Search

With interest we read the article by Assini et al, about a 77 years old male who developed ptosis, diplopia, dysarthria, and chewing difficulty 2 months after a mild infection with SARS-CoV-2, manifesting with fever and bilateral pneumonia (COVID-19) without necessitating continuous positive airway pressure (CPAP), bilevel positive airway pressure (BIPAP), or mechanical ventilation [1] Work-up revealed muscle-specific tyrosine-kinase (MuSK) positive myasthenia gravis (MG) (MuSK-MG), which did not respond to pyridostigmin but to azathioprine [1]. We have the following comments and concerns.

The clinical features of COVID-19 pneumonia range from a mild illness to patients with a very severe illness with acute hypoxemic respiratory failure requiring ventilation and Intensive Care Unit admission.To provide a brief overview of the existing evidence for such differences in host response and outcome, and generate hypotheses for divergent patterns and avenues for future research, by highlighting similarities and differences in histopathological appearance between COVID-19 and influenza as well as previous coronavirus outbreaks, and by discussing predisposition through genetics and underlying disease.We assessed the available early literature for histopathological patterns of COVID-19 pneumonia and underlying risk factors.The histopathological spectrum of COVID-19 pneumonia includes variable patterns of epithelial damage, vascular complications, fibrosis and inflammation. Risk factors for a fatal disease include older age, respiratory disease, diabetes mellitus, obesity and hypertension.While some risk factors and their potential role in COVID-19 pneumonia are increasingly recognized, little is known about the mechanisms behind episodes of sudden deterioration or the infrequent idiosyncratic clinical demise in otherwise healthy and young subjects.The answer to many of the remaining questions regarding COVID-19 pneumonia pathogenesis may in time be provided by genotyping as well careful clinical, serological, radiological and histopathological phenotyping.

Objective: Several studies have shown that the time of day regulates the reinforcing effects of cocaine. Additionally, melatonin and its MT1 and MT2 receptors have been found to participate in modulation of the reinforcing effects of such addictive drugs as cocaine. Loss of the diurnal variation in cocaine-induced locomotor sensitization and cocaine-induced place preference has been identified in pinealectomized mice. In addition, several studies in rodents have shown that administration of melatonin decreased the reinforcing effects of cocaine. The objective of this study was to evaluate the effect of melatonin on cocaine-induced locomotor activity in pinealectomized rats at different times of day (zeitgeber time [ZT]4, ZT10, ZT16, and ZT22). Methods: Naïve, pinealectomized Wistar rats received cocaine at different times of day. Melatonin was administered 30 min before cocaine; luzindole was administered 15 min prior to melatonin and 45 min before cocaine. After administration of each treatment, locomotor activity for each animal was recorded for a total of 30 min. Pinealectomy was confirmed at the end of the experiment through melatonin quantitation by ELISA. Results: Cocaine-induced locomotor activity varied according to the time of day. Continuous lighting and pinealectomy increased cocaine-induced locomotor activity. Melatonin administration decreased cocaine-induced locomotor activity in naïve and pinealectomized rats at different times of day. Luzindole blocked the melatonin-induced reduction in cocaine-induced locomotor activity in pinealectomized rats. Conclusion: Given its ability to mitigate various reinforcing effects of cocaine, melatonin could be a useful therapy for cocaine abuse.

Objective: To review the available data on diffusion tensor imaging (DTI) of subjects with bipolar disorder (BD), with a particular focus on fractional anisotropy (FA) in white matter (WM) tracts. Methods: The PubMed/MEDLINE database was searched for relevant articles, which were included in a systematic review of the literature. FA reductions and WM abnormalities were divided anatomically into three groups: commissural tracts, association tracts, and projection tracts. Results: Eighteen studies met the inclusion criteria. The corpus callosum was the main impaired commissural tract as demonstrated by FA reductions. Five studies reported FA reductions in the cingulum. Two studies reported decreased FA in the anterior thalamic radiation, and one in the corticospinal tract. Conversely, three studies found increased FA values in WM tracts involved in BD pathophysiology. Conclusion: Despite considerable heterogeneity, these results indicate a direct link between executive cognitive functioning and abnormal WM microstructural integrity of fronto-limbic tracts in patients with remitted BD, providing further evidence of the neuronal disruption that underlies BD symptomatology.

Tumour lysis syndrome (TLS) is a life-threatening oncological emergency characterized by hyperuricaemia, hyperkalaemia, hyperphosphataemia, and hypocalcaemia [1, 2] due to the rapid lysis of malignant cells, following the initiation of anticancer therapies [3]. Traditionally, therapy for TLS involved intensive hydration, urinary alkalinization and administration of allopurinol [4–6]. Newer guidelines now include rasburicase, with monitoring of electrolytes, white blood cell counts (WCC) and lactate dehydrogenase (LDH) concentrations [1, 7, 8]. Rasburicase, a recombinant urate oxidase enzyme, effectively decreases existing serum uric acid (UA) by oxidizing it to allantoin which is readily soluble and excretable [3]. Although the recommended dose is 0.2 mg kg−1 day−1 for 5–7 days [9], studies have shown the efficacious use of reduced doses for shorter periods of time and subsequent cost savings [5, 6, 10–17]. Expert guidelines by Coieffer et al. [7] in 2008 and Cairo et al. in 2010 [1] on the management of TLS recommend a rasburicase dose of 0.1–0.2 mg kg−1 on the first day, then repeated for up to 7 days [1] or as necessary [7]. We present an analysis of a fixed 3 mg dose of rasburicase administered to adult patients, treated at a tertiary referral centre. The study was approved by the Alfred Health Human Research Ethics Committee and the Monash University Human Research Ethics Committee. Demographic data were collected. Biochemical parameters (serum creatinine, serum UA, phosphate and LDH concentrations), at baseline, 24 h and 72 h after initial administration of rasburicase were recorded and compared. The institution guideline indicates rasburicase to be given before the first dose of chemotherapy in patients considered high risk for TLS. This includes a diagnosis of Burkitt's lymphoma, acute lymhoblastic leukaemia, bulky non-Hodgkin's lymphoma, lymphoblastic lymphoma or acute myeloid leukaemia with one or more of the following: serum UA>0.46 mmol l−1, white cell count (WCC) >50 × 109 l−1 or LDH >two times normal. Patients who were at an ongoing risk of TLS (i.e. elevated UA or LDH or multiple days of aggressive cytoreductive chemotherapy) were allowed a repeat dose of rasburicase 3 mg. Adherence to the guideline was measured. Forty-one patients received 42 courses of rasburicase over a 40 month period (Figure 1A). Diagnosis, demographic and baseline biochemical data are presented in Table 1. Figure 1 Summaryof rasburicase courses and uric acid concentrations. A) Summary of rasburicase courses administered. B) Median uric acid concentrations over time stratified by presentation a baseline. ♦, normal; ▪, hyperuricaemic; ▴, all ... Table 1 Patientcharacteristics Rasburicase was administered as per institution guidelines in 40 (95%) of the patients. Median serum UA concentrations were within normal range at 72 h in all groups; in those who presented with hyperuricaemia, in those who presented with normal baseline serum UA concentrations and overall (Figure 1B). The majority of patients received one dose of rasburicase 3 mg (Figure 1A). In 34 patient episodes requiring one dose only, there was a decline in the median (range) UA concentration from 0.44 mmol l−1 (0.13–1.15) at baseline to 0.22 mmol l−1 (0.02–0.66) at 24 h. This decrease was maintained at 72 h (P < 0.0001) with a median of 0.21 mmol l−1 (0.02–0.52). Serum creatinine concentrations were within normal range (60–105 μmol l−1) at baseline in 74% of patients, with 82% having a normal creatinine at 72 h. Hyperphosphataemia was present in 29% of patients at baseline and increased to 44% at 72 h. Eight patient episodes required more than one dose due to the ongoing risk of TLS. In these patients the median (range) baseline UA was 0.50 mmol l−1 (0.02–2.0), 0.33 mmol l−1 (0.02−1.10) at 24 h and 0.24 mmol l−1 (0.02−1.10) at 72 h (P < 0.0001). Of these patients only 52% had a normal creatinine at baseline, increasing to 83% at 72 h. Mean phosphate concentrations decreased over time but all patients remained hyperphosphataemic at 72 h. No hypersensitivity reactions were noted, no patients required haemodialysis and no deaths were related to the administration of rasburicase. Our results demonstrate that a single fixed dose of rasburicase 3 mg, repeated if required, should be the standard regimen in the management of TLS. Recent studies and published guidelines have shown cumulative support for the safe and efficacious use of off-label dosing regimens of rasburicase [1, 5–8, 10, 11, 16, 17]. A quarter of our patients presented with a baseline WCC>100 × 109 l−1 (Table 1), which is considered a high risk for developing TLS [1, 7]. The Product Information recommends rasburicase 0.1–0.2 mg kg−1 day−1 for 1–7 days [9]. We successfully used a fixed 3 mg dose for these patients. Our data support that presented by Trifilio et al. [11] in a recent study of 287 episodes, the largest published series at this time, of raised UA concentrations successfully treated with a single 3 mg dose of rasburicase, repeated if required. In our cohort, which was smaller in size, a single 3 mg dose was equally effective in both patients who had a normal baseline UA and those with hyperuracaemia. This differed from that published by Trifilio et al., where the single dose was more successful in patients with a lower baseline UA concentration. Our patient cohort also had a higher median LDH. Suboptimal management of hyperphosphatemia was identified in our cohort. More stringent monitoring of patient phosphate concentrations may be warranted in the future to minimize the risk of renal impairment. Serum creatinine, showing a gradual decrease with time, was used as a surrogate maker to indicate an improvement in renal function. Rasburicase was used in conjunction with allopurinol, urinary alkalinazation and intravenous hydration. This strategy is also supported by recent studies and recommendations [1, 11, 16], although the benefit of administering alkalinization with rasburicase needs further investigation [1, 7]. A single fixed 3 mg dose of rasburicase, in the setting of an institution guideline, was efficacious in the management of TLS.

To the Editor Depression is a multifaceted disorder with diverse causes and has been associated with the risk to develop severe medical disorders.1 Indeed, depression increases the risk of cardiovascular disease by 1.5-fold to 2-fold, of stroke by 1.8-fold, of Alzheimer disease by 2.1-fold, of diabetes by 60%, and of cancer by 1.3-fold to 1.8-fold.1 Fibroblast growth factors (FGFs) are best known for their regulatory roles in cell growth, differentiation, and morphogenesis in early stages of neural development and have been discussed as switch genes, biomarkers, and treatment targets for affective disorders recently.2,3 However, at least FGF-23 has also been proposed as a cardiovascular risk marker,4 a central player of disordered mineral metabolism,5 and acts to decrease phosphate, 1,25-dihydroxyvitamin D, and parathyroid hormone levels.5 A close, bidirectional relationship exists between depression and cardiovascular disease.1 Indeed, major depression is associated with an increased risk of coronary artery disease, myocardial infarction, congestive heart failure, and isolated systolic hypertension leading to increased mortality and morbidity in patients.1 Moreover, a strong relationship has been described between severe coronary and aortic calcifications, intima thickness, osteoporosis, and depressive disorders.1 Fibroblast growth factor 23 lowers serum levels of 1,25(OH)2D3, which in turn up-regulates renal and intestinal phosphate and calcium transport.6–9 In mice, it was shown recently that lithium treatment up-regulates FGF-23 formation, an effect paralleled by substantial decrease of serum 1,25(OH)2D3 and phosphate concentrations.10 The present study explores the effect of lithium treatment on serum FGF-23, 1,25(OH)2D3, calcium, and phosphate concentrations in depressed patients. A total of 95 acute depressive patients (age 48 ± 14 years) were recruited for this study. Inclusion criteria consist of unipolar depression, age older than 18 years, indication for antidepressant pharmacotherapy, insufficient response to an adequate antidepressant pretreatment and clinical indication for lithium augmentation, hamilton depression rating score greater than 12, and written informed consent. Diagnosis was confirmed on the basis of the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders. Fibroblast growth factor 23 serum concentrations were measured first in medicated patients before lithium augmentation and then after 4 weeks of medication with lithium. Detailed clinical data of the patients have already been published.11 All patients reached a lithium serum level of more than 0.4 mmol/L. Serum FGF-23 concentrations were measured by enzyme-linked immunosorbent assay (Immutopics International, California; AVP EIA kit, Phoenix Europe, Karlsruhe, Germany). enzyme-linked immunosorbent assay kits were employed to determine serum concentrations of 1,25(OH)2D3 (IDS, Boldon, United Kingdom). Data are provided as mean ± SEM; n represents the number of independent experiments. All data were tested for significance using unpaired Student t test. Only results with P < 0.05 were considered statistically significant. As illustrated in Figure ​Figure1,1, lithium treatment was followed by a marked increase of serum FGF-23 concentration. As shown in Figure ​Figure1,1, lithium treatment significantly decreased serum 1,25(OH)2D3 concentration. Lithium treatment significantly decreased serum phosphate concentrations (data not shown). FIGURE 1 Serum FGF-23 and 1,25(OH)2D3 levels/concentrations before and after lithium treatment. Arithmetic means ± SEM (n = 95) of serum FGF-23 (A) and 1,25(OH)2D3 levels (B) before (white bars) and after (black bars) lithium treatment. **P < 0.01 ...

Inhaled corticosteroids and long-acting β2-agonists are medications taken daily on a long-term basis to keep asthma under clinical control. Studies have shown that delivering this therapy in a combination inhaler is as effective as giving each drug separately, but fixed combination inhalers are more convenient for adolescents with asthma, increasing treatment adherence and ensuring that long-acting β2-agonists are always accompanied by inhaled corticosteroids [1,2]. An extrafine fixed combination of beclometasone dipropionate (BDP) and formoterol fumarate (FF) is marketed both as a pressurized metered dose inhaler (pMDI) and as a dry powder inhaler (DPI), as Foster® and Foster® Nexthaler® (Chiesi Farmaceutici S.p.A., Parma, Italy) [3], respectively, at the dose strength of 100/6 μg for patients with asthma ≥18 years of age. The same dose strength is currently being developed in asthmatic adolescents aged 12–17 years. The purpose of this study was to investigate the systemic availability of B17MP (active metabolite of BDP) and formoterol after inhalation of an extrafine fixed combination of BDP/FF 100/6 μg via the NEXThaler® DPI in comparison to the free combination of BDP (Clenil® Pulvinal® 100 μg) and FF (Foradil® Aerolizer® 12 μg) DPIs (Novartis Pharmaceuticals Ltd, Frimley, UK) at a total single dose of 400/24 μg in asthmatic adolescents. Adolescents aged 12–17 years with mild-to-moderate asthma in a stable state participated in this randomized, crossover, single-dose study with two active treatment periods conducted at the Children's Asthma Clinic, Copenhagen, Denmark (ClinicalTrials.gov Identifier: NCT01191424). On each treatment day, blood was sampled for pharmacokinetic and pharmacodynamic assessments before and 5, 15 and 30 min and 1, 2, 4, 6 and 8 h after actuation of the DPIs [4]. Lung function [forced expiratory volume in 1 s (FEV1)] and heart rate were assessed concomitantly and adverse events recorded (see Appendix S1 for details). Pharmacokinetic end-points were as follows: area under the plasma drug concentration–time curve (AUC0–t), maximal plasma concentration (Cmax) and terminal half-life (t1/2) for B17MP and formoterol. The AUC0–t for B17MP was the primary end-point. Pharmacodynamic end-points were as follows: plasma potassium and plasma cortisol minimum plasma concentration (Cmin) and AUC0–t, plasma glucose Cmax and AUC0–2h, time-averaged FEV1 (AUC0–8h/8h) and heart rate (AUC0–8h/8h). All variables were log-transformed and treatment comparisons made using ANOVA models estimating the ratio of the adjusted geometric means test/reference (fixed/free combination) with the corresponding 90% confidence interval (CI) for the pharmacokinetic variables and 95% CI for the pharmacodynamic variables. Bioequivalence for the variables between treatments was demonstrated if the CIs were within the 0.8–1.25 acceptance region [5]. The study design had 90% power to reject the null hypothesis that the upper limit of the 90% CI for the ratio of test/reference means above 1.25 for B17MP AUC0–t. Twenty-seven adolescents [55% males; mean age (SD), 14 years (1.7)] completed the study. The B17MP AUC0–t was slightly higher following BDP/FF NEXThaler® vs. BDP and FF DPIs: test/reference ratio 1.14 (90% CI, 1.03–1.28; Table 1). The plasma cortisol test/reference ratio lower 90% CI bound was just below 0.8 [AUC0–t ratio, 0.92 (0.79–1.06)], but no plasma cortisol levels were below the lower clinical normal limit (5 ng ml−1) in either treatment group. Formoterol AUC0–t was higher following test vs. reference treatment [ratio, 1.46 (1.36–1.56)] and Cmax significantly increased [ratio, 2.83 (2.56–3.13)], but time to Cmax was the same for both treatments (median, 0.08 h). The plasma potassium [AUC0–t test/reference ratio, 0.98 (0.95–1.00)], plasma glucose [AUC0–2h ratio, 1.02 (0.99–1.05)] and heart rate [AUC0–8h/8h ratio, 1.05 (1.01–1.09)] were all within the predefined bioequivalence limit. The treatment effects on FEV1 were similar, and no notable differences in adverse events were observed (see Appendix S1). Table 1 Pharmacokinetic and pharmacodynamic comparison of BDP/FF 400/24 μg inhaled from the fixed BDP/FF 100/6 μg NEXThaler® DPI vs. BDP (Clenil® Pulvinal® 100 μg) and FF ... In adolescents with asthma, the systemic exposure to B17MP following four actuations of BDP/FF 100/6 μg NEXThaler® DPI compared with four actuations of BDP (Clenil® Pulvinal® 100 μg) and two actuations of FF (Foradil® Aerolizer® 12 μg) DPIs was slightly above the 125% bioequivalence limit, with a minor suppression of plasma cortisol levels. The clinical relevance of such suppression should be assessed after repeated administration according to European Medicines Agency guidelines [5]. Formoterol exposure was higher after administration of the fixed vs. free combination, but with comparable systemic effect in terms of heart rate, plasma glucose and plasma potassium. The FEV1 and safety profiles were also comparable. Potassium AUC0–t and Cmin were not affected by the increased formoterol exposure, which may be due to the transient formoterol peak concentration and the time delay between concentration and response or, alternatively, assay insensitivity. We speculate that the increased systemic exposure to formoterol and the slightly increased exposure to B17MP following the fixed BDP/FF NEXThaler® is caused by device-dependent different lung deposition. The BDP/FF NEXThaler® is an extrafine particle DPI with a low minimal inhalation flow threshold [6] in comparison to the Foradil® Aerolizer®, which requires a flow >60 l min−1, below which deagglomeration may be inefficient, resulting in a reduced emitted dose with larger particles and reduced lung deposition. In conclusion, inhalation from BDP/FF 100/6 μg NEXThaler® DPI resulted in a very similar exposure to B17MP but a greater exposure to formoterol compared with the licensed free combination in asthmatic adolescents. However, the greater bioavailability of formoterol following dosing with NEXThaler® had no systemic impact and did not affect the safety profile. For conduction of future bioequivalence trials, we highly recommend usage of devices with comparable lung deposition characteristics, because systemic absorption in adolescents seems to differ according to the device, which may have safety implications.

Inhaled corticosteroids are well established as the first choice of anti-inflammatory therapy for the prophylaxis of asthma in both adults and children. Current treatment guidelines recommend that inhaled corticosteroids should be prescribed for individuals with persistent asthma at all severity levels as long term treatment markedly reduces the frequency and severity of exacerbations. A large number of inhalation devices are used for delivery of asthma medication in children, and it is well known that choice of device is key for the amount of drug that reaches the lungs. For infants and preschool children, in whom active cooperation can be problematic, a pressurized metered dose inhaler (pMDI) used in conjunction with a spacer is usually preferred for maintenance therapy whereas from approximately 6 years onwards a dry powder inhaler (DPI) or breath-activated MDI is recommended [1]. The switch from one delivery device to another generates a possibility of either achieving subtherapeutic drug concentrations or excessive drug exposure with the risk of unwanted side effects. However, there are limited childhood studies available comparing systemic exposure of inhaled corticosteroids using different inhalation devices, and thus no clear rationale for dose selection and dose titration following switch between devices in children with asthma [2]. The objective of this single dose, randomized, double-blind, double-dummy, crossover study was to investigate the effect of delivery device on systemic exposure to fluticasone proprionate (FP) in children with asthma. Due to negligible oral bioavailability of FP and absence of pre-systemic metabolism in the lung, systemic appearance of FP following inhalation is considered equivalent to lung deposition [3]. The study was conducted at the Copenhagen Prospective Study on Asthma in Childhood (COPSAC) clinical research unit in Copenhagen, Denmark. Children with a documented clinical history of mild asthma diagnosed according to the GINA guidelines and able to use the inhalation devices properly were included in the study. Subjects were excluded if they had changed their asthma medication, received systemic corticosteroids, had an airway infection or asthma exacerbation within 4 weeks prior to recruitment or were unable to withdraw from their controller therapy for the duration of the study. The local Ethics Committee provided formal approval of the study (KF 02–107/98, KF 12–136/99). Written informed consent to participate in the study was obtained from subjects and their parents/guardians. Systemic exposure to FP was examined in 13 children aged 12–15 years (10 males), following FP 500 μg inhaled via a DPI (Diskus®) or pMDI with spacer (Volumatic™). The FP dose delivered via pMDI plus spacer was given as two actuations of 250 μg where each puff was inhaled with 30 s of tidal breathing causing an exponential emptying of the aerosol plume. One child had parental consent withdrawn and another child was excluded for technical reasons. Blood samples (5 ml) were collected 10 min before drug administration (baseline) and 20 min, 40 min, 1, 2, 3, 4 and 6 h post-dose for determination of FP plasma concentration [4]. The FP analysis method had a calibration range of 10–1500 pg ml−1 from 0.5 ml plasma. Mean peak inspiratory flow rate obtained during inhalation from the DPI was 107 l min−1 (range 45–126). Delivery of FP 500 μg via a pMDI plus spacer compared with the DPI resulted in a 38% higher maximal plasma concentration (Cmax) (P = 0.02) and 70% higher area under the concentration–time curve (AUC(0,tlast)) (P < 0.01) (Figure ​(Figure1).1). Time to median peak plasma FP concentration (tmax) was furthermore longer with pMDI vs. DPI: 2 h vs. 1 h (P = 0.03) (Table S1 Online). Figure 1 Mean plasma concentrations of fluticasone propionate (FP) following administration of a single 500 μg dose via dry powder Inhaler (DPI) (Diskus®) and pressurized metered dose inhaler (pMDI) plus spacer (Volumatic™) in 12–15-year-old ... The higher systemic exposure after pMDI plus spacer may be due to exponential emptying of the spacer following subsequent inhalations resulting in a greater inhaled volume of the aerosol and increased lung deposition compared to DPI. With DPI, the inhaled volume of drug depends on the turbulence created by each single inhalation and increased impaction in the oropharyngeal region may be a limiting factor for lung deposition [3]. To our knowledge, no previous study has sought to titrate DPI and pMDI to deliver an equivalent lung dose in children, but results in adults have also suggested increased systemic activity with pMDI [5]. Inhaled FP follows linear pharmacokinetics in a wide dose range suggesting that the observed differences between devices will be similar for lower doses [6]. In conclusion, systemic exposure reflecting lung deposition of inhaled FP in 12–15-year-old asthmatic children was significantly higher when the dose was delivered via a pMDI plus spacer (Volumatic™) compared with a DPI (Diskus®). Therefore, we recommend that physicians and patients should be made aware that changing the device may significantly affect the lung dose and hence dose adjustment should be considered.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Extrapyramidal side-effects induced by antipsychotic agents are treated with dose reduction, switching of antipsychotic medication or the addition of anticholinergic antiparkinson drugs. WHAT THIS STUDY ADDS • The use of anticholinergic antiparkinson drugs appears to be superfluous in a large number of patients. AIMS Extrapyramidal side-effects induced by antipsychotic drugs are treated with dose reduction or substitution with another antipsychotic drug or by the addition of anticholinergic antiparkinson agents. The withdrawal of orphenadrine from the Norwegian market provided a possibility to investigate to what degree these alternative measures were taken in clinical practice. METHODS Data were drawn from the Norwegian Prescription Database on the sales of antipsychotics and one of the two anticholinergic antiparkinson agents marketed in 2004, orphenadrine and biperiden, to a total of 39 758 outpatients. The patients were reinvestigated in 2007. The consequences of the withdrawal of orphenadrine from the Norwegian market in 2005 regarding dosing, switching and cessation of antipsychotics and use of anticholinergics were assessed for orphenadrine users compared with biperiden users. RESULTS Of the patients originally using orphenadrine, 28.4% stopped using the drug without reducing the antipsychotic dose or replacing orphenadrine with another anticholinergic agent. The corresponding number for biperiden users was 19.3%. Only 11.8% of patients switched to another antipsychotic drug, but they used significantly lower antipsychotic doses than those who stayed on the same drug. CONCLUSION The use of anticholinergic antiparkinson agents could be seen as superfluous for at least one-third of patients.

5-Fluorouracil (5-FU) is widely administered as a continuous infusion to treat gastrointestinal tract or head and neck cancers, and as bolus injections in breast cancer chemotherapy regimens. Grade 3–4 toxicity occurs in about 30% of patients receiving 5-FU as a continuous infusion, and proves lethal in 0.5% of these patients [1]. 5-FU-related toxicity has mostly been reported with intravenous administration [1–3]. However, some cases of severe toxicity, including deaths, have been described after oral administration of 5-FU derivatives, such as capecitabine (Xeloda®) [4, 5]. A polymorphism of the dihydropyrimidine dehydrogenase (DPD) gene has been identified as a frequent cause of such toxicity [6, 7]. DPD catalyses the rate-limiting step of fluoropyrimidine catabolism. Partial or total DPD deficiency therefore leads to substantial overexposure in patients treated with the standard dose, exacerbating drug toxicity. This raises questions about possible screening for DPD deficiency before the administration of fluoropyrimidine drugs, including their oral forms. Patients found to have a deficiency on screening before treatment or following signs of toxicity during a previous course are usually given alternative treatments based on nonfluoropyrimidine compounds. However, 5-FU is highly active and its use may be essential in patients who fail to respond to other treatments. We report the case of a patient with DPD deficiency detected due to severe toxicity during capecitabine treatment, who has since received a continuous infusion of 5-FU at almost the standard dose with no significant signs of toxicity.

Aims To characterize the pharmacokinetics of mycophenolic acid (MPA) in Chinese renal transplant patients. Methods Thirty-one renal transplant patients (17 male, 14 female) receiving mycophenolate mofetil (MMF) 1.0 g twice daily were included in this study. A pharmacokinetic study was performed during an interval in dosing after steady state had been reached within 2 months after transplantation. The plasma MPA concentration were measured by high-performance liquid chromatography (HPLC) at 0.5, 1, 1.5, 2, 4, 6, 8, 10 and 12 h after the administration of a single dose. Pharmacokinetic parameters were calculated with 3P97 software. SAS® software was used for statistical analysis. Multiple linear regression analysis was used to determine limited sampling approaches. Results The mean peak plasma concentration (Cmax) and area under the concentration–time curve (AUC0−12) were 19.67 ± 8.21 µg ml−1 and 52.16 ± 12.50 µg h ml−1, but there was large variability in these pharmacokinetic parameters. Regression analysis between each plasma concentration and AUC for the limited sampling strategy of MMF therapeutic drug monitoring demonstrated that each of the concentrations at 0.5, 1, 4 and 10 h was positively correlated with AUC (r = 0.60, P = 0.0004; r = 0.60, P = 0.0003; r = 0.61, P = 0.0003; r = 0.64, P = 0.0001, respectively). The combined use of these four samples explained over 90% of the variance in the total (nine-point) AUC0−12. A formula was obtained for the assessment of MPA AUC based on four samples: MPA AUC = 12.61 + 0.37 × C0.5 + 0.49 × C1 + 3.22 × C4 + 8.17 × C10. Conclusions Chinese renal transplant patients had higher median AUCs than caucasians and African-Americans. As in other studies, there was large interindividual variability. A limited four-point AUC was in good agreement with the 12-h AUC and provided the basis of a predictive formula.

In comparison with carbamazepine, oxcarbazepine (OXC) has fewer associated side-effects and a reduced number of reported drug–drug interactions. The only cases of serious toxicity have been documented after suicide attempts using multiple drugs [1], but OXC toxicity alone has never been noted to be the only cause of death [2]. The main drug–drug interactions reported (in particular with other antiepileptics such as carbamazepine, phenobarbital and sodium valproate) actually result in the lowering of plasma OXC concentrations [3, 4]. We report a case of severe OXC toxicity after starting clarithromycin in a patient with refractory epilepsy and discuss the mechanism of this potential interaction. We suggest that clarithromycin may inhibit the efflux proteins of the blood–brain barrier (BBB), which are thought to be overexpressed in drug-resistant patients [5]. This inhibition may result in increased cerebrospinal fluid (CSF) concentrations of OXC and explain the signs of toxicity observed. A 10-year-old boy with known refractory epilepsy presented to our department with symptoms suggestive of acute OXC toxicity. His past medical history included a diagnosis of epilepsy at the age of 18 months when he presented with generalized tonic clonic seizures and associated global developmental delay. There were no other significant illnesses or dysmorphism and he had been born at term without complications. The first child of nonconsanguineous North African parents, there was a family history of epilepsy in three paternal second cousins (one with developmental delay). Diagnostic investigations performed included normal brain magnetic resonance imaging and positron emission tomography scan, karyotyping, genetic screening for fragile X syndrome and a metabolic screen, all of which were unremarkable. His medications at the time of presentation included: OXC 540 mg am/510 mg nocte, lamotrigine 100 mg b.d., sodium valproate 100 mg am/300 mg and topiramate 100 mg b.d. Despite the treatment, between two and three epileptic fits were reported per month. A course of clarithromycin (250 mg b.d.) was started due to a mild respiratory tract infection 3 days after the onset of coryzal symptoms. An hour after he had taken the first dose, the parents noticed their son was unsteady on his feet (Figure 1) and had a brief episode where he appeared unresponsive. Twenty-four hours after starting the antibiotic, he was brought to our paediatric emergency department with an increase in symptoms including vomiting, drowsiness and dizzy spells. Clinical neurological examination revealed hyperkinesia, ataxia and nystagmus. At the time of presentation, the patient was already apyrexial with no respiratory signs other than mild coryzal symptoms. The rest of the clinical examination was unremarkable. On admission, blood tests were essentially normal, including: plasma electrolytes, liver enzymes, renal function and inflammatory markers (sodium 142 mmol l−1, potassium 3.5 mmol l−1, C-reactive protein 57 mg l−1). An initial electroencephalogram showed a decrease in paroxysmal activity. Plasma levels of sodium valproate were dosed as suboptimal (21.7 mg l−1, ref 50–100 mg l−1) and as an incidental finding, the patient was noted to be mildly hypocalcaemic (2.08 mg l−1, ref 2.20–2.80 mg l−1). Twelve hours after admission, the dose of OXC was reduced to 420 mg (80% of the original) and the clarithromycin was stopped. The other medications remained unchanged. After a further 12 h, the dose of OXC was increased back to 540 mg as the clinical symptoms were much improved. Following this increase, once again the patient developed drowsiness and ataxia. As a result, the OXC dose was halved for 24 h. No further symptoms were reported and the dose was then progressively increased back to the initial value over a period of 72 h. No further symptoms or seizures were reported during the rest of his hospital stay and the patient was discharged home after 5 days. Figure 1 Clinical symptoms vs. time since starting clarithromycin OXC is particularly recommended due to the minimal side-effects and drug interactions seen in comparison with carbamazepine. We report the first case of OXC toxicity likely to have been induced by a drug–drug interaction with clarithromycin (250 mg b.d.). After two doses of clarithromycin, the patient needed to be hospitalized as an emergency for suspected toxicity. Many of the symptoms observed in our patient are known to be linked to possible OXC toxicity, including drowsiness, dizziness, nausea, vomiting, hyperkinesia, ataxia and nystagmus. Once the clarithromycin was stopped, a clear improvement was seen (t1/2= 4 h). However, the early re-introduction of OXC (back to the initial dose after 12 h) resulted in a further similar episode. The dose was then halved and progressively increased over a period of 72 h with no further problems. This shows there is a latent period in the mechanism of interaction between clarithromycin and OXC. Furthermore, halving the OXC dose did not lead to any seizures in our patient. In the absence of treatment with clarithromycin, the patient had not previously developed any signs of OXC toxicity (despite being on the medication at the same dose for several months). To date, the only reported OXC interactions are due to modifications in liver metabolism. Ninety-five percent of OXC is metabolized to the active monohydroxy derivative (DMH) and 4% to the inactive dihydroxy derivative (DDH). Pisani et al. have shown that an increase in levels of the active metabolite and a decrease in the inactive form occur when OXC is administered in conjunction with viloxazine (an antidepressant) [6]. This inhibition of the conversion of the active DMH to the inactive DDH form has never been linked to any adverse clinical effects. Studies carried out to research possible interactions between macrolides (erythromycin) and OXC have not shown any interactions [7]. However, such studies were conducted in healthy volunteers with no prior drug resistance, and the results were based on potential changes in plasma concentrations of OXC and DMH. It has been shown that normal OXC or DMH serum levels do not exclude central nervous system (CNS) toxicity or the occurrence of serious neurological adverse effects [8]. The lack of correlation between serum OXC levels and neurological side-effects can be explained by the fact that serum levels do not give a reliable reflection of the actual levels in the CNS. Thus, passage across the BBB may be an important factor in the efficacy of OXC and DMH. Numerous studies have demonstrated the role played by efflux proteins present on the membranes of cells which make up the BBB [9]. Increased expression of efflux proteins such as the P-glycoproteins (multidrug resistance 1 and 2) and the Multidrug Resistance Proteins 1–9 has been observed in some drug-resistant patients, which could be responsible for a decreased concentration of OXC in the CSF, resulting in decreased clinical effects [4, 9–11]. Macrolides are known to be potent inhibitors of P-glycoprotein (50% decrease in activity). Therefore, we propose that the toxic side-effects observed in our patient after starting clarithromycin (whilst already on OXC) may be explained by an increase in brain OXC concentrations due to the inhibition of the active BBB efflux proteins. We recommend physicians consider adjusting the dose of OXC when using a macrolide in drug-resistant patients due to the potential risks of drug toxicity.

Azathioprine (AZA), a prodrug of 6-mercaptopurine, is prescribed in evolving forms of inflammatory bowel disease (IBD), affecting predominantly White adolescents and young adults. Thiopurine S-methyltransferase (TPMT) catabolizes AZA and its genetic polymorphism affects the balance between active 6-thioguanine nucleotides (6-TGN) intracellular concentrations [recommended target 235–400 pmol per 8 × 108 red blood cells (RBC)] and hepatotoxic 6-methylmercaptopurine ribonucleotides (6-MMP) [1]. Three polymorphisms (TPMT*2, *3B, *3C; rs1800462, rs1800460, rs1142345, respectively) account for >95% of variant alleles, but additional rare variants are described (TPMT*1S to TPMT*25) [2]. Approximately 90% of Whites are extensive metabolizers with two wild-type TPMT alleles, 6–11% are intermediate metabolizers and 0.2–0.6% are TPMT-deficient patients, exposed to severe myelotoxicity as they accumulate high 6-TGN concentrations under AZA conventional doses [3]. This case reports a pancytopenia under AZA treatment for IBD. As 6-TGN and 6-MMP concentrations and TPMT genotype based on the three predominant polymorphisms were discordant, we conducted additional genetic analysis and identified a new, never described TPMT mutation affecting TPMT activity.

While the cure for pulmonary arterial hypertension (PAH) has been elusive, it has been managed by the use of prostanoids, endothelin receptor antagonists (ERA) and the phosphodiesterase-5 (PDE5) inhibitors [1–7]. Recently, the combination of ERA (e.g. bosentan) and PDE5 inhibitors (e.g. sildenafil) has been explored with encouraging outcome [6, 8–10]. The clinical pharmacology of bosentan, the first approved ERA, has been reviewed by Dingemanse and van Giersbergen [11]. Bosentan apparently undergoes complete elimination via hepatic metabolism, followed by biliary excretion of the metabolites with an elimination half-life of 4–5 h. Apart from mild hepatic dysfunction, other conditions of hepatic dysfunction of increasing severity substantially altered the pharmacokinetic disposition of bosentan. The involvement of both cytochrome P450 (CYP) 3A4 and CYP2C9 has been implicated in bosentan's metabolism to form three oxidative metabolites. Interestingly, bosentan decreases the exposure of both CYP3A4 and CYP2C9 substrates due to induction phenomena, whereas a CYP3A4 inhibitor has the propensity to increase dramatically the exposure to bosentan. The pharmacokinetics and clinical pharmacology attributes of sildenafil have been described [12–15]. The metabolic pathways of sildenafil comprise N-demethylation, aliphatic hydroxylation and oxidation, with major involvement of CYP3A4 (70%) and minor involvement of CYP2C9 (20%) isozymes; upon co-administration, both CYP3A4 and CYP2C9 inhibitors can increase exposure of sildenafil, whereas the inducers of these isozymes drastically reduce exposure to sildenafil. The clearance of sildenafil was described to be moderate in humans and the elimination half-life value is about 3 h. The clinical pharmacology and pharmacokinetic characteristics of tadalafil have been reported [15–18]. Tadalafil's metabolism, controlled by CYP3A4, showed formation of an inactive catechol metabolite. A large portion of the catechol metabolite undergoes Phase II metabolism after methylation step to form a glucuronide conjugate. Tadalafil has been documented not to inhibit or induce important CYP isozymes. However, co-administration of tadalafil with CYP3A4 inducer or inhibitor can decrease or increase the exposure of tadalafil. Clearance of tadalafil is slower compared with sildenafil, with an elimination half-life of 17 h. Recently a systematic pharmacokinetic investigation was published that evaluated the interaction potential of both agents when co-administered vs. single agent treatments [19]. There was a 60% reduction in the exposure of sildenafil, which confirmed the earlier findings of decreased exposure of sildenafil when co-administered with bosentan [19, 20]. However, interestingly, an opposite effect was observed in the exposure of bosentan, which showed about 50% increased exposure as a result of co-administration with sildenafil [20]. The authors postulated that sildenafil may play an inhibitory role in the hepatic transporter uptake/biliary clearance of bosentan [20–22]. Since bosentan does not undergo nonhepatic clearance, an inhibitory effect on hepatobiliary clearance mechanisms may lead to the accumulation of the drug. Although sildenafil is an organic anion-transporting polypeptide (OATP) transport inhibitor [22], it was apparent that a greater threshold concentration was necessary to elicit the desired response. It is quite possible that with a dosing of 80 mg sildenafil (t.i.d.), the desired threshold may have been achieved in this study under in vivo conditions [20]. Almost concurrently, another interesting pharmacokinetic interaction report between bosentan and tadalafil in healthy subjects has been published [23]. Whereas, as expected, bosentan reduced the exposure of tadalafil by almost 40%, tadalafil did not appear to increase the exposure of bosentan, in contrast to what was observed previously with that of sildenafil, although numerically the exposure of bosentan (i.e. AUC) was found to increase marginally by 13% [23]. Although it is difficult to rationalize the unique pharmacokinetic interaction observed in the above-cited examples [20, 23], it appears that differential behaviour is exhibited by the two PDE5 inhibitors. It is unknown whether or not tadalafil has a role to play in the OATP transporter uptake inhibition of bosentan. Additionally, a recent study seems to suggest that tadalafil has a tendency to exhibit mechanism-based inhibition of CYP3A4 isozyme with a very low potency [17] and therefore there was a possible opportunity to increase bosentan levels from both speculative counts (CYP3A4 and hepatic uptake inhibition), although it was not supported by study data [23]. These recently reported differential pharmacokinetic interaction data between bosentan vs. PDE5 inhibitors [20, 23] will pave the way for further in vitro and in vivo experiments to understand fully the nature and consequences of such interactions. In this context, another approved ERA agent, ambrisentan, for PAH treatment, may provide an alternative option for co-administration with PDE5 inhibitor [24]. Since ambrisentan is a substrate for both OATP and P-glycoprotein transporter systems as well as CYP3A4 [25], it could be speculated that a similar type of interaction could possibly occur between sildenafil and ambrisentan. However, a single dose of ambrisentan (10 mg recommended dose) did not influence the pharmacokinetic disposition of sildenafil (20 mg t.i.d. dosing) and its active metabolite [25]. Similarly, the pharmacokinetics of ambrisentan was not altered by a single dose of sildenafil [25]. Although no reports have been published, it is unlikely that a drug–drug interaction would have occurred under steady-state conditions between the two agents, because ambrisentan is not documented to be a CYP3A4 inducer or inhibitor [24]. Although drug–drug interaction represents a liability, it could be countered by proper dosage adjustments of either one of the two agents. Although it is customary to dose adjust one agent per the propensity of the documented interaction, it may be difficult to dose adjust both agents such as the one observed between bosentan and sildenafil, especially when the effect of the two agents is observed to act in opposite directions. The other key question is: does increased exposure to bosentan adequately compensate for the reduced exposure to both sildenafil and its metabolite in terms of the pharmacodynamic attributes so that the requirement for dosage adjustment would not arise. Therefore, from all data gathered from the literature there appears to be scientific merit in rationalizing combination use in PAH patients of ERA and PDE5 inhibitors by choosing the appropriate agents that present limited potential for any drug–drug interaction, and/or titrating to the desired pharmacodynamic end-points by taking advantage of the observed pharmacokinetic interactions.

Sir, We found that four of the 84 B-cell non-Hodgkin’s lymphoma (NHL) patients treated with rituximab in our institution from March 2004 to March 2007 were positive for hepatitis C virus (HCV) antibody. We analyzed the HCV-RNA and HCV antibody levels in these four patients (two male and two female, with ages ranging from 43 to 80) and the characteristics of their cases are listed in Table 1. Each patient had diffuse large B-cell type lymphoma (DLBL) and hepatitis C antibodies (HCV II, this antibody was calculated IgG for HCV). The HCV-RNA load in each patient was measured (in the same laboratory) by using the polymerase chain reaction (PCR) in a method described elsewhere (Takeuchi et al., 1999). Their HCV-RNA loads ranged from 20 to 2100 KIU/ml (more than 5 KIU/ml was positive; max 5000 KIU/ml) in all patients. All cases received rituximab (375 mg/m2 on day 1) plus CHOP or a CHOP-like regimen (cyclophosphamide 750 mg/m2 on day 2, vincristine 1.4 mg/m2 on day 2, doxorubicin 50 mg/m2 on day 2, and with/without prednisolone 60 mg/day from day 2 to day 6) or a THP-CO (cyclophosphamide 500 mg/m2 on day 2, vincristine 1.0 mg/m2 on day 2, pirarubicin 30 mg/m2 from day 2 to day 6) regimen at 3-week intervals. One patient received 40-Gy radiotherapy to the bulky residual mass remaining after chemotherapy. They received three to six courses of these regimens (Figure 1). Three patients (cases 2 and 3) obtained a complete response (CR) and one (case 1) obtained an unconfirmed complete response (CRu). The case-4 patient relapsed three years after chemotherapy, but each of the others kept a CR or CRu from one to four years after chemotherapy. The HCV antibodies in all four patients decreased slightly throughout the clinical course. The HCV-RNA load in case 1 was not elevated after the administration of chemotherapy without rituximab (CHOP) but was elevated after the administration of R-CHO (CHOP without predonisolone) and was decreased after the administration of CHO (without rituximab). In this case, the HCV-RNA load was elevated only after the administration of rituximab. In the other cases, the HCV-RNA load also increased gradually elevated after the administration of R-CHO or R-THP-CO (THP-COP without predonisolone). In case 3, the HCV-RNA load increased gradually elevated after the administration of R-CHO and decreased after the administration of CHO. The HCV-RNA load was elevated after the administration of rituximab or a rituximab-containing regimen and was decreased after the treatment without rituximab. Table 1 HCV antibody or HCV-RNA status of the patients with administration of rituximab Figure 1 Time course of HCV-RNA load and HCV-antibody titer. (a) HCV-RNA load was elevated after treatment with rituximab or a chemotherapy regimen containing rituximab. (b) HCV-RNA load was elevated and HCV-antibody titer was decreased after rituximab and CHO. ... We previously reported changes in the titers of antibodies to HBsAg (anti-HBs) and to hepatitis B core antigen (anti-HBc) that were due to treatment with chemotherapy and rituximab (Tsutsumi et al., 2005). Here, we investigated our HCV-RNA-positive NHL patients after the administration of rituximab and CHO or CHOP. All of these cases showed elevated HCV-RNA load after the administration of chemotherapy and rituximab but showed decreased HCV-RNA load after chemotherapy without rituximab. The HCV-RNA load in case 1 was elevated after the administration of rituximab alone, suggesting that rituximab elevated the HCV viral load. These results suggest that the immune system against HCV may function differently from that against hepatitis B virus. Some reports showed a correlation between HCV and B-cell type NHL (Mele et al., 2003; de Sanjose et al., 2004; Takeshita et al., 2006). But in these cases, HCV-RNA was not positive for the lymph node specimen involved in the lymphoma. HCV-RNA and the development of NHL were discussed in many cases. HCV-RNA load elevation after the administration of rituximab and CHOP has been reported by only two groups of investigators (Aksoy et al., 2006; Lake-Bakaar et al., 2007). In those cases, the reactivation of HCV was shown after chemotherapy and rituximab treatment. Lake-Bakaar et al. (2007) considered how B-cell depletion affected the reduction of neutralizing IgM for HCV. They reported that anti-E1/E2 HCV antibodies were not affected by B-cell depletion, but we found HCV antibodies to be decreased. The HCV antibody we examined was IgG, and the difference between our results and those reported previously suggests that the IgM response for HCV might not be paralleled by the IgG response. Although B-cell depletion continued for several months, the HCV viral load did not remain elevated, suggesting that the B-cell depletion was not the only reason for the elevated HCV viral load. The number of regulatory T cells, on the other hand, was elevated 30 days after administration of rituximab and decreased within 90 days (Vigna-Perez et al., 2006). The decreased population of T cells may have been too small to suppress the HCV viral load. Although aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels were elevated in all cases, cholinesterase was decreased in only one. This may show that HCV-RNA load elevation was not the problem of standard chemotherapy and rituximab treatment for lymphoma patients. But in follicular lymphoma, maintenance therapy of the periodical administration of rituximab may lead to the continuous elevation of the HCV-RNA load and consequently may induce liver cirrhosis. We found that rituximab leads to elevated HCV viral load during the clinical course of lymphoma. Periodic administration of rituximab for an extended period of time may lead to the continuous elevation of HCV-RNA load and compromise the liver function of HCV-positive lymphoma patients.

Aims To quantify and compare the incidence of ventricular arrhythmias associated with the use of five nonsedating antihistamines: acrivastine, astemizole, cetirizine, loratadine and terfenadine. The effects of age, sex, dose, duration of treatment, and the interaction with P450 inhibitor drugs were also examined. Methods We carried out a cohort study with a nested case-control analysis using the UK-based General Practice Research Database (GPRD). The study cohort included persons aged less than 80 years old who received their first prescription for any of the five study drugs between January 1, 1992 and September 30, 1996. We estimated relative risks and 95% confidence intervals of idiopathic ventricular arrhythmias with current use of antihistamines as compared with non use. Results The study cohort included 197 425 persons who received 513 012 prescriptions. Over the study period 18 valid cases of idiopathic ventricular arrhythmias were detected. Nine occurred during the current use of any antihistamine, resulting in a crude incidence of 1.9 per 10 000 person-years (95%CI: 1.0–3.6) and a relative risk of 4.2 (95%CI: 1.5–11.8) as compared with non use. Astemizole presented the highest relative risk (RR=19.0; 95%CI: 4.8–76.0) of all study drugs, while terfenadine (RR=2.1; 95%CI:0.5–8.5) was in the range of other nonsedating antihistamines. Older age was associated with a greater risk of ventricular arrhythmias (RR=7.4; 95%CI: 2.6–21.4) and seemed to increase the effect of antihistamines (RR=6.4; 95%CI: 1.7–24.8). The proportions of high dose terfenadine and the concomitant use with P450 inhibitors among current users of terfenadine were 2.7% and 3.4%, respectively over the study period with no single case of ventricular arrhythmias occurring in the presence of these two risk factors. Conclusions The use of nonsedating antihistamines increases the risk of ventricular arrhythmias by a factor of four in the general population. Yet, the absolute effect is quite low requiring 57 000 prescriptions, or 5300 person-years of use for one case to occur. The risk associated with terfenadine was no different from that with other nonsedating antihistamines.

Aims Propofol is a widely used i.v. anaesthetic agent. However, its binding properties to blood components have not been fully studied. Methods We studied the binding of propofol to erythrocytes, to human serum and to isolated serum proteins. Because propofol bound to ultrafiltration and equilibrium dialysis membranes, we used a co-binding technique with dextran coated charcoal and with erythrocytes. Results Propofol free fraction in blood was 1.2–1.7% at total concentrations ranging from 2.80 to 179 μm (0.5 to 32 μg ml−1 ). Fifty percent was bound to erythrocytes and 48% to serum proteins, almost exclusively to human serum albumin. In the clinical range of concentrations (0.5–16 μg ml−1 ) 40% of the molecules bound to erythrocytes are on the red blood cells membranes. No binding to lipoproteins occurred and binding to α1-acid glycoprotein was less than 1.5% Conclusions We conclude that hypoalbuminaemia may increase propofol free fraction particularly during prolonged administration. Since propofol is non-restrictively cleared, no change in clearance is expected to occur, and the increase in free fraction will not be compensated by a parallel increase in clearance. It is also noted that many in vitro studies used concentrations 50 to 500 times the concentration expected to be encountered in the immediate cellular environment.

Many clinical resources for healthcare providers continue to list erythromycin and clarithromycin as inhibitors of cytochrome P4501A2 (CYP1A2) [1]. This classification is based on the pharmacokinetic interactions of these drugs with theophylline, the magnitudes of which are dependent on macrolide dose and the duration of treatment (either no pharmacokinetic changes, or decreases in theophylline clearance by 10–40%; reviewed by Periti et al. and Westphal) [2, 3]. Since theophylline is metabolized primarily by CYP1A2 at clinically relevant concentrations (fmCYP1A2 estimated as approximately 0.8) [4], it is assumed that perturbations in metabolic clearance must result from altered CYP1A2 activity. However, available data suggest that macrolides are poor inhibitors of CYP1A2. In vitro, the 7-hydroxylation of (R)-warfarin by recombinant CYP1A2 was not inhibited by erythromycin or roxithromycin [5], and high concentrations of various macrolides reduced the activity of CYP1A2 in human liver microsomal preparations by ≤10% in competitive inhibition studies [6]. Furthermore, the in vivo indices of CYP1A2 activity, oral caffeine clearance and 6 h paraxanthine to caffeine plasma concentration ratio, were unchanged following clarithromycin dosing in healthy volunteers (500 mg b.i.d. × 7 days) [7]. Drug–drug interactions involving macrolides are typically attributed to mechanism-based inactivation (MBI) of CYP3A enzymes [8]. This type of inhibition is readily detected in vitro by observing time-dependent inhibition (TDI) (CYP activity is reduced by a ‘pre-incubation step’; reviewed by Polasek and Miners [9]). However, the possibility that weak TDI of CYP1A2 by macrolides may contribute to their interactions with theophylline has not been thoroughly explored. To address this, a conventional in vitro approach ([10]) was used in our laboratory to evaluate potential TDI of recombinant (Escherichia coli-expressed) and human liver microsomal CYP1A2 by troleandomycin, erythromycin, clarithromycin, roxithromycin and azithromycin (0.1–1000 µM). Phenacetin O-deethylation was used to measure CYP1A2 activity. The relative contribution of CYP1A2 in human liver microsomes to this reaction was estimated to exceed 90% (see Polasek et al. [10] for details of the experimental method). As evident from Figure 1, all five macrolides were poor inhibitors of phenacetin O-deethylation using either enzyme source (≤25% inhibition at the highest concentration tested), and TDI was not observed. Consistent with previous reports, fluvoxamine (negative control) did not demonstrate TDI, whereas furafylline (5 µM) and clorgyline (5 µM) (positive controls) both reduced phenacetin O-deethylation rate with time, so that approximately 50% of control activity remained following a 10-min pre-incubation. The lack of TDI seen here with all five macrolides supports recent data for erythromycin, which failed to demonstrate TDI of CYP1A2 using a similar experimental approach [11]. Figure 1 Lack of time-dependent inhibition of phenacetin O-deethylation (CYP1A2) by macrolides. Macrolides (1000 µM) were pre-incubated with either (a) human liver microsomes or (b) Escherichia coli-expressed recombinant CYP1A2 and nicotinamide adenine ... If competitive inhibition and MBI of CYP1A2 are excluded, what explains the macrolide–theophylline interactions? It is possible that CYP3A enzymes play a greater role in the metabolism of theophylline in vivo than predicted from in vitro studies. The poor correlation between the 6-h paraxanthine to caffeine plasma ratio and the oral clearance of theophylline [12] suggests that, although the disposition of caffeine and theophylline are mediated primarily by CYP1A2, there are additional CYP (mostly CYP2E1 and CYP3A) involved in the in vivo disposition of theophylline [7, 13]. Indeed, CYP3A may be the principal CYP implicated when CYP1A2 activity is low, a hypothesis substantiated by Tjia et al., who demonstrated partial restoration of theophylline metabolism when human liver microsomal CYP1A2 was fully inhibited by α-naphthoflavone [14]. Furthermore, the 8-hydroxylation pathway can be activated by nifedipine and α-naphthoflavone in microsomes from liver donors treated with dexamethasone, suggestive of allosteric effects on CYP3A [15]. Intriguingly, the rank order of macrolide interaction potential with theophylline corresponds to that of midazolam, a drug exclusively eliminated by CYP3A, i.e. troleandomycin > erythromycin ≈ clarithromycin > roxithromycin > azithromycin for both affected drugs [2, 8]. Similarly, verapamil and diltiazem, also mechanism-based inactivators of CYP3A (but not CYP1A2 [11]) that interact with midazolam, cause between 10 and 25% reduction in theophylline clearance [16]. Despite these observations, the actual extent of CYP3A involvement in the in vivo metabolism of theophylline remains unclear. In fact, other studies with the prototype CYP3A inhibitors ketoconazole [17] and grapefruit juice [18], and the CYP3A substrate nifedipine [19], have demonstrated essentially no effect on theophylline clearance. Another explanation is that macrolides compete with theophylline uptake into hepatocytes via organic anion transporter 2, as shown recently for erythromycin and clarithromycin [20]. It is also known that macrolides inhibit P-glycoprotein [21] and various organic anion transporting polypeptides [22]; however, the degree to which these transporters influence the disposition of theophylline is still unknown (T. Yamamoto, personal communication). Inhibition of CYP2E1 by macrolides is another possibility, although no data are available to support this line of reasoning. It is therefore proposed that the pharmacokinetic interactions between older macrolides and theophylline probably arise via a combination of potent CYP3A inactivation and the inhibition of theophylline uptake into hepatocytes. Substantial evidence is now available to exclude CYP1A2 inhibition as the molecular mechanism responsible for the macrolide–theophylline interactions, and clinical resources for healthcare providers should be updated accordingly.

Spontaneous reporting systems remain the cornerstone of the early detection of previously unknown adverse drug reactions (ADRs) [1]. However, a large proportion of ADRs are known and preventable and they are often due to the coadministration of drugs known to interact [2]. Spontaneous reports of known ADRs can provide insight into the inappropriate co-prescribing of medications. The World Health Organization (WHO) ADR Database (Vigibase) contains more than 3.8 million suspected ADR reports from 82 countries [3]. We examined the coreporting in Vigibase of all drugs classified as ‘established’ and ‘clinically important’ in the Swedish, Finnish, INteraction X-referencing drug–drug interaction database (SFINX database) [4] used in a Swedish patient record system. Thirty-five ‘established and clinically important’ drug–drug interactions (DDIs) were identified. Co-prescribing of these drugs was then searched for in VigiBase. Subsequently, data were retrieved on the severity and evidence for interactions involving these pairs, and actions recommended in Stockley's Interaction Alert [5]. Of those 35 ‘established and clinically important’ drug pairs, 31 were reported in Vigibase, involving 9547 reports from 50 countries. The reported DDIs are listed in Table 1. The serious nature of many of the ADRs listed in Table 1 makes this a major patient safety issue. Also, seven pairs had had only theoretical evidence previously available, and another four pairs had had no previous evidence. Table 1 Clinically important drug–drug interactions Amongst a wide range of drugs, the majority of reports concerned anticonvulsants and anticoagulants. Many of the most reported drug pairs included drugs with narrow therapeutic indexes, such as warfarin, carbamezepine, phenytoin and theophylline. This was further emphasized by the nature of the adverse events reported for the drug pairs: ‘therapeutic level increased’, ‘drug level increased’, ‘drug level decreased’ and ‘therapeutic level decreased’. Spontaneous reports sometimes lack detail, which makes the analysis difficult. For example, risperidone/carbamezepine and convulsions could be due to underlying disease or an overdose effect of risperidone on discontinuation of carbamazepine. In many reports one drug only was reported as ‘suspected’. For example, only 149/661 cases of decreased prothrombin and 197/408 cases of gastrointestinal haemorrhage with warfarin and acetylsalicylic acid were reported as co-suspected or interacting. Judging by attribution of suspicion, it seems that potential interactions were not recognized, although we should not assume that all reports are necessarily results of inappropriate use. The continuing reporting of seemingly well-established interactions strongly suggests insufficient impact of drug information on routine prescribing practices. For example, the US Food and Drug Administration (FDA) has warned of concurrent therapy of rosiglitazone and insulin [6], as it was associated with increased risk of cardiac failure [7]. Since that FDA warning in May 2004, 402 reports of the pair, 52 reports of cardiac failure and 46 reports of the most common symptom, peripheral oedema, have been entered into VigiBase. Studies have shown that education can improve both doctors' and medical students' prescribing patterns [8], and electronic advice can significantly improve recognition of dangerous drug combinations [9]. This review has focused on an analysis of spontaneous reports, with no estimate of drug use. The raw number of reports of combinations should not be interpreted as an estimate of incidence. For some combinations, increased recent reporting might be explicable by increased drug use. Many of the drug pairs have been marketed for several years, and for two-thirds of thepairs reporting started >10 years ago. Our results illustrate a longstanding international problem of comedication of contraindicated drugs. This is in agreement with national studies that have shown that physicians fail to recognize [9] and continue to prescribe contraindicated drugs [10]. We contend that VigiBase and other available data sources could, and should, be utilized to identify preventable ADRs through active screening for potential DDIs. Also, much more effort is needed to communicate patient safety findings appropriately to healthcare providers and patients.

Slow gastric emptying and intolerance to nasogastric feeds occurs in up to 40–50% of critically ill patients [1, 2]. Not only does this result in inadequate nutritional support, but it is also a major risk factor for gastro-oesophageal reflux and aspiration, with potential adverse affects on both morbidity and mortality [2, 3]. The currently available therapeutic options for managing delayed gastric emptying and feed intolerance in critically ill patients are: total parenteral nutrient therapy, prokinetic therapy and postpyloric feeding [4, 5]. Of these, treatment with prokinetic agents is efficacious and frequently used as the first-line therapy to avoid the septic complications associated with total parenteral nutrient therapy and the technical demand of postpyloric feeding [4, 5]. Low-dose erythromycin (1–3 mg kg−1), a motilin agonist, is a widely used prokinetic agent in critically ill patients. However, erythromycin has recently been reported to effect human haemodynamics adversely, with a fall in systolic blood pressure (SBP) of 10 ± 9 mmHg 1.5–2.5 h after an oral dose of 300 mg [6]. The mechanism responsible for the hypotension following erythromycin remains unclear. In animals, infusion of motilin was found to induce endothelial-dependent vasodilation and a transient reduction in blood pressure (BP) [7]. As erythromycin leads to an increase in plasma motilin concentrations in humans, it is conceivable that the hypotension associated the drug is related to the endothelium-mediated vasodilation exerted by motilin [8]. Although erythromycin is frequently used in critically ill patients, its haemodynamic effects in this group are unknown. A reduction of 10 mmHg in SBP after erythromycin may not be important in healthy subjects but may be clinically relevant in patients with potential cardiovascular compromise such as the critically ill [6]. This study therefore aimed to examine the acute effects of a single intravenous prokinetic dose of erythromycin on BP) and heart rate (HR) in critically ill patients, who were intolerant to nasogastric feeds and were not on inotropic supportive therapy. Nineteen mechanically ventilated, critically ill patients (age 52 ± 18 years, M:F 10 : 9, Acute Physiology and Chronic Health Evaluation II score 21 ± 6, length of Intensive Care Unit stay 10 ± 9 days) were randomized to either erythromycin (i.v. 200 mg) or placebo (i.v. normal saline) in a cross-over study, 12 h apart. Intolerance to intragastric feeding was defined as vomiting or regurgitation during feeding, or a 6-hourly gastric aspirate > 250 ml [9]. The cut-off gastric aspirate > 250 ml used in this study is a previously published clinical marker of feed intolerance [9, 10]. The majority of patients were sedated with morphine and midazolam and only two patients received propofol alone. Five patients received nasogastric antihypertensive medications (ACE inhibitors n = 3, β-blockers n = 1 and calcium channel blockers n = 1). Continuous lying BP (systolic, diastolic and mean) and HR were measured via an arterial line at 15-min intervals for 60 min before and 180 min after the administration of prokinetic therapy by using an automatic device (TRAM-RAC 4A; General Electric, Milwaukee, WI, USA). A reduction in SBP of >10% from baseline was defined as a clinically significant change. The study was approved by the Local Research Ethics Committee. Each subject gave written informed consent prior to the study. The effects of erythromycin on BP and HR were analysed using a linear mixed effects model fitted to the data. In this model, group status (erythromycin or placebo) and time were treated as fixed effects, while subject was treated as a random effect. Data are expressed as mean ± SD, except in Figure 1, where the error bars represent 95% confidence intervals. A P-value

To the Editors Sleep-related eating disorder (SRED) is defined as recurrent episodes of involuntary eating and drinking during arousal from sleep with problematic consequences.1 Patients are partially or fully amnestic for this eating behavior. The pathophysiologic mechanism of SRED is uncertain but it has been suggested that it may be related to dopaminergic dysfunction. This theory is supported by the increased prevalence of SRED in restless legs syndrome (RLS).2 Several case reports have been reported in which SRED was associated with zolpidem use.3–6 The authors present a case of a patient who showed binge eating behavior after sleep-onset due to mirtazapine treatment. The patient showed complete remission after mirtazapine treatment was discontinued. On the basis of a literature review, this is the first report of SRED linked to the use of mirtazapine.

We read with interest the paper ‘Thiazolidinediones and associated risk of bladder cancer: a systematic review and meta-analysis’ by Turner et al. [1]. The authors present the results of a meta-analysis including a large number of patients. They concluded that pioglitazone use is associated with a modest but significant increase in the risk of bladder cancer, which further increases with both higher cumulative dose (>28 g) and duration of exposure (>12–24 months). Interestingly, the effect of rosiglitazone on bladder cancer risk was not significant [1]. A few comments might be of interest, based on the results of a recent study (published in August 2013), not included in the meta-analysis [2]. This was an observational follow-up study of patients included in the PROspective pioglitAzone Clinical Trial In macroVascular Events (PROactive) trial, who had received pioglitazone for 2.6 years. PROactive had shown a modest but significant reduction in the composite of all cause mortality, non-fatal myocardial infarction (MI) and stroke in high cardiovascular disease (CVD) risk type 2 diabetes mellitus (T2DM) patients [3]. After a mean follow-up time of 8.7 years (including the PROactive period), the CVD benefit was lost, since only 13.5% continued on pioglitazone [2]. There was no evidence of increased risk of bladder cancer in these patients (89% of them were at the maximum dose of 45 mg day−1) [2]. Interestingly, no significant between group differences were observed in the percentage of patients reporting any other malignancies, except for prostate malignancy, a finding that needs further confirmation [3]. The leading cause of death in patients with T2DM is CVD [3]. As PROactive has shown, 40 patients would need to be treated for 3 years in order to prevent one first CVD event. In other words, the number needed to treat is approximately 120 per year [3], while the number needed to treat for harm (that is to develop one case of bladder cancer) shown by the meta-analysis was 3408 for ever pioglitazone use, 1119 for >28 g cumulative dose and 1404 for >24 months cumulative duration [1]. On the contrary, rosiglitazone use has been associated with increased risk for MI (although not for CVD or all cause mortality) in an older meta-analysis, showing one additional MI per 52 patients treated for 5 years [4]. These results were confirmed by a comparative meta-analysis, showing a significant increase in the odds of MI, congestive heart failure and death (170 excess MIs, 649 excess cases of heart failure and 431 excess deaths for every 100 000 patients receiving rosiglitazone rather than pioglitazone) [5]. It seems therefore prudent to prescribe an agent that has been shown to protect the cardiovascular system, for at least 3 years, rather than avoid it for the fear of causing bladder cancer, the possibility of which for such a period seems very low (taking into account that the cumulative dose of 28 g stands for a 31 month period of 30 mg day−1, which is the usual pioglitazone dose). This becomes more important in an era when clinicians, the Food and Drug Administration and the European Medicines Agency are very cautious about the effect of any anti-diabetic and anti-obesity drug on the cardiovascular system [6]. New studies are already being conducted to test the effect of other drug categories, such as glucagon-like peptide (GLP)-1 based therapies, on the cardiovascular system [6]. In conclusion, we believe that pioglitazone should continue to be considered a reliable therapeutic option in patients with T2DM for a period of up to 2 years (with a potential extension to 3 years), since its benefit and safety on the cardiovascular system overweigh the potential risk for bladder cancer. Patients at high risk for bladder cancer, such as those with a family history, microscopic haematuria and exposure to carcinogenic substances, should be excluded.

Pholcodine is a commonly used antitussive medication. In France, its use is limited because of the risk of an allergic cross-reaction with curare. Here we report the case of a 52-year-old man who ingested 750 mg of pholcodine syrup. An emergency medical team found him at home in nonshockable cardiac arrest. Orotracheal intubation was impossible because of instantaneous rigor associated with trismus, so an emergency cricothyrotomy was performed. Return of spontaneous circulation was obtained 5 min later. Cardiac arrest recurred upon arrival at the intensive care unit, leading to death. Toxicological analysis showed a pholcodine blood level of 2500 ng ml−1 (a lethal dose is >1000 ng ml−1, extrapolated from animal studies). Pholcodine is an opioid derivate with a central antitussive effect that is indicated for unproductive cough in adults. No case of fatal intoxication has ever been reported. We hypothesize that cardiac arrest was the result of hypoxia due to respiratory arrest connected to the opioid nature of pholcodine. Interestingly, instantaneous rigor occurred, which should be not confused with rigor mortis. Instantaneous rigor is a rarely reported condition that persists until rigor mortis and disappears in the stage of secondary flaccidity. Instantaneous rigor can lead to trismus, making orotracheal intubation impossible and necessitating emergency cricothyrotomy. This case shows that pholcodine overdose can be lethal and can lead to instantaneous rigor.

We thank Dr Galmozzi and Dr Lampertico for theircomment on our recently published paper on the effectof the dinucleotide frameshift variant in ss469415590 inthe interferon (IFN)-k4 gene on interferon/ribavirintreatment and its relationship with the two commonlyused single nucleotide polymorphisms (SNP) in IL28B(rs12979860, rs8099917).

Although anthracyclines are recognized as efficacious chemotherapeutic agents with broad-spectrum anticancer activity, their clinical use is limited by their chronic accumulative dose-dependent cardiac toxicity. Three forms of anthracycline-induced cardiotoxicity have been described: acute or subacute cardiac injury, chronic cardiotoxicity resulting in cardiomyopathy, and late-onset ventricular dysfunction with arrhythmias. Acute and subacute anthracycline toxicities are most often manifested as arrhythmias, pericarditis-myocarditis, subclinical cardiomyopathy, left ventricular dysfunction, and sudden death [1, 2]. However, acute cardiac toxicity is uncommon and is usually subclinical in nature or is associated with mild clinical symptoms lacking significant consequences. This report describes a case of severe subacute congestive heart failure (CHF) and ventricular tachycardia (VT) developing in response to the first exposure to idarubicin. A pale-faced 34-year-old woman presented to our haematology outpatient clinic with the complaint of general malaise of 1 month's duration. No systemic disease had occurred prior to this illness and she had no history of coronary artery disease, smoking, or illegal substance abuse. Bone marrow examination confirmed the presence of acute myeloid leukaemia (AML), M6 subtype. Induction chemotherapy with idarubicin and cytarabine was therefore initiated. Idarubicin was administered at 12 mg m−2 day−1 for 3 days by a 30-min intravenous infusion, and cytarabine was administered at 100 mg m−2 day−1 for 7 days by continuous (24 h) intravenous infusion. A neutropenic fever developed on day 10, and empirical antibiotic therapy with piperacillin/tazobactam and amikacin was prescribed. Because the fever persisted, antibiotic therapy was changed to meropenem on day 15 and fluconazole was added on day 18. When blood laboratory analyses conducted on day 17 revealed the presence of hypokalaemia, potassium (KCl solution) was given intravenously. Even after aggressive potassium chloride supply, serum levels of potassium on day 27 were 2.53 mmol l−1. On day 20, the patient displayed tachypnoea and shortness of breath. Chest x-ray revealed cardiomegaly and right pleural effusion. Echocardiography performed on day 26 revealed chamber dilation of the left atrium and left ventricle, generalized hypokinetic wall motion, and a left ventricular ejection fraction (LVEF) of 23% (Figure 1). Prior to the development of CHF, the patient exhibited no symptoms or signs of arrhythmia or pericarditis-myocarditis. Cardiac marker measurements of creatine kinase isoenzyme (CK-MB) and troponin-I on day 24 were all within normal ranges. Figure 1 The echocardiogram on day 26 shows chamber dilation of left atrium and left ventricle and left ventricle generalized hypokinetic wall motion with left ventricular ejection fraction of 23% Frequent ectopic premature ventricular beats were detected on day 27, with the arrhythmia progressing to VT and ventricular fibrillation on day 28. Because of a sudden loss of consciousness, cardiopulmonary resuscitation with defibrillation was performed immediately. Intubation with ventilatory support and an intra-arterial balloon pump were placed to manage cardiogenic shock and pulmonary oedema. On day 38 the intra-arterial balloon pump and ventilator were no longer required, and the patient was transferred to a general ward. Echocardiography performed 4 months after the induction chemotherapy showed no chamber dilation and adequate global left ventricular performance with a LVEF of 64.2%. Idarubicin (4-demethoxydaunorubicin) is a newer congener with lesser degrees of cardiotoxicity compared with other anthracyclines. In a retrospective investigation of idarubicin-related cardiac toxicities [3], only one of 115 idarubicin-treated patients developed definite CHF with four patients developing possible CHF. No patient with asymptomatic decreased LVEF progressed to CHF. The patient who developed definite CHF received a total idarubicin dose of 92 mg m−2. The investigators therefore concluded that idarubicin-related cardiomyopathy is uncommon with cumulative idarubicin doses of up to 290 mg m−2. Our patient, a 34-year-old woman, had no risk factors for heart disease. Nonetheless, she developed severe CHF after her first induction chemotherapy involving a total cumulative idarubicin dose of 36 mg m−2. To our knowledge, no previous reports of subacute CHF developing after first exposure to idarubicin have been published. However, the present report underscores the possibility of severe CHF developing even after an initial exposure to this drug. The causality assessment of this adverse drug reaction (ADR) according to the Naranjo Algorithm is 6, placing the reaction in the probable ADR category [4]. The clinical course of the severe subacute CHF exhibited by our patient was complicated by VT. We postulate that this arrhythmia was precipitated by the hypokalaemia in the situation of idarubicin-associated cardiomyopathy. Another possible precipitating factor was fluconazole-induced prolongation of the cardiac QTc interval; however, the electrocardiogram measured 2 h before the attack of VT revealed sinus rhythm and frequent premature ventricular contractions with QTc interval of 400 ms. Chronic anthracycline-induced cardiomyopathy is irreversible and the prognosis for cancer patients with this complication is poor. The prognosis for patients with subacute symptomatic anthracycline-induced CHF is unknown because of the low incidence of this disorder. Our patient developed clinically significant CHF after her first treatment with idarubicin. Four months later, however, her LVEF had increased to 64.2%. This observation supports the hypothesis that the subacute CHF developing in response to short-term anthracycline therapy can be reversed totally or partially. The present case illustrates that severe subacute anthracycline-induced CHF, although rare, can develop after the first exposure to idarubicin. To our knowledge, this report is the first to describe a patient with AML who developed severe subacute CHF with VT after the first cycle of induction chemotherapy with idarubicin and cytarabine. For such patients, early detection and aggressive treatment of these cardiac disturbances are anticipated to restore cardiac function partially or fully.

Lung cancer is the second-most common cancer in men and women, accounting for about 13% of all diagnosed cancers. It is, however, the leading cause of cancer-related deaths in industrialized countries, exceeding the mortality from breast, colorectal, and prostate cancer combined. Erlotinib is an orally administered, quinazoline-based agent that competes with adenosine triphosphate for binding to the intracellular catalytic domain of the epidermal growth factor receptor (HER1/EGFR) tyrosine kinase, inhibiting phosphorylation. Inhibition of tyrosine kinase activity prevents HER1/EGFR phosphorylation and its associated downstream signaling events, and it may block tumorigenesis that is mediated by inappropriate HER1/EGFR signaling [1]. In November 2004, the U.S. Food and Drug Administration (FDA) approved erlotinib as a single-agent treatment for patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) after failure with at least one standard chemotherapy regimen. Erlotinib is better tolerated and causes fewer adverse reactions than cytotoxic drugs. The most common adverse reactions in patients are rash (acneform eruptions) and diarrhoea [2]. The majority of hepatotoxicity presents as mild or moderate hepatic dysfunction; severe hepatic impairment has been documented rarely. Here, we report three cases of severe hepatic impairment which was caused by erlotinib. Erlotinib is cleared predominantly by the liver and is metabolized primarily by oxidation of CYP3A4, which is excreted in bile [3]. CYP3A4 exhibits remarkable interindividual activity as high as 20-fold. Genetic polymorphisms are a common source of these differences in the context of drug metabolism [4]. There are three mutations of CYP3A4 in the Chinese population that have been reported to attenuate CYP3A4 activity. These mutations include A13989G, C15820G and an A17776 insertion [5]. Additionally, CYP2D6 belongs to the cytochrome P450 oxidase family and is responsible for the majority of the interindividual variability in drug metabolism. There are four phenotypes of CYP2D6: poor metabolizer (PM), intermediate metabolizer (IM), extensive (normal) metabolizer (EM), and ultrarapid metabolizer (UM). If a substrate of the enzyme is given to a patient as medication, and if the patient has impaired CYP2D6, the patient will accumulate the drug and experience severe side effects. In contrast, for the UM patient, drug concentrations might be too low to have a therapeutic effect. Thus, assessing the patient's phenotype will help determine the optimal dose of a drug. One mutation in the CYP2D6 coding sequence that frequently occurs in the Chinese population is C188T(CYP2D6*10) [6].Therefore, we analyzed DNA samples from two subjects by polymerase chain reaction and direct sequencing of three mutations in the CYP3A4 coding sequence and one mutation in the CYP2D6 coding sequence. Primer design, polymerase chain reaction, and CYP3A4 and CYP2D6 sequencing were performed as described [5, 6].

The first case of angioedema associated with angiotensin converting enzyme (ACE) inhibitors was described nearly 30 years ago [1]. Since then various forms of ACE inhibitor-induced angioedema have been described including angioedema of the face, airway, viscera, and genitalia [2]. We present, to our knowledge, the first case of enalapril-induced angioedema of the brain. A 28 year old woman from the Democratic Republic of the Congo presented to Groote Schuur Hospital, Cape Town, South Africa, with diffuse alveolar haemorrhage requiring ventilation. She was diagnosed with systemic lupus erythematosus (SLE) with renal and pulmonary manifestations. Antibodies to double-stranded DNA were markedly raised at 331 IU ml−1 (>15 is regarded as positive). She responded well with resolution of her alveolar haemorrhage and improvement of her nephritis on prednisone 1mg kg−1 day−1 and an intravenous infusion of cyclophosphamide. She was discharged on prednisone 60 mg daily, atenolol 50 mg daily, amlodipine 10 mg daily, enalapril 10 mg 12 hourly, furosemide 40 mg daily and simvastatin 10 mg daily as well as calcium and iron supplements. She had no known drug allergies. She was reviewed 2 weeks after discharge. Her blood pressure remained uncontrolled at 170/110 mmHg and she had dependent oedema and ongoing severe proteinuria. The dose of enalapril was increased to 20 mg 12 hourly and she was given another intravenous infusion of cyclophosphamide. Three days later she presented to the emergency department with angioedema of the lower face and lip without airway involvement. The enalapril was discontinued and she was admitted for observation. Several hours later she developed generalized tonic-clonic seizures, which were terminated with intravenous diazepam and an intravenous loading dose of phenytoin. Her blood pressure was 170/110 mmHg. There was no evidence of hypertensive retinopathy and her serum creatinine remained normal. Computed tomography (CT) of the brain was performed, which showed extensive cerebral oedema involving the white matter. There were no features of obstructive hydrocephalus, no contrast enhancement, and the venous sinuses were patent. C3 complement was reduced (0.720 g l−1, range 0.9–1.8), C4 was normal and C1 esterase inhibitor concentration was mildly elevated (0.45 g l−1, range 0.21–0.40 g l−1). The cerebrospinal fluid findings were: 1 polymorphonuclear cell and 1 lymphocyte per cu mm, protein 1.17 g l−1, glucose 7.3 mmol l−1 and IgG index 0.8. Bacterial and mycobacterial cultures of cerebrospinal fluid were negative. Anti-double stranded DNA remained slightly elevated (23.2 IU ml−1), but was much lower than at her initial presentation. Her lupus anticoagulant and anticardiolipin antibodies were negative. After the seizures, she remained in a semi-comatose state with a Glasgow coma score of 9. She received supportive treatment, and 10 mg dexamethasone intravenously 12 hourly was added. Over the next 5 days, she made a full recovery to normal mental state and the facial angioedema resolved. Her hypertension was controlled (blood pressure on discharge 140/80 mmHg) with atenolol, doxazosin, amlodipine, and hydralazine. At follow up, 5 months later, she remained well on maintenance cyclophosphamide and reducing doses of prednisone. We believe that our patient developed enalapril-associated angioedema of the brain due to the temporal association between the angioedema of the lip and face, and the exclusion of other causes, notably C1 esterase inhibitor deficiency. To our knowledge, no case of ACE inhibitor-induced cerebral angioedema has been described. A definitive diagnosis of enalapril-associated angioedema of the brain would require a rechallenge with enalapril, but this would clearly be inappropriate in this case. The differential diagnosis of the cerebral oedema and seizures in this patient included other causes of angioedema affecting the brain, and alternative causes of the cerebral oedema, notably a neuropsychiatric manifestation of SLE. Neurological manifestations of hereditary angioedema have been previously described [3]. The absence of a family history of angioedema and the absence of C1 esterase inhibitor deficiency rule this diagnosis out. Other drugs causing the angioedema are extremely unlikely. Although type 1 hypersensitivity reactions to glucocorticoids and cyclophosphamide have been described [4, 5], the resolution of the angioedema despite ongoing administration of cyclophosphamide and prednisone makes this diagnosis very unlikely. Infective causes of the cerebral oedema are effectively ruled out by the normal cerebrospinal fluid findings, the absence of a focal lesion on the CT scan, and the recovery without specific therapy. The neuro-imaging abnormalities of neuropsychiatric SLE include infarcts, high intensity lesions in periventricular or subcortical white matter, and cortical atrophy[6, 7]. To our knowledge, diffuse white matter brain involvement has not been described as a presentation of neuropsychiatric SLE. Posterior reversible encephalopathy syndrome (PRES) is characterized by various neurological manifestations and transient changes on neuro-imaging consistent with cerebral oedema, which typically, but not exclusively, involves the posterior circulation [8]. Although the exact physiopathology remains incompletely understood, it is hypothesized that it is caused by a brain capillary leak syndrome secondary to the cytotoxic effect of, among other causes, immunosuppressive drugs and SLE. The CT of the brain in our patient demonstrated extensive cerebral oedema involving the white matter of the entire brain, thus steering the diagnosis away from PRES. Furthermore, PRES has not been associated with angioedema. ACE inhibitor-induced angioedema occurs in 1 to 6.8 patients per 1000 treated [9, 10]. African-Americans are more than four times more likely to develop ACE inhibitor-induced angioedema than Caucasians [11, 12]. Ethnicity-related differences between the kallikrein-kinin system may underlie the increased rate of angioedoema among Black subjects [11]. Despite the fact that our patient presented with ACE inhibitor-induced angioedema after an increase in her ACE-I dose, there is no evidence that ACE inhibitor-induced angioedema is dose-related [13]. Although the pathophysiology of ACE inhibitor-induced angioedema is not well understood, various mechanisms have been proposed. Apart from acting on angiotensin I, ACE inhibitors also prevent inactivation of bradykinin. Bradykinin is a potent inflammatory autocoid causing vascular permeability and vasodilatation. However, bradykinin inactivation is blocked in all patients on ACE inhibitors, yet only a small fraction of patients develop angioedema. This suggests that factors other than bradykinin are involved in the development of angioedema. Further evidence against the bradykinin hypothesis is that angiotensin receptor blockers, which do not affect bradykinin, also cause angioedema, albeit at a lower frequency than ACE inhibitors [14]. Angioedema has also been described in patients receiving renin inhibitors [15]. In conclusion, we have presented a case of diffuse cerebral oedema temporally associated with angioedema of the lip and lower face. Alternative causes were excluded and the condition resolved on withdrawal of enalapril. We propose that enalapril-induced angioedema of the face and brain was responsible for this presentation.

A 30-year-old female patient was prescribed oral cetirizine 10 mg at night for the treatment of chronic idiopathic urticaria. Within 15 min of oral ingestion of cetirizine 10 mg, the patient experienced severe pruritis and urticarial eruption all over the body. She developed severe breathlessness and was unable to speak. The patient became restless, disoriented and lost consciousness. She was rushed to the emergency room. Her pulse and blood pressure were unrecordable and air entry was decreased in both lungs. A diagnosis of anaphylactic shock was made. Cardiopulmonary resuscitation was started and epinephrine 0.5 mg of 1:10 000 was given intravenously. She also received intravenous crystalloid. After approximately 30 min, the pulse rate increased to 100 beats min−1 and blood pressure to 124/80 mmHg. Hydrocortisone 100 mg was then given intravenously. The patient remained haemodynamically stable. She had no previous history of allergic reactions to any drug. There was no history of concomitant use of any other medication or alcohol intake, nor of previous exposure to cetirizine or any other piperazines. The patient received only one oral dose of cetirizine. The causality assessment of the adverse drug reaction (ADR) by Naranjo Algorithm was 7, putting it in a ‘probable’ ADR category [1]. The ADR was reported to the peripheral pharmacovigilance centre of the state under the National Pharmacovigilance Programme, India. Histamine-1 (H1) receptor antagonists have an established and valued place in the symptomatic treatment of various immediate hypersensitivity reactions. Nevertheless, it is a little known fact that although H1 receptor antihistamines are used in the treatment of drug-mediated allergy, they themselves can provoke allergic reactions. Although they have shown good tolerance in humans, no currently available antihistaminic is completely free from potential adverse effects under all circumstances [2]. There have been several reports of cetirizine causing multiple fixed drug eruptions and urticaria [3–6]. However, anaphylaxis due to oral ingestion of cetirizine is extremely rare. All the available H1 receptor antagonists are reversible competitive inhibitors of the interaction of histamine with H1 receptors. Cetirizine, a human metabolite of hydroxyzine, is a selective H1 receptor antagonist belonging to the second-generation piperazine class. Cetirizine is well absorbed orally and is excreted in the urine mainly in the unmetabolized form. Many drug reactions attributable to allergic phenomena respond to therapy with H1 antagonists, particularly those characterized by itch, urticaria, and angio-oedema; serum-sickness reactions also respond to intensive treatment. In humans, during hypersensitivity reactions, oedema formation and itch are effectively suppressed by histamine antagonists. Other effects, such as hypotension, are less well antagonized. This may be explained by the participation of other types of histamine receptors and by effects of other mast cell mediators such as prostaglandins, eicosatetratenoic acid derivatives, leukotrienes and others. Prophylactic treatment with a H1 antagonist may reduce symptoms of the hypersensitivity reaction to a tolerable level. However, in a patient with known hypersensitivity to cetirizine, repeat administration of cetirizine or hydroxyzine is contraindicated [7]. The exact mechanism by which cetirizine can cause anaphylaxis is not known, but may be linked to the piperazinic ring that is well known as an antigen [8]. Also, cetirizine has no effect on mast cell activation [9]. In conclusion, even though the safety of cetirizine has been widely established, there is an extremely rare chance of it causing anaphylaxis. Cetirizine may be used in the treatment of anaphylaxis. Hence this possibility (and similarly with other antihistamines) needs to be considered in the differential diagnosis of a patient not responding to treatment or deteriorating. Cetirizine may also mimic the underlying disease that led to its intake [10].

We report a case of severe unexplained hypoglycaemia occurring in a surgical patient during a routine hospital admission. This case caused significant diagnostic problems and highlights a number of important learning points. A 66-year-old male inpatient on a surgical ward was found unrousable by a member of staff after a visit from a friend. Until this episode he had been making an uneventful recovery from a complicated open cholecystectomy 13 days earlier. He had Type 2 diabetes that was treated with diet alone, and during the admission his blood sugars were in the range of 4.7–7.7 mmol l−1. He was known to have chronic renal insufficiency secondary to hypertension and had had a renal transplant 5 years earlier. A recent serum creatinine concentration was 372 µmol l−1 (normal range 70–150). His blood glucose concentration was found to be 1.7 mmol l−1. He was treated initially with 50 ml of 50% intravenous glucose, but became symptomatically hypoglycaemic again within 1 h. He was normotensive throughout. The endocrinology team was contacted and they recommended that insulin, pro insulin, C-peptide and glucose concentrations should be measured and the presence of a sulphonylurea excluded by analysis. They also advised that all current infusions should be changed. It soon became apparent that the patient required repeated injections of 50% glucose to maintain euglycaemia. A continuous infusion of 20% glucose was started after he had received 300 ml of 50% glucose. His blood glucose concentration stabilized only after treatment with 650 g of i.v. glucose over 41 h. Results showed raised insulin (364 pmol l−1) and C-peptide (7.67 nmol l−1) concentrations in the presence of a low blood glucose concentration (1.1 mmol l−1). The sulphonylurea screen was strongly positive. Using selective and sensitive high-performance liquid chromatogrphy mass spectrometry, the Regional Laboratory for Toxicology, Birmingham, confirmed the presence of gliclazide. The plasma concentration 20 h after the initial hypoglycaemic event was 3.44 mg l−1. As our patient weighed 80 kg and the apparent volume of distribution of gliclazide is 0.28 l kg−1, there was approximately 77 mg gliclazide in his body at the time the sample was taken. Although it is difficult to assess accurately the half-life of gliclazide in renal impairment, extrapolation of this plasma concentration using a half-life of approximately 10 h [1] showed that the presenting hypoglycaemia could have been the result of a single oral dose of approximately 320 mg gliclazide given at 14.00 h. Although the cause of the hypoglycaemia was now clear, the circumstances leading to the ingestion of the gliclazide were not. As the patient had not been prescribed gliclazide during this admission, the possible causes were considered to be a medication dispensing error, a medication administration error, deliberate self-harm or malicious intent. This prompted a thorough investigation by a multidisciplinary team, which included a clinical pharmacologist, hospital pharmacist and senior members of the medical team. Initially it was felt the most likely cause was an administration error; however, gliclazide was not a stock item on the ward. When the ward drug cupboard was examined a gliclazide packet was found next to furosemide (Figure 1). After significant investigation it became clear that 1 month earlier a ward patient had received gliclazide. This should have been kept in the Patient Own Drugs locker beside the bed and then removed on discharge, but contrary to hospital policy it had been placed in the ward drug cupboard. Figure 1 Gliclazide and furosemide in the ward drug cupboard Our patient was due to receive furosemide 160 mg (4 × 40-mg tablets) at 14.00 h. As well as the alphabetical proximity of the two drugs, the packaging of gliclazide (Figure 1) and size of the tablet (Figure 2) are very similar and could easily be mistaken. It seems likely that the four tablets that our patient received were four tablets of gliclazide 80 mg (320 mg) rather than four tablets of furosemide 40 mg. The nurse involved with the administration of the medicines was unaware that an error had occurred. The patient made a full recovery, with no long-term consequences. A thorough investigation has been undertaken and corrective action has been implemented. Figure 2 Similarities between the tablet size of gliclazide and furosemide This case raises several important learning points. First, it illustrates the diagnostic challenges faced in identifying the cause of unexplained hypoglycaemia and the need to make prompt and appropriate investigations if the situation arises. It also highlights that involving a multidisciplinary team, including help from the National Poisons Information Service and the Regional Laboratory for Toxicology, can be extremely valuable. Third, it demonstrates the intractable hypoglycaemia that can ensue following administration of a sulphonylurea to patients with renal impairment. Finally, this case is a sobering reminder of how easily medication errors can occur. Up to 33% of all medication errors are to due to packaging and/or labelling confusion [2]. Approximately 9% of patients staying in hospital will experience medication-related harm – many of these incidents are preventable [3].

Stevens–Johnson syndrome (SJS) is a rare, life-threatening and severe blistering mucocutaneous disease, most commonly caused by drugs [1]. The annual incidence of SJS is estimated to 1.1–7.7 cases per 1 million, and the risk of SJS is highest in the first weeks after drug use [2]. Individuals with the alleles HLA-B*1502 and HLA-B*5801 are more susceptible to develop SJS by carbamazepine and allopurinol, respectively [3, 4]. Aggrenox is a fixed-dose combination of aspirin 25 mg and dipyridamole 200 mg in a modified-release form and is recommended for secondary prevention of ischaemic stroke [5, 6]. Common adverse effects of Aggrenox include headache, bleeding and gastrointestinal events. Post-marketing data have reported rare cases of SJS in patients receiving treatment with either aspirin or dipyridamole (Prod. Info. AGGRENOX(R) extended-release oral capsules, 2006) [7]. However, no formal report of SJS associated with Aggrenox has ever been published. Here, we report a patient who developed SJS acutely several hours after exposure to a single dose of Aggrenox.

5-Fluorouracil (5-FU) is a cornerstone in the treatment of many cancers, including colorectal, head and neck, stomach, and breast carcinomas. Recently, 5-FU oral prodrugs, such as capecitabine, have been successfully introduced in cancer therapy, and their clinical use is rapidly and constantly growing. The approach to the prediction of severe toxicities due to 5-FU (and its oral prodrugs) has been matter of debate for many years and still remains a hot topic in oncology. The efforts in this field are almost entirely focused on the analysis of dihydropyrimidine dehydrogenase (DPD) gene mutations and of peripheral blood mononuclear cell (PBMC) DPD activity. For these reasons, in this letter we would like to suggest a novel, rational diagnostic algorithm that, integrating the analysis already available, is centred on the use of 5-FU and 5-fluoro-5,6-dihydrouracil (5-FDHU) pharmacokinetics as a tool to prevent severe and life-threatening 5-FU toxicities in patients with impaired 5-FU metabolism. DPD plays a pivotal role in the metabolism of 5-FU [1] and, as such, a deficiency of DPD has been recognized as an important risk factor, predisposing patients to the development of severe toxicity. Numerous genetic [2, 3] and phenotypic (i.e. DPD activity, breath test or plasma dihydrouracil/uracil ratio) [4–6] approaches have been proposed to prevent life-threatening toxicities, and, in our opinion, the time has come to develop an integrated approach to this clinically relevant issue. The screening of DPYD mutations [3] and of peripheral blood mononuclear cell DPD activity [7] in patient candidates for 5-FU treatment has been proposed as a routine approach to identify severely reduced DPD activity. However, both the genotype and phenotype options have some advantages but also limitations, as comprehensively pointed out by Ezzeldin and Diasio [8]. In order to identify all patients with impaired 5-FU clearance, no matter which type of DPYD mutations or DPD activity in PBMC compartment they have, in the last decade some authors have suggested a phenotypic approach of screening, looking at the systemic 5-FU catabolism and measuring the pharmacokinetic parameters of the parental drug and of its principal metabolite 5-FDHU [9–11]. As an example, our group has recently proposed the administration of a 5-FU test dose in patient candidates for 5-FU chemotherapy to calculate the pharmacokinetic parameters, such as 5-FU clearance and t1/2β or 5-FDHU Cmax, Tmax and t1/2β, that could be profoundly altered in the presence of an impaired systemic clearance [12]. Indeed, our study revealed markedly impaired 5-FU and 5-FDHU kinetics in some patients, as previously shown for patients with severe toxicities in other published studies [13], suggesting a possible profound alteration of 5-FU metabolism; owing to the detection of this abnormality, these subjects were not given a potentially life-threatening standard dose of 5-FU. Moreover, based on our experimental data, statistically significant relationships have been demonstrated between 5-FDHU pharmacokinetic parameters and moderate to severe degrees of three major dose-limiting toxicities related to 5-FU treatments (stomatitis, diarrhoea and neutropenia) after the first cycle of 5-FU standard therapy. In particular, a prolonged 5-FDHU t1/2β and a 5-FDHU Tmax higher than the median value of our population (30 min) could help identify patients at risk of developing moderate to severe neutropenia or diarrhoea [12]. The 5-FU test dose can be easily performed in a hospital setting with a clinical pharmacology unit such as those usually present in medium- or large-sized university hospitals of Western countries. In particular, an organized regional network among major clinical oncology units may allow screening patients within 2–3 days. The analysis can be available in a few days and the patients can be ready to start the 5-FU therapy at standard or reduced dose in the following week when 5-FU and 5-FDHU kinetic parameters are available. Based on this clinical experience, we detail the principles that should guide the decision-making process regarding the prevention of 5-FU severe toxicity and propose a diagnostic algorithm (Figure 1) in order to screen candidate patients to fluoropyrimidine therapy. In the suggested diagnostic algorithm (Figure 1), the predictive 5-FU test dose could be regarded as a triage test, allowing detection of the fraction of patients with normal, impaired or absent fluoropyrimidine metabolism. Other analyses, such as DPD genotyping or even DPD PBMC activity, could be used later as add-on tests and, limited to the still undiagnosed subgroup, to detect those degrees of enzyme activity impairment suitable for possible reduction of 5-FU dose or different treatments. Overall, the published data strongly suggest the use of a diagnostic algorithm based on the sequential application of a 5-FU pharmacokinetic test followed by DPD genotyping and activity in order to make a highly probable diagnosis of altered 5-FU metabolism. Moreover, the application of this model could result in a consistent reduction of costs and morbidity, by limiting genotyping and PBMC DPD activity analysis to only selected subgroups of patients. Figure 1 Suggested diagnostic flow chart for the detection of patients with impaired fluoropyrimidine metabolism. 5-FU, 5-fluorouracil; 5-FDHU, 5-fluoro-5,6-dihydrouracil; DPD, dihydropyrimidine dehydrogenase; PBMC, peripheral blood mononuclear cell; PK, pharmacokinetics; ... In conclusion, the published clinical experience suggests that an integrated approach based on pharmacokinetic analysis combined with DPD genotyping and/or phenotyping seems to be a safer strategy for optimizing the administration of 5-FU and its oral prodrugs, which remain major drugs used extensively in clinical oncology.

Solifenacin, an antimuscarinic drug, has been widely used for the treatment of overactive bladder (OAB), but severe cardiac adverse effects have not been reported. An 81-year-old woman was prescribed solifenacin 5 mg day−1 for OAB. Two weeks later she developed the first syncope. Nine days after the first syncope she developed recurrent syncope, and electrocardiogram monitoring showed marked QT prolongation and torsade de pointes (TdP). Concomitant drugs remained unchanged. Serum electrolytes and hepatic function were normal. Calculated creatinine clearance was mildly decreased. We considered that the loss of consciousness was associated with solifenacin. Although intravenous magnesium sulphate could not terminate the recurrence of TdP, increasing the pacing rate prevented further attacks of TdP. Solifenacin might be a possible cause of QT prolongation and TdP. Solifenacin is a newer bladder-selective antimuscarinic drug for the treatment of OAB [1]. Although terodiline, an older antimuscarinic drug for OAB, has been reported to predispose to QT prolongation and TdP and was withdrawn from the market in the early 1990s [2–4], solifenacin has not been reported to have severe cardiac adverse effects [1]. An 81-year-old woman was admitted to the division of orthopaedics with dislocation of hip joint and infection of decubitus. One year before admission she had undergone total hip arthroplasty. Her past medical history included hypertension and pacemaker implantation for sick sinus syndrome. Her medication included amlodipine, but not any over-the-counter drugs or herbals. Electrocardiogram (ECG) on admission showed sinus rhythm with normal QT interval (QT400 ms/QTc360 ms) (Figure 1a). Solifenacin 5 mg day−1 was started for OAB after admission. Her infection was initially treated with intravenous cefazolin, but was changed to intravenous teicoplanin because of methicillin-resistant Staphylococcus aureus infection. Two weeks later she suddenly developed loss of consciousness, but she spontaneously regained full consciousness. Figure 1 ECG monitoring. (a) Sinus rhythm with normal QT interval on admission. (b) Marked QT prolongation after the first syncope. (c) Typical episode of torsade de pointes 9 days after the first syncope Although ECG was not recorded during the episode, ECG monitoring showed QT prolongation (QT600 ms/QTc581 ms) after regaining consciousness (Figure 1b). Nine days after the first syncope she developed recurrent loss of consciousness and ECG monitoring showed TdP (Figure 1c). She was resuscitated with a single DC shock. She was immediately transferred to the division of cardiology. ECG monitoring showed QT prolongation (QT600 ms) and recurrent TdP. Serum electrolytes and hepatic function were normal. Calculated creatinine clearance was 60 ml min−1. We considered that solifenacin was closely related to syncope and TdP. We stopped solifenacin. Intravenous magnesium sulphate could not terminate recurrent episodes of TdP. The pacing rate was increased 60 to 90 beats min−1 to shorten the QT interval, resulting in a QT interval of 600 to 500 ms (QTc 408 ms). There were no further attacks of TdP. Electrocardiographic abnormalities resolved a few days after solifenacin was discontinued. The high bladder selectivity of solifenacin might be expected to reduce adverse effects [1], which include dry mouth, constipation and blurred vision, but severe cardiac adverse effects have not been reported [1]. Known risk factors for drug-induced TdP are female sex, hypokalaemia, hypomagnesaemia, bradycardia, simultaneous administration of inhibitor compounds, and genetic factors [4–6]. Serum electrolytes, especially potassium and magnesium, were normal. Age and mild renal dysfunction had no clinically relevant effects on the pharmacokinetics of solifenacin [1]. The main metabolic pathway of solifenacin is CYP3A4 [1]. Although hepatic dysfunction decreased clearance of solifenacin [1], hepatic function was also normal. Anti-infective agents that were administered intravenously did not include CYP3A4 inhibitors such as erythromycin [4–6]. She had no other structural heart diseases, nor any family history of sudden death. Concomitant drugs remained unchanged. Amlodipine would not have interacted with solifenacin because of little influence of first-pass effect by CYP3A4 at therapeutic dose [7]. Marked QT prolongation and TdP were considered to be related to solifenacin. Intravenous magnesium sulphate, the first-choice treatment of drug-induced TdP [6], was not effective. Recurrence of TdP was prevented after the QT interval was shortened by increasing the pacing rate. We did not investigate her genetic factors and plasma drug concentration. Although the mechanism is not fully understood, the start of solifenacin might have influenced the outcome in our elderly female patient. To our knowledge, this is the first reported case of QT prolongation and TdP associated with solifenacin.

We report a case of spontaneous hyphaema with no apparent predisposing cause except the assumption of an excessive warfarin dosage leading to over-anticoagulation; a literature search performed in Medline revealed only one case of spontaneous hyphaema resulting from warfarin therapy and no other ocular cause [1]. In case of overdosing, the incidence of warfarin-related hyphaemas could be higher, and it should be taken into account in clinical practice. A 72-year-old woman presented complaining of blurred vision and discomfort in her right eye of 1 day's duration. She had been taking 5 mg of warfarin sodium daily for atrial fibrillation for 2 years; she denied any other systemic disorder except hypertension and the history was negative for eye disease or treatment. The International Normalized Ratio (INR)/dosing was stable and the INR was regularly monitored every 3–4 weeks. The patient's compliance with the regimen was good; two episodes of self-limiting subconjunctival haemorrhage during the previous 12 months were reported. There was no recent illness and no new concurrent medications. Slit-lamp examination of the right eye revealed diffuse heame within the anterior chamber and a 2-mm layered hyphaema. No iris abnormalities were present. Gonioscopy was unremarkable and dilated fundus examination was within normal limits for age. The left eye was normal. Haematological evaluation disclosed prolonged activated partial thromboplastic time of 73.4 s (normal range 26–36 s) and INR of 5.56 (normal range 0.80–1.20). By the consent of the patient's haematologist, warfarin was discontinued until a subsequent haematological evaluation 3 days later. At that time she was asymptomatic and visual acuity was normal (best corrected visual acuity 1.0 decimels, or 20/20 snellen). The anterior chamber had cleared completely; minimum blood was visible on the iris surface and within the anterior iris stroma at 6 o'clock position. Gonioscopy and fundus examination were still negative for ocular abnormalities. Warfarin was reintroduced at a dose of 2.5 mg/day and the INR monitored 3 days later; the ocular bleeding has not recurred up to now. The use of the Naranjo probability scale revealed that the adverse event was possibly due to warfarin therapy (final score 4). Most spontaneous hyphaemas are associated with iris abnormalities, but this condition has been reported to occur from a variety of ocular causes (Table 1). Nunziata has reported a case of bilateral hyphaema in which no predisposing condition could be identified [2]. Table 1 Possible causes of hyphaema Various systemic conditions have been associated with spontaneous hyphaemas: haematological alterations such as sickle cell disease, acute lymphoblastic and myelocytic leukaemia, lymphomas, juvenile xanthogranuloma, histiocytosis X and many rheumatological disorders causing uveitis, such as Reiter's syndrome or ankylosing spondylitis (Table 1). Warfarin is the most commonly used drug for outpatient anticoagulation therapy and its main side-effect is bleeding; theoretically, this can occur in all organs, including the eye. Ocular bleeding can occur as subconjunctival, vitreal, retinal or choroidal haemorrhages; bloody tears have been also reported [3]. Cases of bleeding within the anterior chamber in non-operated eyes and linked to warfarin therapy in eyes with predisposing abnormalities have been previously reported by Greenfield and coworkers [4]. Aspirin and Ginkgo biloba also have been linked with spontaneous hyphaema [5, 6]. Ocular haemorrhages in warfarinized patients can be sight-threatening events, but often they are clinically benign and resolve without any sequelae. However, they may be the only indication that the patient is at risk for major bleeding episodes linked to over-anticoagulation. A number of studies have shown what amounts to an exponential increase in haemorrhagic complications as the INR increases to >5.0 [7]. Patients on warfarin therapy should be instructed to notice any change in their quality of vision; should any intraocular bleeding be diagnosed by the ophthalmologist, patients require immediate blood work and consultation with their primary care provider.

A 42-year-old man presented to his general practitioner (GP) with a history of several weeks of a painful left knee, which had prevented him doing his usual jogging for 20 min several times each week. There was no history of trauma or other precipitant. Past history revealed a 30-year history of insulin-dependent diabetes, for which he took insulin lispro 5 IU t.d.s. and glargine 20 IU nocte. Four weeks earlier, he had increased simvastatin from 10 to 40 mg daily following the finding of changes at retinal screening. There was no history of previous allergy. Examination revealed a small effusion of the left knee. This was confirmed on X-ray, which showed no other changes. Bloods for arthopathy screen were normal. Simvastatin was stopped for 2 weeks, following which the symptoms completely resolved. He then started pravastatin 20 mg daily and pain returned, although it resolved completely after reducing the dose to 10 mg daily. Although the Summaries of Product Characteristics and Patient Information Leaflets for simvastatin, atorvastatin, pravastatin and rosuvastatin all list arthralgia as a possible side-effect, the British National Formulary (BNF) is not consistent with this advice since arthralgia is listed as a side effect for atorvastatin and rosuvastatin but not for simvastatin, fluvastatin or pravastatin [1]. BNF does not list arthopathy as a side-effect of any statin. However, the Medicines and Healthcare products Regulatory Agency has reported the following cases of suspected arthralgia/arthopathy as a result of statin use in Table 1. Table 1 UK reports of statins and arthralgia/arthopathy between 1 July 1963 and 18 March 2008 Some statins are more lipophilic (atorvastatin, fluvastatin, simvastatin), whereas others are more hydrophilic (pravastatin, rosuvastatin) [2]. Table 1 shows that for lipophilic statins there were 294 cases of arthralgia and nine cases of arthropathy, whereas for hydrophilic statins there were cases of 75 arthralgia and one case of arthropathy. However, although there are relatively high numbers of reports for the more lipophilic simvastatin and atorvastatin, there are very few for fluvastatin. The risk of arthralgia for one of the more hydrophilic compounds, pravastatin, was detected in clinical trials, indicating that the incidence was relatively common; yet in rosuvastatin post marketing studies, arthralgia has only been detected at a very rare reporting rate of

Gatifloxacin is a 8-methoxyfluoroquinolone antimicrobial with an extended spectrum of antimicrobial activity. It was approved for use in the United States in 1999 and was introduced in India in October 2001. The drug is approved for use in the treatment of various respiratory infections including bronchitis, urinary tract infections and gonorrhoea [1]. We report a case of haemoptysis associated with gatifloxacin. A 27 year old male patient, known to have bronchial asthma which was well controlled, attended the Respiratory and Chest Diseases outpatient department with the complaint of frank blood in the sputum. He had had a cough and mucopurulent sputum for the last 10 days. On the fourth day of cough he took gatifloxacin 400 mg (Gatikind, Mankind India) once daily (self medication being a doctor) for 5 days. The symptoms of cough and sputum improved but he had a bout of frank haemoptysis on the fifth day of the treatment for which he presented to the physician. The drug was stopped and thereafter, no episode of haemoptyis occurred. There was no history of violent coughing or any concomitant medication. On examination bilateral breath sounds were present and no added sounds were heard. Spirometry was performed and FEV1 was found to be more than 80% of the predicted value. The chest X-ray showed no significant finding. Bleeding and clotting times were in the normal range. Complete blood count was not available. The diagnosis of bronchitis was made as the patient had symptoms consistent with upper respiratory tract infection and normal chest radiograph [2]. There was no history of gatifloxacin intake in the past. The patient provided written informed consent for publication of this report. The case was reported to the zonal centre under the national pharmacovigilance programme. Although bronchitis is a common cause of haemoptysis [2], in this case the event surfaced when the symptoms of bronchitis were improving. The temporal relationship between the administration of gatifloxacin with the occurrence of the event, and no further episode of haemoptysis on stopping the drug, also supports that the event could be due to gatifloxacin. There are reports suggesting occurrence of haemorrhage with gatifloxacin [3] and increased risk of bleeding with the concomitant use of warfarin and gatifloxacin [4, 5]. The strength of association was examined using the Naranjo's Adverse Drug Reaction Probability Scale, in which a score of +4 was obtained suggesting a ‘possible’ link. The Naranjo's algorithm defines adverse reactions as definite (score > 9), probable (score between 5 and 8), possible (1–4) and doubtful (

Rituximab is an anti-CD20 autoantibody approved for rheumatoid arthritis. It induces deep and prolonged depletion of CD20-bearing lymphocytes. Rituximab is increasingly used off-label for autoimmune diseases (AIDs) in immunocompromised patients (ICP), whereas its safety is not well documented in this setting. We assessed off-label rituximab use in AIDs through a drug-utilization survey in Toulouse University Hospital (2834 beds) from January 2004 to December 2005. Patients who had received at least one rituximab infusion for AIDs were identified from the pharmacy department database. We used the World Health Organization definition for serious adverse events (SAEs) [1]. Patients taking >20 mg day−1 prednisone and/or an immunosuppressive drug at the time of first rituximab infusion were considered immunocompromised. All patients were followed 1 year after the first rituximab infusion. Thirty-seven patients (18 women), mean age 51.7 years (95% confidence interval ±17.6) were included in the study. Median disease duration was 87 months (range 1–396). Diagnostic groups were: autoimmune cytopenia (n = 19), autoimmune coagulation disorder (n = 5), cryoglobulinaemia (n = 7), Wegener's granulomatosis (n = 3), pemphigus (n = 2) and lupus erythematosus (n = 1). The mean daily corticosteroid dosage at the time of rituximab first infusion was 35.2 mg day−1 (median 30; range 0–60). There was 30 ICPs (81.1 ± 12.6%); 75.7% (±13.8) of the patients received a complete cycle of four 375 mg kg−1 day−1 infusions. Eight then had maintenance therapy. We estimated that the complete remission rate after rituximab was 20/37 (54 ± 16.1%) according to criteria used in major international publications. One patient had a partial response. Rituximab was the main contributor to complete remission in 14 patients (37.8 ± 15.6) who had no intensification of other therapies. Among 20 complete responders, three were treated again because of relapse between 12 and 13 months after the first infusion. SAEs occurred in 14/37 patients (37.8 ± 15.6%) (Table 1), including death in six with uncontrolled disease. Seven (18.9 ± 12.6%) had serious infections, of whom two had pneumocystosis. Six of these seven patients were immunocompromised and another had undergone splenectomy 3 months earlier. The estimated incidence rate of infectious SAEs was 20.7 (±14.5) per 100 patient-years in ICPs. Table 1 Serious adverse events (SAE) among 37 patients treated by Rituximab for AIDs To our knowledge, this is the first report of a systematic hospital-based safety survey of rituximab off-label utilization for AIDs. Incidence of SAE, especially infectious, was much higher than in another study including adult patients with various AIDs [2]. In this retrospective study, 1/3 of patients had rheumatoid arthritis, some had a short follow-up, and patients were included on a voluntary basis by their attending physician. We cannot exactly determine the contribution of rituximab to infectious SAEs, as SAEs occur in about 13.5 per 100 years in patients receiving chronic immunosuppressive therapy for various AIDs [3]. Given a large confidence interval, this may not be very different from the 20.7 (±14.5) per 100 years infection rate we have found. However, hypogammaglobulinaemia occurring in some patients [4], loss of IgM-only producing memory B cells that are crucial for defence against bacteria [5], alteration of antigen-presenting cell function due to B-cell depletion [6] and the possibility of delayed neutropenia [7] may worsen susceptibility to infection in previously immunocompromised patients exposed to rituximab. In conclusion, in this study SAEs were frequent among patients treated off-label by rituximab for AIDs. The infection rate was perhaps abnormally high. Benefit-to-risk ratio of rituximab off-label use for immune diseases in real life should be further systematically assessed.

Celecoxib is a commonly used selective cyclooxygenase (COX)-2 inhibitor. Sporadic cases of hepatic or renal toxicity have been described with its use. All but three of these cases were reported with short-term use, typically a couple of days or weeks [1–3]. We report the first known case of late-onset celecoxib-induced hepato-nephrotoxicity, of which we obtained histological evidence.

In recent years the use of so-called fatburners such as Stacker® has gained widespread popularity in the USA. These dietary supplements contain substances such as Ephedra and caffeine.The drugs are supposed to stimulate athletic performance and reduce body weight [1]. Ephedra, also known as the Chinese ‘Ma Huang’, is a plant-derived natural source of the sympathicomimetic substance ephedrine. Caffeine (1,3,7-methylxanthine) is also a plantderived stimulant alkaloid, which can be obtained from tea leaves, coffee beans, cacao beans and cola nuts. Its pharmacological actions are diverse, but finally result in an increasing release of endogenous catecholamines and therefore augment the effect of Ephedra alkaloids. For years, Ephedra-containing food supplements were easily available over-the-counter herbal products in the USA and the Netherlands. When serious adverse events including stroke, heart attacks, cardiac arrhythmias, seizures and psychotic disorders were reported, the general sale of Ephedra-containing products was prohibited. However, Ephedra alkaloids can still easily be obtained through the internet or at gyms. Furthermore, an increase in the use of Ephedra-free fatburners, which are considered as ‘safe’ products, has been observed. In the following case report we describe a remarkable, potential lethal intoxication with Stacker 2®. A 22-year-old woman with no previous medical history was admitted to our emergency room because of attempted suicide. She claimed to have ingested approximately 50 tablets of Stacker 2® ephedra, which had previously been provided by her gym. According to the label on the bottle, its main constituents were Ephedra, cola nuts and white willow bark (NVE Pharmaceuticals®, Andover, NJ, USA).The patient reported not having taken any alcohol or other medication. Furthermore, she had not been exercising on the day of admission. On arrival, she complained of thirst, headache, abdominal pain, chest pain and she vomited several times. On examination, an anxious, hyperventilating and extremely agitated woman was observed with clammy peripheries. Vital signs included a temperature of 37.5 °C, blood pressure of 122/66 mmHg, a regular pulse of 110 bpm and a respiratory rate of 25/min. Her arterial saturation was measured at 99%. Pupils were bilaterally dilated and responsive. Apart from modest abdominal tenderness, physical examination revealed no other abnormalities. Laboratory results are shown in Table 1. Because of the strikingly low serum potassium concentration (1.6 mmol l-1), laboratory measurements were verified several times. Also remarkable was the elevated serum lactate (7.2 mmol l-1). Electrocardiography demonstrated sinustachycardia with ST-depression and U-waves in precordial leads V1–V3. Potassium chloride at a rate of 20 mmol h-1 was administered. Furthermore, sodium-potassium-phosphate was supplemented.The patient was transferred to the Intensive Care Unit for haemodynamic monitoring. Polyuria was observed with a diuresis of 250 ml h-1. The following day, the patient was less agitated, but still complained of nausea, vomiting and abdominal pain. Her respiratory rate still measured 22/min. Tachycardia had disappeared. The serum potassium concentration had increased from 1.6 to 3.8 mmol l-1. Serum lactate had decreased to 3.5 mmol l-1 (Table 1). The patient was transferred to the ward and discharged home 7 days after admittance. Subsequently, toxicological analysis for caffeine was performed by means of high-pressure liquid chromatography UV detection: platinum enhanced polar selectivity C18 column, particles; 3 mm, size 10 ¥ 4.6 cm; Alltech®, photodiode array detector (Waters®, Milford, MA, USA). The mobile phase consisted of a solution of water, phosphor acid, nonilamine (67%) and acetonitril (33%). Ephedrine British Journal of Clinical Pharmacology DOI:10.1111/j.1365-2125.2008.03279.x

The study reported in the paper by Forrest et al.[1] was based on the assumption that melatonin administration could be beneficial in rheumatoid arthritis (RA) because of its antioxidant activity. The results obtained were somewhat disappointing and ‘surprising’ as the authors stated in the discussion. We would like to draw your attention on the fact that before being ‘one of the most powerful endogenous free radical scavengers’ melatonin is a chronological pacemaker signalling the time of the day and of the year to the body. This function is achieved by the circadian activation of specific high affinity melatonin receptors expressed on a variety of cell types including immunocompetent cells [2]. A Pubmed search with the key words ‘melatonin and radical scavenger’ gave 338 items including 69 reviews. A similar search with the key words ‘melatonin and immune’ resulted in 495 items of which 157 were reviews. The large majority of the studies addressing the effect of melatonin on the immune system report an immunoenhancing effect. Melatonin is recognized to increase the production of Th1-type and inflammatory cytokines in RA and to enhance both cell mediated and humoral responses [3]. In regard to RA, melatonin has been shown to exacerbate collagen-induced arthritis and, as Forrest et al.[1] quoted, we have suggested that it might exert a disease promoting role in patients [4]. Recently, serum TNFα was found to be higher in RA patients (Estonia) than in their controls and was correlated with the increased serum melatonin concentrations, at least in winter [5]. However, altered serum concentrations and circadian rhythms of melatonin have been implicated in clinical RA symptoms [6]. In addition, a ‘relative adrenal insufficiency’ in chronic RA, allows Th1 type cytokines to be produced in higher amounts during the late night under the enhancing effect of increased melatonin [7]. For these reasons, we would have never dared to administer melatonin to RA patients. We are not surprised at all from the results obtained in the study, rather, we are amazed that melatonin did not worsen the clinical symptoms. However, this benign outcome might depend on mechanisms not considered by the authors. Beside the presence of anti-inflammatory therapies that could have neutralized the effect of melatonin, the daily administration of 10 mg of the hormone during 6 months might have produced a desensitization of the melatoninergic system. The plasma concentration of 280 pg ml−1 found 12 h after administration is very high considering the half-life of the molecule. As the melatonin concentration was determined at a single time point, it is not possible to know whether its concentration declined to reach the physiological day-time concentration. This is a crucial issue because the expression and activity of the melatonin receptors are regulated by their ligand, as occurs for all hormones. Thus, the continous presence of a supraphysiological concentration of melatonin might have resulted in a chronic down regulation of the specific receptors. In addition, melatonin may accumulate in tissue like the skin and be released during the day once saturation has been reached [8]. Last but not least, melatonin may be synthesized and be released by activated human T lymphocytes [9, 10]. It is thus possible that autoreactive T cells in RA patients do synthesize and release melatonin that, in turn, might contribute in the disease pathogenesis. In this possible situation, addition of exogenous melatonin would hardly exert any significant therapeutic effect in RA.