0-8 days), temperature (4 degrees C and 30 degrees C in dark and light), and freeze-thaw cycles on the stability of sirolimus in blood were examined. Sirolimus quantification was undertaken using HPLC-electrospray-tandem mass spectrometry. Whole blood samples supplemented with sirolimus (5.0, 15.0, and 30.0 microg/L) and pooled renal and heart transplant samples were found to be stable during the 8 days under all conditions (<10% decrease in concentration). No significant difference was observed in sirolimus concentration between freshly collected patient samples and sirolimus-supplemented samples (5.0, 15.0, and 30.0 microg/L) after three freeze-thaw cycles (p > 0.198). In conclusion, blood samples can be transported with or without cooling for up to 8 days without sirolimus results being compromised. The reanalysis of sirolimus samples, which may entail freeze-thaw cycles, can be undertaken if the number of cycles is three or less.

The quantification of sirolimus by high-performance liquid chromatography-tandem mass spectrometry and microparticle enzyme immunoassay in renal transplant recipients.

BACKGROUND: Sirolimus, an immunosuppressive agent, is undergoing clinical trials in the prophylaxis of organ rejection. OBJECTIVES: The aim of this study was to compare the performance of the semi-automated prototype (mode IA) microparticle enzyme immunoassay (MEIA) against a validated high-performance liquid chromatography-mass spectrometry (HPLC-MS) method for measuring sirolimus concentrations. A secondary objective was to identify potential factors that may influence sirolimus measurement. METHODS: The comparison was based on predose samples (n = 841) from 74 renal transplant patients receiving sirolimus therapy. Samples were collected up to 12 months after transplantation. RESULTS: The mean (+/- SD) overestimation by MEIA was 42.5%+/-16.9%. Several variables were investigated to determine potential contributors to the observed overestimation. Stratification of the data based on the mean sirolimus concentrations determined by both assays yielded no statistically significant differences in bias between concentration subgroups within the clinically relevant range. Multiple linear regression analysis identified HPLC-MS sirolimus concentration (P = 0.03), hemoglobin concentration (P < 0.001), and time after transplantation (P < 0.001) as significant variables in the prediction of overestimation by MEIA. Analysis of the effect of time after transplantation on overestimation yielded a statistically significant difference up to 6 months after transplantation (35.6% to 46.4%) compared with 9 (23.9%) and 12 months (24.4%). A relationship between hemoglobin concentration and time after transplantation may explain the reduction in bias observed after 6 months. CONCLUSION: The MEIA overestimates sirolimus concentrations in renal transplant patients compared with HPLC-MS. The clinical importance of this observed overestimation requires further investigation.

Concordance between use of proton pump inhibitors and prescribing guidelines.

OBJECTIVE: To determine (i) the relationship between prescriptions for proton pump inhibitors (PPIs) and upper gastrointestinal conditions, and (ii) compliance with Pharmaceutical Benefits Scheme (PBS) prescribing guidelines for PPIs. DESIGN: Drug utilisation evaluation. SETTING: 800-bed metropolitan teaching hospital. PARTICIPANTS: 253 patients dispensed PPIs from the hospital pharmacy over five consecutive weeks (11 January to 15 February 1999). MAIN OUTCOME MEASURES: Recorded gastrointestinal conditions; previous trial of H2-antagonist therapy; compliance with PBS criteria for prescribing PPIs. RESULTS: Seventy patients (27.7%) had no appropriate upper gastrointestinal tract investigations, and 62 patients (24%) did not receive an adequate trial of H2-antagonist therapy before the commencement of a PPI. The major indications for use of PPIs in investigated patients were gastro-oesophageal reflux in 99 (54%) and peptic ulcer disease in 30 (16.4%). In only 57 patients (22.5%) did PPI prescriptions comply with PBS prescribing guidelines. Clinical indications that failed to meet prescribing criteria included milder forms of gastro-oesophageal reflux, gastritis/duodenitis, and non-specific dyspepsia with normal endoscopy results. CONCLUSION: Drug utilisation data indicate widespread use of PPIs outside current prescribing guidelines. Many patients have not had relevant investigations and/or an adequate trial of H2-antagonist therapy. These findings explain the considerable hospital expenditure on PPIs.