Preclinical Pharmacology of Diprafenone

  • Mark E. Sullivan
  • H. J. Reiser
Conference paper

Abstract

The development of antiarrhythmic agents and their eventual clinical success depend predominantly on two aspects: efficacy and safety. In the setting of drug development, these data are acquired from a variety of pre-clinical studies conducted in animal models intended to mimic the clinical setting. Diprafenone, a dimethyl analog of propafenone (Fig. 1), is undergoing extensive clinical development in Europe and the United States. A limited number of studies have reported on the cellular electrophysiological properties of the drug [20, 36], as well as its antiarrhythmic efficacy in animal models [13, 36, 29]. Results of recent clinical testing of diprafenone in patients have correlated reasonably well with the pre-clinical arrhythmia models. Manz et al. [23] studied the effects of diprafenone in 31 patients and reported that the drug increased refractoriness throughout the heart (atria, ventricle, A-V node). In addition, these authors reported that diprafenone (1.5 mg/kg, i.v.) was also effective in suppressing programmed electrical stimulation (PES)-induced supraventricular tachycardia in 12 of 17 patients and PES-induced ventricular tachycardia in seven of 10 patients. Heur et al. [16] reported that diprafenone was effective in 21 of 27 patients for controlling ventricular arrhythmias in patients that were refractory to other antiarrhythmic drug therapies. Kunze and Kuck [21] have shown that oral diprafenone (100 mg, t.i.d.) was effective in 13/15 patients in preventing recurrences of supraventricular tachycardia (WPW syndrome) during 10 months of follow-up.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Anderson JL (1984) Experience with electrophysiologically guided therapy of ventricular tachycardia with flecainide: summary of long-term follow-up. Am J Cardiol 53: 79B–86BPubMedCrossRefGoogle Scholar
  2. 2.
    Attwell D, Cohen I, Eisner, D, Ohba, M, Ojeda, C (1979) The steady-state TTX-sensitive (“window”) sodium current in cardiac Purkinje fibers. Pflugers Arch 379: 137–142PubMedCrossRefGoogle Scholar
  3. 3.
    Cantor EH, Greenberg LH, Weiss B (1981) Effect of long-term changes in sympathetic nervous activity on the beta-adrenergic receptor — adenylate cyclase complex of rat pineal gland. Mol Pharmacol 19: 21–26PubMedGoogle Scholar
  4. 4.
    Carson DL, Dresel PE (1981) Effects of lidocaine on conduction of extrasystoles in the normal canine heart. J Cardiovasc Pharmacol 3: 924–935PubMedCrossRefGoogle Scholar
  5. 5.
    Chilson DA, Heger JJ, Zipes DP, Browne KF, Prystowsky EN (1985) Electrophysiologic effects and clinical efficacy of oral propafenone therapy in patients with ventricular tachycardia. J Am Coll Cardiol 5:1407–1413PubMedCrossRefGoogle Scholar
  6. 6.
    Colatsky TJ, Bird LB, Jurkiewicz NK, Wendt RL (1987) Cellular electrophysiology of the new antiarrhythmic agent recainam (Wy-42,362) in canine cardiac Purkinje fibers. J Cardiovasc Pharmacol 9: 435–444PubMedCrossRefGoogle Scholar
  7. 7.
    DiMarco JP, Garan H, Ruskin JN (1983) Quinidine for ventricular arrhythmias: value of electrophysiologic testing. Am J Cardiol 51: 90–95CrossRefGoogle Scholar
  8. 8.
    Doherty JU, Waxman HL, Kienzle MG, Cassidy DM, Marchlinski FE, Buxton AE, Josephson ME (1984) Limited role of intravenous propafenone hydrochloride in the treatment of sustained ventricular tachycardia: electrophysiologic effects and results of programmed ventricular stimulation. J Am Coll Cardiol 4: 378–381PubMedCrossRefGoogle Scholar
  9. 9.
    Greenberg S, Cantor EH, Paul J (1989) Beta adrenoceptor blocking activity of diprafenone in anesthetized dogs: comparison with propafenone and propranolol. J. J.Cardiovasc Pharmacol 14: 444–453.PubMedCrossRefGoogle Scholar
  10. 10.
    Greenberg S, Luisi A. General pharmacology of diprafenone, a new class IC antiarrhythmic agent, and 5-hydroxydiprafenone, an active metabolite (manuscript in preparation).Google Scholar
  11. 11.
    Greenberg S, Touhey, B Evidence for an effect of diprafenone, a new class IC antiarrhythmic agent, on potassium conductance in vascular smooth muscle (manuscript in preparation).Google Scholar
  12. 12.
    Greene HL, Werner JA, Gross BW, Sears GK, Trobaugh GB, Cobb LA (1983) Prolongation of cardiac refractory times in man by clofilium phosphate, a new antiarrhythmic agent. Am Heart J 106: 492–501PubMedCrossRefGoogle Scholar
  13. 13.
    Gulker H, Thale J, Olbing B, Heuer H, Frenking B, Bender F (1985) Assessment of the antiarrhythmic profile of the new class I agent diprafenone. Arzneim Forsch 35: 1387–1393Google Scholar
  14. 14.
    Heger JJ, Hubbard J, Zipes DP, Miles WM, Prystowsky EN (1984) Propafenone treatment of recurrent ventricular tachycardia: comparison of continuousd electrocardiographic recording and electrophysiologic study in predicting drug efficacy. Am J Cardiol 54: 40D–44DPubMedCrossRefGoogle Scholar
  15. 15.
    Harris, AS (1950) Delayed development of ventricular ectopic rhythms following experimental coronary occlusion. Circulation 1: 1318–1328PubMedGoogle Scholar
  16. 16.
    Heuer H, Gulker H, Hasfeld M, Frenking B, Behrenbeck Th (1987) Treatment of chronic ventricular arrhythmias with the new class IC antiarrhythmic agent, diprafenone. Results of long-term therapy. Z Kardiologie 76: 415–420Google Scholar
  17. 17.
    Horowitz LN, Spielman SR, Greenspan AM, Webb CR (1985) The selection of antiarrhythmic regimens by electrophysiologic studies: techniques and results. In: Josephson ME, ed., Sudden Cardiac Death, FA Davis & Co., Philadelphia, pp. 187–197Google Scholar
  18. 18.
    Karagueuzian HS, Fenoglio, JJ, Weiss, MB, Wit, AL (1979) Protracted ventricular tachycardia induced by premature stimulation of the canine heart after coronary occlusion and reperfusion. Circ Res 44: 833–846PubMedGoogle Scholar
  19. 19.
    Keefe D, Kates R, Harrison DC (1981) New antiarrhythmic drugs: their place in therapy. Drugs 22: 363–400PubMedCrossRefGoogle Scholar
  20. 20.
    Kohlhardt M, Seifert C (1983) Tonic and phasic INa blockade by antiarrhythmics. Different properties of drug binding to fast sodium channels as judged from Vmax studies with propafenone and derivatives in mammalian ventricular myocardium. Eur J Physiol 396: 199–209CrossRefGoogle Scholar
  21. 21.
    Kunze KP, Kuck KH (1988) Intravenous and oral diprafenone for treatment of patients with Wolff-Parkinson-White syndrome. J Am Coll Cardiol 11: 11Google Scholar
  22. 22.
    Lynch JJ, Lucchesi BR (1987) How are animal models best used for the study of antiarrhythmic drugs? In: Hearse DJ, Manning AS, Janse MJ, eds. Life-Threatening Arrhythmias During Ischemia and Infarction, Raven Press, New York, pp. 169–196Google Scholar
  23. 23.
    Manz M, Gerckens U, Lüderitz B, (1986) Diprafenone: electrophysiologic effects in patients with supraven-tricular and ventricular tachycardia. Circulation 74: 11–99Google Scholar
  24. 24.
    Morganroth J, Horowitz LN (1984) Flecainide: its proarrhythmic effect and expected changes on the surface electrocardiogram. Am J Cardol 53: 89B–94BCrossRefGoogle Scholar
  25. 25.
    Nademanee K, Feld G, Hendrickson J, Singh P, Singh B (1985) Electrophysiologic and antiarrhythmic effects of tachycardias. Circulation 72: 555–564PubMedCrossRefGoogle Scholar
  26. 26.
    Platia E, Reid PR (1984) Dose ranging studies of clofilium, an antiarrhythmic quarternary ammonium compound. Clin Pharmacol Ther 35: 193–212PubMedCrossRefGoogle Scholar
  27. 27.
    Scherlag BJ, Kabell G, Brachmann J, Harrison L, Lazzara R (1983) Mechanisms of spontaneous and induced ventricular arrhythmias in the 24-hour infarcted dog heart. Am J Cardiol 51: 207–213PubMedCrossRefGoogle Scholar
  28. 28.
    Senges J, Lengfelder W, Jauernig R, Czygan E, Brachmann J, Rizos I, Cobbe S, Kubler W (1984) Electrophysiologic testing in assessment of therapy with sotalol for sustained ventricular tachycardia. Circulation 69: 577–584PubMedCrossRefGoogle Scholar
  29. 29.
    Thale J, Gulker H, Hindricks G, Haverkamp W, Bender F (1987) Use of diprafenone, a new potent propafenone-analogue, in acute experimental myocardial ischaemia and infarction. Eur Heart J8: 107–115PubMedGoogle Scholar
  30. 30.
    Thormann J, Kramer W, Kindler M, Kremer P, Schlepper M (1987) Influence of diprafenone on the LV end-systolicpressure-volume relationships. Continuous analysis using the conductance (volume) catheter technique and the transient inferior vena cava balloon occlusion for rapid load changes. Herz/Kreisl 19:487–496Google Scholar
  31. 31.
    Vaughan Williams EM (1970) Classification of antiarrhythmic drugs. In: Sandoe E, Flensted-Jensen E, Olesen KH, eds. Symposium on Cardiac Arrhythmias, AB Astra, Sweden, pp. 449–469Google Scholar
  32. 32.
    Velebit V, Podrid P, Lown B, Cohen BH, Graboys TB (1982) Aggravation and provocation of ventricular arrhythmias by antiarrhythmic drugs. Circulation 65: 886–894PubMedCrossRefGoogle Scholar
  33. 33.
    Verrier RL, Hagestad EL (1985) Neural mechanisms in cardiac arrhythmias. In: Reiser HJ, Horowitz LN, eds. Mechanisms and Treatment of Cardiac Arrhythmias; Relevance of Basic Studies to Clinical Management, Urban & Schwarzenberg, Baltimore, pp. 39–56Google Scholar
  34. 34.
    Wagner F, Sachs W, Trenk D, Jahnchen E (1987) Beta Adrenozeptoren blockierende Wirking von Diprafenon im Vergleich zu Propranolol. Z Kardiologie 76: 99Google Scholar
  35. 35.
    Weidmann, S (1955) The effect of the cardiac membrane potential on the rapid availability of the sodium-carrying system. J Physiol. 127: 213–224PubMedGoogle Scholar
  36. 36.
    Wong S, Sullivan ME, Ambelas E, Troy H, Barbati R, Winters R, Reiser HJ (1985) Electrophysiologic and antiarrhythmic actions of diprafenone and propafenone. Pharmacologist 27: 126.Google Scholar

Copyright information

© Dr. Dietrich Steinkopff Verlag, GmbH & Co. KG, Darmstadt 1990

Authors and Affiliations

  • Mark E. Sullivan
    • 1
  • H. J. Reiser
    • 1
  1. 1.Department of PharmacologyBerlex Laboratories, Inc.Cedar KnollsUSA

Personalised recommendations