Evidence for possible involvement of 5-HT(2B) receptors in the cardiac valvulopathy associated with fenfluramine and other serotonergic medications

Background—Serotonergic medications with various mechanisms of action are used to treat psychiatric disorders and are being investigated as treatments for drug dependence. The occurrence of fenfluramine-associated valvular heart disease (VHD) has raised concerns that other serotonergic medications might also increase the risk of developing VHD. We hypothesized that fenfluramine or its metabolite norfenfluramine and other medications known to produce VHD have preferentially high affinities for a particular serotonin receptor subtype capable of stimulating mitogenesis. Methods and Results—Medications known or suspected to cause VHD (positive controls) and medications not associated with VHD (negative controls) were screened for activity at 11 cloned serotonin receptor subtypes by use of ligand-binding methods and functional assays. The positive control drugs were (±)-fenfluramine; (+)-fenfluramine; (−)-fenfluramine; its metabolites (±)-norfenfluramine, (+)-norfenfluramine, and (−)-norfenfluramine; ergotamine; and methysergide and its metabolite methylergonovine. The negative control drugs were phentermine, fluoxetine, its metabolite norfluoxetine, and trazodone and its active metabolite m-chlorophenylpiperazine. (±)-, (+)-, and (−)-Norfenfluramine, ergotamine, and methylergonovine all had preferentially high affinities for the cloned human serotonin 5-HT2B receptor and were partial to full agonists at the 5-HT2B receptor. Conclusions—Our data imply that activation of 5-HT2B receptors is necessary to produce VHD and that serotonergic medications that do not activate 5-HT2B receptors are unlikely to produce VHD. We suggest that all clinically available medications with serotonergic activity and their active metabolites be screened for agonist activity at 5-HT2B receptors and that clinicians should consider suspending their use of medications with significant activity at 5-HT2B receptors

Predicting new molecular targets for known drugs

Although drugs are intended to be selective, at least some bind to several physiological targets, explaining side effects and efficacy. Because many drug–target combinations exist, it would be useful to explore possible interactions computationally. Here we compared 3,665 US Food and Drug Administration (FDA)-approved and investigational drugs against hundreds of targets, defining each target by its ligands. Chemical similarities between drugs and ligand sets predicted thousands of unanticipated associations. Thirty were tested experimentally, including the antagonism of the β1 receptor by the transporter inhibitor Prozac, the inhibition of the 5-hydroxytryptamine (5-HT) transporter by the ion channel drug Vadilex, and antagonism of the histamine H4 receptor by the enzyme inhibitor Rescriptor. Overall, 23 new drug–target associations were confirmed, five of which were potent (less than 100 nM). The physiological relevance of one, the drug N,N-dimethyltryptamine (DMT) on serotonergic receptors, was confirmed in a knockout mouse. The chemical similarity approach is systematic and comprehensive, and may suggest side-effects and new indications for many drugs

Lexical processing in bilinguals and multilinguals: The word selection problem

This chapter considers a number of linguistic factors that appear to help the word selection process in visual word recognition by multilinguals: item related characteristics having to do with neighborhood density, language-specific cues, language distance, and script type; and linguistic context aspects having to do with morphological, syntactic, and language membership information. The theoretical analysis suggests that multilinguals do not require any special processing mechanisms to solve the word selection problem they are faced with during reading. A multilingual framework for relating various aspects of word identification and task/decision factors (extending the BIA+ model) is discussed

The motivational effects of cross-linguistic awareness : developing third language pedagogies to address the negative impact of the L2 on the L3 self-concept

Learning a third language (TL) brings with it particular pedagogical demands. In the pedagogy of TL learning now emerging, the development of students' metalinguistic and crosslinguistic awareness is of central importance. In particular, emphasis is placed on the benefits of cross-referencing with supporter languages. While comparisons with supporter languages have been shown to facilitate L3 production, recent research suggests that cross-referencing with the L2 may be detrimental to motivation. In the current study, 21 students learning L2 English and L3 German or Spanish were interviewed about comparisons involving L3 and L2 self-concepts. Results revealed that nearly all of the students were aware of making such comparisons. A number, however, had developed strategies to counteract the potentially detrimental effect that comparisons with the L2-speaking/using self-concept can have on L3 motivation. It is argued here that in emerging pedagogies of L3 learning proper account needs to be taken of cognitive and affective individual difference factors. In particular, as a means of offsetting the negative impact that a high-status supporter language can have on the learner's L3 self-concept, students should be made aware of the problem and helped to develop and make use of counteracting strategies