Objective To estimate the analgesic efficacy of non-steroidal anti-inflammatory drugs (NSAIDs), including selective cyclo-oxygenase-2 inhibitors (coxibs), in patients with osteoarthritis of the knee. Design Systematic review and meta-analysis of randomised placebo controlled trials. Studies reviewed 23 trials including 10 845 patients, median age of 62.5 years. 7807 patients received adequate doses of NSAIDs and 3038 received placebo. The mean weighted baseline pain score was 64.2 mm on 100 mm visual analogue scale (VAS), and average duration of symptoms was 8.2 years. Main outcome measure Change in overall intensity of pain. Results Methodological quality of trials was acceptable, but 13 trials excluded patients before randomisation if they did not respond to NSAIDs. One trial provided long term data for pain that showed no significant effect of NSAIDs compared with placebo at one to four years. The pooled difference for pain on visual analogue scale in all included trials was 10.1 mm (95% confidence interval 7.4 to 12.8) or 15.6% better than placebo after 2-13 weeks. The results were heterogeneous, and the effect size for pain reduction was 0.32 (0.24 to 0.39) in a random effects model. In 10 trials that did not exclude non-responders to NSAID treatment the results were homogeneous, with an effect size for pain reduction of 0.23 (0.15 to 0.31). Conclusion NSAIDs can reduce short term pain in osteoarthritis of the knee slightly better than placebo, but the current analysis does not support long term use of NSAIDs for this condition. As serious adverse effects are associated with oral NSAIDs, only limited use can be recommended.

Clinical effects from pharmacological interventions in OAK are small and limited to the first 2-3 weeks after start of treatment. The pain-relieving effects over placebo in OAK are smaller than the patient-reported thresholds for relevant improvement.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• High dose methotrexate (HD MTX) is generally well tolerated, although unpredictable acute toxicities occur frequently.• Low overall toxicity in paediatric patients and increased liver toxicity in adults has been reported, but there are no reports addressing the relationship between acute liver toxicity and gender in patients treated with HD MTX. • Previous studies in animals suggested involvement of the 7-hydroxy-methotrexate metabolite in acute liver toxicity, but this has not been investigated in humans and the aetiology of acute liver toxicity remains unclear. WHAT THIS STUDY ADDS• Survival has increased dramatically over the past decades for patients with malignancies such as osteosarcoma and since these patients are frequently children or adolescents at the time of high dose methotrexate, identification of risk factors for toxicity increases the possibility for tailoring treatment.• Our study presents a detailed analysis of acute toxicity, folate concentrations and pharmacokinetics of both methotrexate and its major extracellular metabolite 7-hydroxy-methotrexate and identifies several factors that are highly correlated with acute liver toxicity. AIMSTo investigate the relationships between pretreatment folate concentrations, MTX pharmacokinetics and acute toxicities following high dose methotrexate (HD MTX) therapy. METHODSMTX and its major extracellular metabolite 7-OH-MTX were measured in eight serum samples per HD MTX cycle in 65 consecutive osteosarcoma patients (288 cycles) and AUC (area under the blood concentration-time curve) was calculated. Pretreatment concentrations of folate in serum (S) and erythrocytes (ER) were determined. Hepatic, renal and haematological toxicities, assessed by routine laboratory parameters, as well as mucositis were graded according to National Cancer Institute Common Terminology Criteria for adverse events (CTCAE v.3.0). Dermatitis and pleuritis were reported as occurred or not. RESULTSS-and ER-folate pretreatment concentrations increased significantly with increasing number of HD MTX cycles (P < 0.001). ER-folate pretreatment concentrations were higher among males (median 610 nmol l , 95% CI 430, 520, P < 0.001), but showed no correlation with MTX or 7-OH-MTX pharmacokinetics. We found correlations between alanine aminotransferase peak concentration (ALATmax) and clearance of MTX (P < 0.001), gender (P < 0.001), age (P < 0.001) and 7-OH-MTX concentrations (P < 0.001), the latter being the main factor influencing ALATmax. CONCLUSIONOur results suggest that 7-OH-MTX is involved in the development of HD MTX hepatic toxicity and that young female patients are most affected.

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Although heart failure is predominantly caused by cardiovascular conditions such as hypertension, coronary heart disease and valvular heart disease, it can also be an adverse reaction induced by drug therapy. In addition, some drugs have the propensity to adversely affect haemodynamic mechanisms in patients with an already existing heart condition. In this article, non-cardiac drugs known to be associated with the development or worsening of heart failure are reviewed. Moreover, drugs that may adversely affect the heart as a pump without causing symptoms or signs of heart failure are also included. The drugs discussed include anticancer agents such as anthracyclines, mitoxantrone, cyclophosphamide, fluorouracil, capecitabine and trastuzumab; immunomodulating drugs such as interferon-alpha-2, interleukin-2, infliximab and etanercept; antidiabetic drugs such as rosiglitazone, pioglitazone and troglitazone; antimigraine drugs such as ergotamine and methysergide; appetite suppressants such as fenfulramine, dexfenfluramine and phentermine; tricyclic antidepressants; antipsychotic drugs such as clozapine; antiparkinsonian drugs such as pergolide and cabergoline; glucocorticoids; and antifungal drugs such as itraconazole and amphotericin B. NSAIDs, including selective cyclo-oxygenase (COX)-2 inhibitors, are included as a result of their ability to cause heart disease, particularly in patients with an already existing cardiorenal dysfunction. Two drug groups are of particular concern. Anthracyclines and their derivatives may cause cardiomyopathy in a disturbingly high number of exposed individuals, who may develop symptoms of insidious onset several years after drug therapy. The risk seems to encompass all exposed individuals, but data suggest that children are particularly vulnerable. Thus, a high degree of awareness towards this particular problem is warranted in cancer survivors subjected to anthracycline-based chemotherapy. A second group of problematic drugs are the NSAIDs, including the selective COX-2 inhibitors. These drugs may cause renal dysfunction and elevated blood pressure, which in turn may precipitate heart failure in vulnerable individuals. Although NSAID-related cardiotoxicity is relatively rare and most commonly seen in elderly individuals with concomitant disease, the widespread long-term use of these drugs in risk groups is potentially hazardous. Pending comprehensive safety analyses, the use of NSAIDs in high-risk patients should be discouraged. In addition, there is an urgent need to resolve the safety issues related to the use of COX-2 inhibitors. As numerous drugs from various drug classes may precipitate or worsen heart failure, a detailed history of drug exposure in patients with signs or symptoms of heart failure is mandatory.

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The purpose of this study was to establish and validate a driving simulator method for assessing drug effects on driving. To achieve this, we used ethanol as a positive control, and examined whether ethanol affects driving performance in the simulator, and whether these effects are consistent with performance during real driving on a test track, also under the influence of ethanol. Twenty healthy male volunteers underwent a total of six driving trials of 1h duration; three in an instrumented vehicle on a closed-circuit test track that closely resembled rural Norwegian road conditions, and three in the simulator with a driving scenario modelled after the test track. Test subjects were either sober or titrated to blood alcohol concentration (BAC) levels of 0.5g/L and 0.9g/L. The study was conducted in a randomised, cross-over, single-blind fashion, using placebo drinks and placebo pills as confounders. The primary outcome measure was standard deviation of lateral position (SDLP; "weaving"). Eighteen test subjects completed all six driving trials, and complete data were acquired from 18 subjects in the simulator and 10 subjects on the test track, respectively. There was a positive dose-response relationship between higher ethanol concentrations and increases in SDLP in both the simulator and on the test track (p<0.001 for both). In the simulator, this dose-response was evident already after 15min of driving. SDLP values were higher and showed a larger inter-individual variability in the simulator than on the test track. Most subjects displayed a similar relationship between BAC and SDLP in the simulator and on the test track; however, a few subjects showed striking dissimilarities, with very high SDLP values in the simulator. This may reflect the lack of perceived danger in the simulator, causing reckless driving in a few test subjects. Overall, the results suggest that SDLP in the driving simulator is a sensitive measure of ethanol impaired driving. The comparison with real driving implies relative external validity of the simulator.

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