Na+ currents in cardioprotection: better to be late.

We report the discovery of a selective, potent inhibitor of the late current mediated by the cardiac isoform of the sodium channel (Na(V)1.5). The compound, 3,4-dihydro-N-[(2S)-3-[(2-hydroxy-3-methylphenyl)thio]-2-methylpropyl]-2H-(3R)-1,5-benzoxathiepin-3-amine (2d) (F 15741), blocks the late component of the Na(+) currents and greatly reduces veratridine- or ischemia-induced contracture in isolated tissue and whole heart. The cardioprotective action of 2d was further established in a model of myocardial infarction in the pig in which 2d prevents ischemia-reperfusion damage after 60 min of coronary occlusion and 48 h reperfusion. Under these experimental conditions, only 2d and cariporide reduce infarct size. Remarkably, myocardial protection afforded by 2d occurs in the absence of hemodynamic effects. These data expand the therapeutic potential of late I(Na) blockers and suggest that 2d could be useful in pathologies for which pharmacological treatments are not yet available.

Sodium late current blockers in ischemia reperfusion: is the bullet magic?

We describe the discovery of the first selective, potent, and voltage-dependent inhibitor of the late current mediated by the cardiac sodium channel Na V1.5. The compound 3,4-dihydro- N-[(2 S)-3-[(2-methoxyphenyl)thio]-2-methylpropyl]-2 H-(3 R)-1,5-benzoxathiepin-3-amine, 2a (F 15845), was identified from a novel family of 3-amino-1,5-benzoxathiepine derivatives. The late sodium current inhibition and antiischemic effects of 2a were studied in various models in vitro and in vivo. In a rabbit model of ischemia-reperfusion, 2a exhibited more potent antiischemic effects than reference compounds KC 12291, ranolazine, and ivabradine. Thus, after a single administration, 2a almost abolished ST segment elevation in response to a transient coronary occlusion. Further, the antiischemic activity of 2a is maintained over a wide range of doses and is not associated with any hemodynamic changes, contrary to conventional antiischemic agents. The unique pharmacological profile of 2a opens new and promising opportunities for the treatment of ischemic heart diseases.

[Acamprosate (Aotal): could adverse effects upset the treatment of alcohol dependence?]. / Acamprosate (Aotal): les effets indésirables peuvent-ils entraver le traitement du sevrage alcoolique?

Acamprosate, a stimulant of central inhibitory GABA neurotransmision and an antagonist of excitatory amino acids, is used in alcohol withdrawal and for the maintenance of abstinence. After identification of several cases of treatment discontinuation during alcohol abstinence because of acamprosate-induced adverse drug reactions (ADRs), a retrospective study was conducted in order to investigate and quantify acamprosate-induced ADRs. Up to July 2002, 472 patients were included for treatment of alcohol withdrawal: of these, 68% (n = 322) received acamprosate. At least one ADR occurred in 98 patients (30%). The mean age of the patients was 41.5 +/- 8.8 years (range: 24-65) and 70% were male. All ADRs were classified as 'non serious'. However, ADRs required a dose decrease in 61 cases or acamprosate discontinuation in 76 cases (62.2% and 77.5%, respectively, of patients with an ADR). We identified mainly gastrointestinal ADRs in 67 patients (mean delay before occurrence: 7.6 days), i.e. 20.8% of patients treated with acamprosate (corresponding to 68.3% of ADRs), with a positive rechallenge in five cases. Moreover, cutaneous ADRs (pruritus) occurred in 29 patients (mean delay before occurrence: 9.0 days), and required acamprosate withdrawal in 22 patients (75.9%) with a prior dose decrease in 18 of these patients (62.1%). Our results show that a dose decrease or withdrawal of acamprosate was necessary in 18.9% and 23.6%, respectively, of patients because of the occurrence of ADRs. The present study shows the important role of acamprosate-induced ADRs among the various causes for failure of alcohol abstinence.