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Background Cytostatic drugs that typically may cause encephalopathy comprise methotrexate and ifosfamide. For cisplatin, neurotoxicity is a common adverse effect, mainly limited to axonal sensory neuropathy, but CNS disorders have also been reported. Purpose To present a patient with symptoms of encephalopathy while receiving chemotherapy with cisplatin and etoposide and the successful treatment and prophylaxis with thiamine. Material and methods A 9-year-old male patient with neuroblastoma stage 4 was treated according to the trial NB2004-HR. Chemotherapy consisted of alternate application of vindesin/cisplatin/etoposide (N5) and vincristine/dacarbacine/ifosfamide/doxorubicine (N6) at intervals of 3 weeks for a total of three cycles each. During his first N6 cycle, he developed ifosfamide induced encephalopathy with symptoms of confusion, disorientation and slurred speech, which was successfully treated with thiamine. During the second N5 cycle, the symptoms recurred, and after review of the literature and discussion, it was decided to prescribe thiamine (75 mg every 6 h). The symptoms resolved immediately. During the following N5 and N6 cycles, the patient was prophylactically treated with thiamine and no signs of central neurotoxicity were observed. Retrospectively, during the first N5 cycle, milder symptoms of encephylopathy did also occur. Results Employing widely accepted causality scales for adverse effects (Naranjo scale or WHO-UMC causality categories), it was probable that cisplatin (Naranjo score 6, WHO-UMC probable/likely) or etoposide (Naranjo score 5 points, WHO-UMC probable/likely) caused the encephalopathy. Several aspects support thiamine’s efficacy: (1) reasonable time relationship of adverse neurologic symptoms to N5 cycle, (2) effect is unlikely to be explained by other drugs and (3) response to thiamine was reasonable. As we did not withdraw thiamine in one of the following N5 cycles, it was not possible to evaluate whether the symptoms would have reappeared without thiamine, which would further corroborate our hypothesis. Conclusion To our knowledge, this is the first report of successful use of thiamine against non-ifosfamide induced encephalopathy. Thiamine might provide a reasonable option for the treatment and prevention of cisplatin/etoposide induced encephalopathy in children with neuroblastoma. No conflict of interest.

This is a case report of a 44-year-old obese female who developed subclinical hepatic injury 4 weeks after starting metformin for type 2 diabetes. She had a rise in her alanine aminotransferase which peaked at 5 months (738 U/l) and rapidly declined within days of discontinuing her metformin. No other positive evidence of alternative causes for the hepatic injury was found. The likelihood of metformin-induced injury was 7 on the Naranjo scale of adverse drug reactions. A brief review of the 11 previously reported cases in the English medical literature is also made.

Objective: To document the frequency of abacavir hypersensitivity reactions in HIV-positive patients followed in a Veterans Affairs outpatient clinic. Methods: Abacavir's manufacturer lists the incidence of hypersensitivity as 5%. We conducted a retrospective review of all patients in our clinic who received abacavir from January 1999 to December 1999 to document the rate of discontinuation of the drug due to possible hypersensitivity reactions. The duration of abacavir therapy, concomitant antiretrovirals, most recent CD4+ count, most recent viral load, number of antiretroviral regimens previously tried, and the number and types of new antiretrovirals started concomitant with abacavir were collected. Results: Of 24 patients analyzed, nine (38%) discontinued abacavir, with six (25%) having a potential hypersensitivity reaction. Four reactions were classified as probable and two as possible according to the Naranjo scale. Only one patient was hospitalized for the reaction. Patients who discontinued abacavir due to a hypersensitivity reaction had similar CD4+ counts, viral loads, and had received a similar number of antiretroviral regimens compared with patients who continued the drug. However, 67% of patients who discontinued abacavir due to a hypersensitivity reaction had at least one previously documented adverse event that led to the discontinuation of another antiretroviral, compared with 7% of the patients who continued the drug (p = 0.02). Conclusions: The frequency of possible hypersensitivity reactions to abacavir in patients seen in our HIV clinic is higher than the manufacturer's reported rate of 5%. These patients may be more prone to adverse reactions based on previous medication history and adverse events.

Bone mineral density may be negatively influenced by hyperprolactinemia, which can be caused by atypic neuroleptics and antidepressants. Case description The present paper reports about a spontaneous rib fracture in a female patient (age 52) taking neuroleptics (mainly risperidone), antidepressants (mainly sertraline), and anxiolytics (mainly lorazepam). At the time of the fracture a severe osteoporosis and a strongly enhanced plasma prolactin level (117 ng/ml; normal values: 3–24 ng/ml) were detected. The latter one normalized 2 months after abandoning sertraline and risperidone. After this normalization, the patient did not report further accidents up to now. Discussion Enhancement of plasma prolactin levels is linked to the mechanism of action of risperidone. Mammoplasia and increased plasma prolactin can occur during SSRI (Selective Serotonin Reuptake Inhibitors) or trazodone administration. The role of anxiolytics is less clear. The causal relationship between osteoporosis and long-term use of neuroleptics and antidepressants was assessed using probability scores, more particularly the Naranjo probability scale and the Bradford-Hill criteria of causality. A score of 6/13 (probable) was obtained with the Naranjo scale, whereas all 9 Bradford-Hill criteria were fulfilled. Conclusion Although this case could not be fully explored, attention should be paid to bone mineral density loss in depressed patients taking a combined therapy of atypic antipsychotics and antidepressants.

Objective Dietary supplement use has increased over past decades, resulting in reports of potentially serious adverse events. The aim of this study was to develop optimised methods to evaluate the causal relationships between adverse events and dietary supplements, and to test these methods using case reports. Design Causal relationship assessment using prospectively collected data. Setting and participants 4 dietary supplement experts, 4 pharmacists and 11 registered dietitians (5 men and 14 women) examined 200 case reports of suspected adverse events using the modified Naranjo scale and the modified Food and Drug Administration (FDA) algorithm. Primary outcome measures The distribution of evaluation results was analysed and inter-rater reliability was evaluated for the two modified methods employed using intraclass correlation coefficients (ICC) and Fleiss’ κ. Results Using these two methods, most of the 200 case reports were categorised as ‘lack of information’ or ‘possible’ adverse events. Inter-rater reliability among entire assessors ratings for the two modified methods, based on ICC and Fleiss’ κ, were classified as more than substantial (modified Naranjo scale: ICC (95% CI) 0.873 (0.850 to 0.895); Fleiss’ κ (95% CI) 0.615 (0.615 to 0.615). Modified FDA algorithm: Fleiss’ κ (95% CI) 0.622 (0.622 to 0.622). Conclusions These methods may help to assess the causal relationships between adverse events and dietary supplements. By conducting additional studies of these methods in different populations, researchers can expand the possibilities for the application of our methods.

Background Drug related problems (DRPs) are a system dysfunction that occurs due to complex drug regimens. This pilot program was conducted on patients after a femur neck fracture admitted to the orthopaedic ward. There is a great variety of papers published in the field of DRPs but none that focus on the said population. During hospitalisation, against a background of numerous co-morbidities, patient treatment focuses on the acute problem. Hence a breeding ground is created for DRPs. Purpose To identify and characterise DRPs in an effort to prevent and treat them, thus improving patient safety and quality of care. Materials and methods The DRPs identified were characterised using the Cipolle & Strand classification, the probability of an adverse reaction (ADR) assessed with the Naranjo Scale and the possibility of a drug-drug interaction (DI) with the Hansten & Horn scale. The severity of ADR/DI was calculated using the Hartwing & Seigel scale. The analytical tests conducted include the Chi-square and the Spearman correlation. Results The clinical pharmacist reviewed 45 patient records and identified 113 DRPs; 27% pertained to indication, 35% to safety, 23% to documentation and 4% to monitoring. Upon division of the DRPs according to drug groups 26% were gastrointestinal, 13% anti-platelets or anticoagulant, 25% cardiovascular, 24% central nervous system, 4% musculoskeletal, 3% hormonal and 3% anti-infective agents. Additional results will be presented at the conference. Conclusions Preliminary results from the pilot reinforce the importance of the issue and influenced the initiation of a full scale trial and an institutional policy to treat DRPs. Furthermore, these results instigated a change in the process of care by permanently allocating a clinical pharmacist to the orthopaedic ward. No conflict of interest.

isotretretinoin (positive de-challenge) and re-emerged whenever the drug was re-administered (positive re-challenges); the remaining cases scored 3 on the Naranjo scale (“possible” ADR). In all four cases, however, the temporal relationship (1- or 2-month interval) between isotretinoin administration and the appearance of psychiatric symptoms shows that the drug was the most probable triggering factor.The multiformity of isotretinoin-induced psy-chiatric adverse events is only partly accounted for by the multiplicity of the drug’s effects on various neurotransmitter systems and brain structures (Goodman 1998; Bremner and McCaffery 2008). In this case series, we speculate a potential role for the various types of genetic vulnerability of the exposed individuals in the emergence of diverse psychiatric symptoms, an effect that has scarcely been investi-gated to date (Barak et al. 2005). For example, in cases #1 and #3 each of which had a family history loading for both psychosis and affective disorder, isotretinoin induced a mixed clinical syndrome with both psychotic and depressive features (“schizo-affective disorder”, “psychotic depression”). In cases #2 and #4 which had a loading for affective disor-der or psychosis, the induced syndrome was (non-psychotic) “major depression” or “schizophrenia”, respectively. We suggest that isotretinoin-induced psychiatric symptoms might be generated through a gene–environment interaction, with isotretinoin as an undifferentiated environmental stressor and its effects being modulated by the various types of genetic vulnerability of the exposed individuals.In conclusion, cases reported add to a few pre-vious similar reports of isotretinoin-induced psychi-atric manifestations in individuals with a positive To the Editors,Isotretinoin, a synthetic retinoid that is used against severe, recalcitrant nodulocystic acne, has been asso-ciated in several case-series and some retrospective and uncontrolled studies with various psychiatric side-effects (depression, violent behaviour, suicidality and psychotic symptoms) (Ng et al. 2001; Hull and d’Arcy 2003; Kontaxakis et al. 2009). Depressive symptoms are most often reported at 1 month after isotretinoin initiation at an estimated incidence of 1–11% (Bremner and McCaffery 2008). The first controlled study to find a statistically significant asso-ciation between isotretinoin and depression (relative risk 2.68) was recently published (Azoulay et al. 2008). However, the causal link between isotretinoin use and psychiatric adverse events remains controver-sial mainly due to poor quality of existing evidence (Strahan and Raimer 2006). We present four patients consecutively hospital-ized in our department during 2008 whose psychi-atric symptoms (depression, suicidality, psychotic symptoms) were possibly induced by isotretinoin administration. All patients had a positive family his-tory for psychiatric disorders. In Table I, clinicode-mographic characteristics of the four patients are presented. Determining the likelihood of whether a symptom is actually an adverse drug reaction (ADR) is often quite complicated (Naranjo et al. 1981; Mann et al. 2008). It is obvious that an association of isotretinoin use with psychopathology is not equally demonstrated by all cases presented. The strongest association can be established for case #3 (Naranjo score 5: “probable” ADR), whose psychi-atric symptoms remitted upon discontinuation of

Objective. To evaluate the toxicity of slow-acting anti-rheumatic drugs (SAARDs) and non-steroidal anti-inflammatory drugs (NSAIDs) in early rheumatoid arthritis.Methods. Patients were randomized to receive a SAARD-hydroxychloroquine (HCQ; n = 120, i.m. gold (n = 114) or methotrexate (MTX; n = 118)-or a NSAID only (n = 67). Patients in the three SAARD groups were allowed to take NSAIDs. Follow-up included 545 patient-years Cp-yr). Adverse effects were attributed to specific medications using the Naranjo scoring method.Results. Fifty-five per cent of the patients suffered from adverse effect(s). Adverse effects were most common during i.m, gold therapy (87 per 100 p-yr), which led to permanent discontinuation of this treatment in 31 cases. The incidences of adverse effects that were probably attributable to NSAIDs in patients treated simultaneously with a SAARD were similar for the three SAARD groups. The mean period until the first adverse effect was longer in the MTX group (39 weeks) than in the HCQ group (27 weeks). Baseline clinical and sociodemographic parameters were not predictive of the occurrence of adverse effects.Conclusion. No adverse effect could be classified as definitely related to either SAARDs or NSAIDs by the Naranjo scoring method. The incidence of possible adverse effects of NSAIDs and SAARDs was 72 per 100 p-yr, and adverse effects led to permanent discontinuation of the therapy in 56 cases (13%) (31 patients receiving i.m. gold, 12 receiving MTX, 10 receiving HCQ and three receiving NSAID only).

Drug hypersensitivity syndrome is characterized by fever, skin rash and internal organ involvement. It is commonly seen with aromatic group of anticonvulsants viz. phenytoin, carbamazepine and phenobarbitone. Here, we report a case of hypersensitivity reaction to pregabalin, used for treating postherpetic neuralgia.

Whilst the debate on the safety of selective COX-2 inhibitors continues, articles such as the paper presented by Titchen et al. [1] do little to allay public fears about NSAIDs in general. This hospital based study of adverse drug reactions (ADRs) was effectively a retrospective audit of reactions suffered by children attending one paediatric facility in Australia. The authors’ conclusion that NSAIDs as a class are a significant cause of morbidity in children is without foundation. Firstly, no data are given about numbers of children who received NSAIDs without adverse effect. Secondly, from their data, 19/754 children suffered a probable or possible ADR to NSAIDs (2.5%). Of these, only 10/754 (1.3%) children had an ADR to ibuprofen alone. In comparison, the paracetamol ADR was 0.8%, which given the small sample size is in my view a comparable figure. Interestingly, of the 10 children who had a reaction to ibuprofen, haematemesis occurred in three cases, all in adolescents taking between 1600 and 1800 mg day−1 of the drug. This dose is in excess of UK recommendations for this age group, where the dose for juvenile rheumatoid arthritis is a maximum of 15 mg kg−1, so that even a 70 kg teenager would not receive a dose greater than 1050 mg under normal circumstances. Finally, the authors report one tragic case of a death with respiratory complications in a 10 year old girl on one tablet a day rofecoxib, and in whom the likelihood of an ADR was probable (Naranjo scale). Whilst I agree with the authors that we should develop better guidelines and carry out vigilant surveillance of ADRs in the paediatric population there is a risk that data such as those presented in this study could be misinterpreted by the media, the lay press and the public at large, causing further confusion and anxiety.

The estimation of the probability that a drug caused an adverse clinical event is usually based on clinical judgment. Lack of a method for establishing causality generates large between-raters and within-raters variability in assessment. Using the conventional categories and definitions of definite, probable, possible, and doubtful adverse drug reactions (ADRs), the between-raters agreement of two physicians and four pharmacists who independently assessed 63 randomly selected alleged ADRs was 38% to 63%, kappa (k, a chance-corrected index of agreement) varied from 0.21 to 0.40, and the intraclass correlation coefficient of reliability (R[est]) was 0.49. Six (testing) and 22 wk (retesting) later the same observers independently reanalyzed the 63 cases by assigning a weighted score (ADR probability scale) to each of the components that must be considered in establishing causal associations between drug(s) and adverse events (e.g., temporal sequence). The cases were randomized to minimize the influence of learning. The event was assigned a probability category from the total score. The between-raters reliability (range: percent agreement = 83% to 92%; κ = 0.69 to 0.86; r = 0.91 to 0.95; R(est) = 0.92) and within-raters reliability (range: percent agreement = 80% to 97%; κ = 0.64 to 0.95; r = 0.91 to 0.98) improved (p < 0.001). The between-raters reliability was maintained on retesting (range: r = 0.84 to 0.94; R(est) = 0.87). The between-raters reliability of three attending physicians who independently assessed 28 other prospectively collected cases of alleged ADRs was very high (range: r = 0.76 to 0.87; R(est) = 0.80). It was also shown that the ADR probability scale has consensual, content, and concurrent validity. This systematic method offers a sensitive way to monitor ADRs and may be applicable to postmarketing drug surveillance. Clinical Pharmacology and Therapeutics (1981) 30, 239–245; doi:10.1038/clpt.1981.154

Purpose Community-acquired acute kidney injury (CA-AKI) is a frequent and severe adverse drug reaction (ADR) among older patients. The combination of drugs and other CA-AKI risk factors was barely evaluated. The objectives of our study were to both accurately identify CA-AKI induced by drugs in older patients, and to describe their combination with other risk factors. Patients and methods We conducted a retrospective, single-center study in a general hospital over a two-year period. An automated detection identified CA-AKI according to KDIGO criteria, amongst 4,767 eligible inpatient stays among patients aged 75 years or older. Two independent experts reviewed all CA-AKI events to adjudicate drug involvement (Naranjo scale), identify inappropriate prescriptions (STOPP criteria), evaluate avoidability (Hallas criteria) and identify combined risk factors. Results An expert review confirmed 713 CA-AKI (15.0% of inpatient stays) and determined that 419 (58.8%) CA-AKI were induced by drugs. A multifactorial cause (i.e., at least one drug with a precipitating factor) was found in 63.2% of drug-induced CA-AKI. Most of the drug-induced events were avoidable (66.8%), mainly in relation to a multifactorial cause. Conclusion Drug-induced CA-AKI were frequent, multifactorial events in hospitalized older patients and their prevention should focus on combinations with precipitating factors.