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Background & Aims: Golexanolone is a novel small molecule GABA-A receptor-modulating steroid antagonist under development for the treatment of cognitive and vigilance disorders caused by allosteric over-activation of GABA-A receptors by neurosteroids. It restored spatial learning and motor coordination in animal models of hepatic encephalopathy (HE) and mitigated the effects of intravenous allopregnanolone in healthy adults in a dose-dependent fashion. Herein, we report data on the safety, pharmacokinetics (PK) and efficacy of golexanolone in adult patients with cirrhosis. Methods: Following single/multiple ascending dose studies, adults with Child-Pugh A/B cirrhosis and abnormal continuous reaction time (CRT) on screening were randomized to 3 weeks' dosing with golexanolone (10, 40 or 80 mg BID) or placebo. CRT, psychometric hepatic encephalopathy score (PHES), animal naming test (ANT), Epworth sleepiness scale (ESS) and electroencephalogram (mean dominant frequency [MDF]; delta+theta/alpha+beta ratio [DT/AB]) were obtained at baseline, 10, and 21 days. Results: Golexanolone exhibited satisfactory safety and PK. Baseline characteristics were similar between the 12 and 33 patients randomized to placebo or golexanolone, respectively. By prespecified analyses, golexanolone was associated with directionally favourable changes vs. placebo in ESS (p = 0.047), MDF (p = 0.142) and DT/AB (p = 0.021). All patients also showed directionally favourable changes in CRT, PHES and ANT, but with no statistical difference between golexanolone and placebo. Post hoc analyses taking into account the variability and improvement in CRT, PHES and ANT observed between screening and baseline suggested an efficacy signal by cognitive measures as well. Conclusion: Golexanolone was well tolerated and associated with improvement in cognitive performance. These results implicate GABA-A receptor-modulating neurosteroids in the pathogenesis of HE and support the therapeutic potential of golexa

Background: Current thrombolytic-antithrombotic regimens in acute myocardial infarction (AMI) are limited by incomplete early coronary reperfusion and by reocclusion and reinfarction. We compared the effects of low molecular weight heparin (LMWH) versus unfractionated heparin (UFH) as an adjunct to recombinant tissue-plasminogen activator (alteplase) on coronary artery patency and clinical outcomes in AMI. Methods: Patients with AMI treated with alteplase (n = 439) were randomised to either subcutaneous dalteparin (120 IU/kg every 12 h) for 4-7 days or intravenous infusion of UFH for 48 h. Coronary angiography was performed between day 4 and hospital discharge. Clinical events and safety were evaluated until day 30. Results: Overall there were higher thrombolysis in myocardial infarction (TIMI) flows in the infarct related coronary artery in the dalteparin group (p = 0.01 6). The predefined primary end-point, TIMI grade 3 flow, did not reach statistical significance (dalteparin 69.3% versus heparin 62.5%, p = 0.163). However, TIMI 0-1 flow (13.4 versus 24.4%, p = 0.006) and its combination with intraluminal thrombus (27.9 versus 42.0%, p = 0.003) were less common in the dalteparin group. During the period of randomised treatment there were less myocardial reinfarctions in the dalteparin group (p = 0.010) but after cessation of dalteparin there were more reinfarctions resulting in no difference in death or MI at 30 days. There were no significant differences in major bleeding or stroke after 30 days. Conclusions: In alteplase treated AMI adjunctive dalteparin for 4-7 days seems to reduce the risk of early coronary artery occlusion and reinfarction. However, early after cessation of treatment there is a raised risk of events, which might eliminate any long-term gains. ⌐ 2003 The European Society of Cardiology. Published by Elsevier Science Ltd. All rights reserved.