The optimal dose of intrathecal morphine for postoperative analgesia after major surgery is a matter of debate, with some uncertainty concerning the therapeutic potential and safety of intrathecal morphine in the dose range 0.3-1.0 mg. This randomised double-blind study compared the efficacy and side-effect profile of 0.2 mg and 0.5 mg intrathecal morphine in 70 patients undergoing knee replacement surgery. The primary endpoint was the number of patients requiring rescue analgesia (tramadol) during the first 24 h postoperatively. Secondary endpoints included consumption of tramadol and the incidence of adverse effects. Fewer patients in the 0.5-mg group required rescue analgesia in the first 24 h than in the 0.2-mg group (16 (48%) vs 28 (85%), respectively; p = 0.003). Median (IQR [range]) tramadol consumption was lower in the 0.5-mg group than in the 0.2-mg group (0 (0-100 [0-350]) mg vs 100 (50-100 [0-350]) mg, respectively; p = 0.02). The incidence of adverse effects was similar in both groups. This study has demonstrated that 0.5 mg intrathecal morphine produces better analgesia than 0.2 mg after knee replacement without any increase in side-effects.

1 The plasma levels of verapamil and its major metabolite norverapamil were related to its effect as a Ca‐antagonist on atrio‐ventricular (AV) conduction, judged from prolongation of the PR interval in six normal volunteers. 2 Intravenous administration (0.1 mg kg‐1) was compared to oral administration (120 mg) in each subject. 3 Intravenous verapamil showed a mean distribution half‐life (alpha) of 8.5 min and elimination half‐life (beta) of 2.0 h. The volume of distribution was about 112.1. Oral dosage gave an elimination half‐life of 2.7 h, and a norverapamil half‐life which averaged 4.6 h. The bioavailability of the oral dose averaged 22% (17 to 29%). 4 After the oral dose the percentage change in PR interval in the five appropriate subjects correlated significantly with the log plasma verapamil level (r = 0.732), but not with the log plasma norverapamil level (r = 0.078); norverapamil could not be detected after the intravenous dose. One subject developed Wenckebach type second degree AV block after each dose.

I n the Western world, atrial fibrillation affects an estimated 4 million individuals, most of whom are elderly. 1 A primary, independent risk factor for stroke, atrial fibrillation age dependently increases stroke risk such that it accounts for 1.5% of the attributable risk in 50-to 59-year-olds and 23.5% of the risk in 80-to 89year-olds. 2 One third of all strokes among those older than 80 years are attributed to atrial fibrillation. 3,4 As the population continues to age in Western countries, the incidence of stroke associated with atrial fibrillation is expected to increase. 4 Oral anticoagulation therapy (namely, the coumarin warfarin) significantly reduces the risk of stroke among elderly patients with chronic nonvalvular atrial fibrillation and is recommended in treatment guidelines for the prevention of thromboembolism in such patients. 5,6 Across 5 well-controlled clinical trials in which patients were followed for approximately 1 to 2 years, warfarin compared with placebo reduced the rate of ischemic stroke by 68% and the rate of the combined endpoint of death, stroke, or systemic embolism by 48%. 5 Aspirin also reduces the risk of stroke among patients with chronic nonvalvular atrial fibrillation, although its benefits are less pronounced than those of warfarin. 7 Treatment guidelines and the well-established efficacy of oral anticoagulation therapy in preventing 1063The oral direct thrombin inhibitor ximelagatran is being developed for the prevention and treatment of thromboembolism. This single-blind, randomized, placebo-controlled, parallel-group study investigated the potential for the interaction of ximelagatran (36 mg every 12 hours for 8 days, measured as its active form melagatran in blood) and amiodarone (single 600-mg oral dose on day 4) in healthy male subjects (n = 26). For amiodarone + ximelagatran versus amiodarone + placebo, geometric mean ratios (90% confidence intervals for amiodarone AUC 0-120 and C max were 0.87 (0.69-1.08) and 0.86 (0.66-1.11), respectively. For desethylamiodarone, the principal metabolite of amiodarone, the corresponding ratios were 1.00 (0.89-1.12) for AUC 0-120 and 0.92 (0.77-1.09) for C max . The geometric mean ratios (90% confidence intervals) for ximelagatran + amiodarone versus ximelagatran were 1. 21 (1.17-1.25) for melagatran AUC 0-12 and 1.23 (1.18-1.28) for melag-atran C max . These confidence intervals were within or only slightly outside the interval, suggesting no interaction (0.8-1.25 for the effect of amiodarone on melagatran and 0.7-1.43 for the effect of melagatran on amiodarone or desethylamiodarone). Amiodarone did not affect the concentration-effect relationship of melagatran on activated partial thromboplastin time. Ximelagatran was well tolerated when coadministered with a single dose of amiodarone. Evaluation of the safety of the combination is needed to confirm that the relatively small pharmacokinetic changes in this study are of no clinical significance.

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