REVIEW ARTICLE Jpn Circ J 1999; 63: 1–12 Profiles of Aprindine, Cibenzoline, Pilsicainide and Pirmenol in the Framework of the Sicilian Gambit Itsuo Kodama, MD*; Satoshi Ogawa, MD**; Hiroshi Inoue, MD†; Hiroshi Kasanuki, MD††; Takao Kato, MD‡; Hideo Mitamura, MD**; Masayasu Hiraoka, MD‡‡; Tsuneaki Sugimoto, MD§; The Guideline Committee for Clinical Use of Antiarrhythmic Drugs in Japan (Working Group of Arrhythmias of the Japanese Society of Electrocardiology) The Vaughan Williams classification has been used widely by clinicians, cardiologists and researchers engaged in antiarrhythmic drug development and testing in many countries throughout the world since its initial proposal in the early 1970s. However, a major criticism of the Vaughan Williams system arose from the extent to which the categorization of drugs into classes I–IV led to oversimplified views of both shared and divergent actions. The Sicilian Gambit proposed a two-dimensional tabular framework for display of drug actions to solve these problems. From April to December 1996, members of the Guideline Committee met to discuss pharmacologic profiles of 4 antiarrhythmic drugs (aprindine, cibenzoline, pilsicainide, and pirmenol) that were not included in the original spreadsheet but are used widely in clinical practice in Japan. The discussion aimed to fit the drug profiles into the Gambit framework based on all the important literature published to date regarding the actions of the 4 drugs. This report is a summary of that deliberation. (Jpn Circ J 1999; 63: 1–12) Key Words: Antiarrhythmic drugs; Cardiac electrophysiology; The Sicilian Gambit; The Vaughan Williams classification he Vaughan Williams classification has been used approaches to antiarrhythmic therapy. The second and the widely by clinicians, cardiologists and researchers third Gambit meetings were held at Arden House in T engaged in antiarrhythmic drug development and Harriman, New York in 1993 and 1996. The conclusions of testing in many countries throughout the world since its the second meeting, published as a monograph in 1994,3 initial proposal in the early 1970s.1 This classification is were translated into Japanese by Ogawa in 1995.4 Two admirable in its simplicity with respect to the physiologic Japanese investigators, (Drs S. Ogawa and M. Hiraoka), basis of effects, and it has facilitated education and discus- joined the third meeting. Thus, the Gambit classification sion concerning the beneficial and deleterious actions of process is progressing and expanding. In accord with this drugs. During the past 2 decades, however, our knowledge trend, the Guideline Committee for Clinical Use of of the electrophysiologic mechanisms of arrhythmias has Antiarrhythmic Drugs was organized in Japan in 1996 as a expanded tremendously, and the number of antiarrhythmic Working Group of Arrhythmias of the Japanese Society of agents available for clinical practice has greatly increased. Electrocardiology. Accordingly, updated concepts are becoming progressively A major criticism of the Vaughan Williams system arose difficult to incorporate into the general scheme of the from the extent to which the categorization of drugs into Vaughan Williams classification in the process of ratio- classes I–IV led to oversimplified views of both shared and nally determining the optimal pharmacologic treatment of divergent actions.2,3 Briefly, the problems with the older arrhythmias. In 1991, the Sicilian Gambit was proposed by classification areas follows. the Task Force of the Working Group on Arrhythmias of (1) The classification is hybrid, with classes I and IV the European Society of Cardiology,2 as the outcome of the representing blockade of ion channels, class II, blockade first Gambit meeting in Taormina, Sicily (1990) where of receptors, and class III, a change in a specific electro- basic and clinical investigators attempted a break from physiologic variable (action potential duration). traditional approaches to drug classification. The Sicilian (2) Some drugs, such as amiodarone and bepridil, have Gambit aimed to construct a system where current diverse actions representing several such classes. knowledge and information on arrhythmias could be inte- (3) The classification essentially describes antiarrhyth- grated into a framework of universal pathophysiologic mic drugs as acting via blockade of channels and recep- tors. The alternate possibility that activation of certain (Received October 15, 1998; accepted November 5, 1998) channels or receptors might be antiarrhythmic is not *Research Institute of Environmental Medicine, Nagoya University, considered. Nagoya, **Keio University, School of Medicine, Tokyo, †Toyama (4) The classification is incomplete; several drugs Medical and Pharmaceutical University, Faculty of Medicine, currently available for the treatment of arrhythmias, such Toyama, ††Tokyo Women’s Medical College, Tokyo, ‡Nippon Medical as cholinergic agonists, digitalis, and adenosine, are not ‡‡ School, Tokyo, Tokyo Medical and Dental University, Medical included. Research Institute, Tokyo, and §Kanto Central Hospital, Tokyo, Japan Mailing address: Satoshi Ogawa, MD, Cardiopulmonary Division, The Sicilian Gambit proposed a 2-dimensional tabular Department of Medicine, Keio University, School of Medicine, 35 framework (spreadsheet) for display of drug actions to Shinanomachi, Shinjuku-Ku, Tokyo, Japan solve these problems.2,3 In the second version of the frame- Japanese Circulation Journal Vol.63, January 1999 2 KODAMA I et al. work, the molecular targets to be affected by antiarrhyth- and in ventricular myocytes isolated from guinea pig hearts mic drugs (ion channels, receptors, and pumps) are listed using single-sucrose gap or whole-cell voltage-clamp tech- on the left side, with the corresponding clinical effects of niques.13,18,19 In ventricular muscles or myocytes treated the drugs (heart rate, electrocardiographic intervals, with aprindine (2–5μmol/L), application of conditioning ventricular performance, and side-effect potential) appear- depolarization to 0 mV from a holding potential (HP) at ing on the right side of the columns.3 The antiarrhythmic resting level (–80 to –90mV) caused a decrease in Vmax of drugs are listed in vertical rows in order of their predomi- a test action potential elicited 100ms after the clamp pulse. nant molecular targets. This decrease became more marked as clamp pulse dura- The spreadsheet (Gambit framework) has the following tion was prolonged.13,18,19 These authors estimated the advantages. extent of sodium channel block by various antiarrhythmic (1) It does not discard useful information about a drug. drugs, including aprindine, during activated and inactivated Most antiarrhythmic drugs act at several sites, sharing a states.18,19 A percentage decrease in Vmax by the shortest spectrum of action with other agents. Such multifaceted clamp pulse (10ms) from the reference level (tonic block- drug actions can be presented appropriately. ade subtracted value) was defined as an activated channel (2) The listing is flexible. The vertical order of the blockade (ACB), while an additional percentage decrease antiarrhythmic drugs may be changed to emphasize in Vmax occurring when clamp pulse duration was pro- different drug clusters. For example, drugs that act atβ- longed from 10 to 500 ms was defined as an inactivated receptors or those that block potassium channels can be channel blockade (ICB). Blockade of sodium channels placed together. If important new molecular targets are during slow inactivation can be neglected in this definition, found in future basic research, they can be added as new because Vmax of control muscles or myocytes decreased columns. As new effective antiarrhythmic drugs are significantly only when the conditioning 0mV clamp was developed, they would be added by expanding rows. maintained for longer than 500 ms.18,19 ACB and ICB (3) The tabular approach is suitable for programming induced by 2–5μmol/L aprindine were estimated to be diverse drug information into computer software for 1.3–5.4% and 14.6–49.6%, respectively, giving rise to a availability from single channel, single cell to bedside. ratio (ICB/ACB) of 7.4–11.2.13,18,19 In single-cell experi- From April to December 1996, members of the Guide- ments, ICB/ACB ratios for aprindine, mexiletine, and lido- line Committee met 4 times to discuss pharmacologic caine were all larger than 5.0, while those for quinidine and profiles of 4 antiarrhythmic drugs (aprindine, cibenzoline, disopyramide were much less (1.5–1.6).18,19 The authors pilsicainide, and pirmenol) that were not included in the therefore concluded that aprindine appears to block the original spreadsheet but used widely in clinical practice in sodium channel mainly during the inactivated state. Japan. The discussion aimed to fit the drug profiles into the In ventricular muscles or cells treated with aprindine, Gambit framework based on all the important literature additional application of lidocaine or mexiletine has been published to date regarding the actions of the 4 drugs in demonstrated to cause an increase in tonic blockade, but a experimental as well as clinical studies. This report is a decrease of use-dependent blockade, often resulting in a net summary of that deliberation. increase in Vmax at certain stimulation rates.10,13,14,20 In the presence of both aprindine and lidocaine (or mexiletine), Vmax recovered from use-dependent blockade according to Aprindine a dual exponential function, where the short- and long-time Action Potentials constants