2221–2222 24 Chueh, S.C. et al. (1997) Induction of tolerance toward rat cardiac allografts by treatment with allochimeric class I MHC antigen and FTY720. Transplantation 64, 1407–1414 25 Suzuki, S. et al. (1997) The in vivo induction of lymphocyte apoptosis in MRL-lpr/lpr mice treated with FTY720. Clin. Exp. Immunol. 107, 103–111 26 Matsuda, S. et al. (1999) Differential activation of c-Jun NH2-terminal kinase and p38 pathways during FTY720-induced apoptosis of T lymphocytes that is suppressed by the extracellular signal-regulated kinase pathway. J. Immunol. 162, 3321–3326 27 Li, X.K. et al. (1997) FTY720, a novel immunosuppressive agent, enhances upregulation of the cell adhesion molecular ICAM-1 in TNF- treated human umbilical vein endothelial cells. Transplant. Proc. 29, 1265–1266 28 Luster, A.D. (1998) Chemokines – chemo- tactic cytokines that mediate inflammation. New Engl. J. Med. 338, 436–445 29 Brunkhorst, R. et al. (1999) Human safety and pharmacology of FTY720. Transplantation 67, S153 30 Neumeyer, H. et al. (1999) Human pharmaco- kinetics of FTY720. Transplantation 67, S204 52 TiPS – February 2000 (Vol. 21) 0165-6147/00/$ – see front matter © 2000 Elsevier Science Ltd. All rights reserved. PII: S0165-6147(99)01437-6 CURRENT AWARENESS M. Taglialatela, Associate Professor, Section of Pharmacology, Department of Neuroscience, School of Medicine, University of Naples Federico II, Naples, Italy. E-mail: mtaglial@ unina.it L. Annunziato, Professor and Chairman, Section of Pharmacology, Department of Neuroscience, School of Medicine, University of Naples Federico II, Naples, Italy. E-mail: lannunzi@ unina.it and H. Timmerman, Professor and Director of Research, Department of Farmacochemie, Leiden/Amsterdam Center for Drug Research, Vrije Universiteit, Amsterdam, The Netherlands. E-mail: timmermn@ chem.vu.nl Chemical name FTY720: 2-amino-2-[2-(4-octylphenyl) ethyl]propane-1,3-diol hydrochloride The recent discovery of the serious cardiotoxic potential of the second- generation antihistamines terfenadine and astemizole has prompted a re- examination of the possible adverse effects exerted by older compounds be- longing to this therapeutic class of drugs. Several clinical and preclinical studies suggest that these first-generation mol- ecules share similar pharmacodynamic properties with newer cardiotoxic his- tamine H 1 receptor antagonists. Both first-generation antihistamines hydrox- yzine (HYD) and diphenhydramine (DPH), like astemizole and terfenadine, can act as blockers of the K + channels encoded by the human ether-á-go-go- related gene (HERG), termed K V(r), which are the molecular determinants of the rapid component of the cardiac repo- larizing current I K(Vr) , and are involved in the control of neuronal excitability. Experiments performed with DPH deriv- atives (including the anti-parkinsonian drug orphenadrine) suggest that block- ade of K V(r) channels by these compounds is independent of their ability to antag- onize H 1 receptors. Therefore, caution should be exercised when administering first-generation antihistamines to patients at risk of developing cardiac arrhythmias, epileptic manifestations, or both. Cardiac toxicity of second-generation antihistamines Pharmacological treatment of allergic diseases with second-generation anti- histamines is characterized by improved selectivity for H 1 receptors, absence of sedation, and, possibly, additional anti- allergic properties different from anti- histaminic activity 1 . A major concern in the therapeutic selection of newer antihistamines has recently focused on their potential cardiotoxicity 2 . In fact, the second-generation antihistamines astemizole and terfenadine have recently been withdrawn from the market in sev- eral countries because they caused the rare occurrence of ‘torsade de pointes’ (TdPs). TdPs is a potentially fatal poly- morphic ventricular arrhythmia that occurs in the setting of a marked pro- longation of the QT interval either in patients taking intentional or acciden- tal overdoses of these two second- generation antihistamines or in subjects with several predisposing factors 3 (Table 1). These factors, among others, included a reduced capacity of the cytochrome P450 isoform CYP3A4 to metabolize drugs. In fact, both astemi- zole and terfenadine undergo liver metabolism via this pathway. In addi- tion, it should be emphasized that the two metabolic products of astemizole desmethylastemizole and norastemizole appear to be cardiotoxic, whereas fexo- fenadine, the main active metabolite of terfenadine, seems to be devoid of car- diotoxicity, although this has recently been questioned (Table 1). A major breakthrough in the under- standing of the molecular mechanisms involved in the QT-prolonging effects of second-generation antihistamines has come from the characterization of the molecular defects in the long QT syndrome (LQTS), which is a life- threatening disease characterized by a marked prolongation of the QT inter- val and frequent episodes of syncope or cardiac arrest as a result of ventricular arrhythmias of TdPs (Ref. 4). This genetically transmitted disease has been associated with mutations in five genes that encode main or accessory ion chan- nel subunits. Among these genes, HERG encodes the main channel subunit underlying the fast component of the delayed-rectifying cardiac repolarizing K + current I K(Vr) (Ref. 5). K V(r) channels appear to be one of the major targets that mediate the pro-arrhythmic activity of second-generation antihistamines and other drugs, although their interaction with other ion channels might also exert cardiotoxic effects; in fact, both terfe- nadine 6 and astemizole 7 potently inhibit this channel, which suggests that both mutation- or drug-induced blockade of K V(r) channels might delay the repolariz- ation of the ventricular cells, thus predis- posing to the occurrence of arrhythmic episodes. Cardiovascular adverse effects of older first-generation antihistamines Older first-generation antihistamines are widely sold in most countries as ‘over the counter’ (OTC) or prescribed medi- cations and are frequently implicated in accidental or intentional poisoning. The issue of the potential cardiotoxicity of older antihistamines has been raised by recent studies. Khalifa et al. 8 reported that DPH blocks the repolarizing I K(Vr) currents in guinea-pig ventricular myocytes, an effect shared by other older H 1 receptor antagonists such as Cardiotoxic potential and CNS effects of first-generation antihistamines Maurizio Taglialatela, Henk Timmerman and Lucio Annunziato