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-
1
Anonymous, 2005. ICH S7B: The nonclinical evaluation of the potential for delayed ventricular repolarization (QT interval prolongation) by human pharmaceuticals. London, 25 May 2005. CPMP/ICH/423/02. http://www.emea.eu.int/pdfs/human/ich/042302en.pdf
-
2
Anonymous, 2005. ICH E14: The clinical evaluation of QT/QTc interval prolongation and proarrhythmic potential for non-antiarrhythmic drugs. London, 25 May 2005. CPMP/ICH/2/04. http://www.emea.eu.int/pdfs/human/ich/000204en.pdf
-
3
Owens RC Jr, 2004. QT prolongation with antimicrobial agents: understanding the significance. Drugs 64 :1091–1124.
-
4
Shah RR, 2005. Drugs, QT interval prolongation and ICH E14. Drug Saf 28 :115–125.
-
5
Finlayson K, Witchel HJ, McCulloch J, Sharkey J, 2004. Acquired QT interval prolongation and HERG: implications for drug discovery and development. Eur J Pharmacol 500 :129–142.
-
6
Fermini B, Fossa AA, 2003. The impact of drug-induced QT interval prolongation on drug development and discovery. Nature Reviews 2 :439–447.
-
7
Redfern WS, Carlsson L, Davis AS, Lynch WG, MacKenzie I, Palethorpe S, Siegl PK, Strang I, Sullivan AT, Wallis R, Camm AJ, Hammond TG, 2003. Relationships between preclinical cardiac electrophysiology, clinical QT interval prolongation and torsade de pointes for a broad range of drugs: evidence for a provisional safety margin in drug development. Cardiovasc Res 58 :32–45.
-
8
Ohrt C, Willingmyre GD, Lee P, Knirsch C, Milhous W, 2002. Assessment of azithromycin in combination with other anti-malarials drugs against Plasmodium falciparum in vitro. Animicrob Agent Chemother 46 :2518–2524.
-
9
Dunne MW, Singh N, Shukla M, Valecha N, Bhattacharyya PC, Dev V, Patel K, Mohapatra MK, Lakhani J, Benner R, Lele C, Patki K, 2005. A multicenter study of azithromycin, alone and in combination with chloroquine, for the treatment of acute uncomplicated Plasmodium falciparum malaria in India. J Infect Dis 191 :1582–1588.
-
10
Traebert M, Dumotier B, Meister L, Hoffman P, Dominguez-Estevez M, Suter W, 2004. Inhibition of hERG K+ currents by antimalarial drugs in stably transfected HEK293 cells. Eur J Pharmacol 484 :41–48.
-
11
Touze J-E, Heno P, Fourcade L, Deharo J-C, Thomas G, Bohan S, Paule P, Riviere P, Kouassi E, Buguet A, 2002. The effects of antimalarial drugs on ventricular repolarization. Am J Trop Med 67 :54–60.
-
12
Thomsen MB, Beekman JDM, Attevelt NJM, Takahara A, Sugiyama A, Chiba K, Vos MA, 2006. No proarrhythmic properties of the antibiotics moxifloxacin or azithromycin in aneaesthetized dogs with chronic-AV block. Br J Pharmacol 149 :1039–1048.
-
13
Bustos MDG, Gay F, Diquet B, Thomare P, Warot D, 1994. The pharmacokinetics and electrocardiographic effects of chloroquine in healthy subjects. Trop Med Parasitol 45 :83–86.
-
14
Walker ML, Rosenbaum DS, 2003. Repolarization alternans: implications for the mechanism and prevention of sudden cardiac death. Cardiovasc Res 57 :599–614.
-
15
Gilmour RF Jr, 2003. A novel approach to identifying antiar-rhythmic drug targets. Drug Disc Today 8 :162–167.
-
16
Karagueuzian HS, Chen PS, 1999. Graded response and restitution hypotheses of ventricular vulnerability to fibrillation: insights into the mechanism of initiation of fibrillation. J Electrocardiol 32 :S87–S91.
-
17
Fossa AA, Wisialowski T, Wolfgang E, Wang E, Avery M, Raunig DL, Fermini B, 2004. Differential effect of HERG blocking agents on cardiac electrical alternans in the guinea pig. Eur J Pharmacol 486 :209–221.
-
18
Fossa AA, Gorczyca W, Wisialowski T, Yasgar A, Wang E, Crimin K, Volberg W, Zhou J, 2007. Electrical alternans and hemodynamics in the anesthetized guinea pig can discriminate the cardiac safety of antidepressants. J Pharmacol Toxicol Methods 55 :78–85.
-
19
Wisialowski T, Crimin K, Engtrakul J, O’Donnell J, Fermini B, Fossa AA, 2006. Differentiation of arrhythmia risk of the antibacterials moxifloxacin, erythromycin and telithromycin based on analysis of monophasic action potential duration alternans and cardiac instability. J Pharmacol Exp Ther 318 :352–359.
-
20
Cook JA, Randinitis EJ, Bramson CR, Wesche DL, 2006. Lack of a pharmacokinetic interaction between azithromycin and chloroquine. Am J Trop Med Hyg 74 :407–412.
-
22
Pastore JM, Rosenbaum DS, 2000. Role of structural barriers in the mechanism of alternans-induced reentry. Circ Res 87 :1157–1163.
-
23
Demaziere J, Fourcade JMN, Bussiuil CTA, Adeleine P, Meyer SM, Saissy JM, 1995. The hazards of chloroquine self prescription in West Africa. Clin Toxicol 33 :369–370.
-
24
Fauchier JP, Lanfranchi J, Ginies G, Raynaud R, 1974. Syncope through multifocal ventricular tachycardia during treatment with chloroquine. Study of the hisian electrogram and treatment by verapamil. Ann Cardiol Angeiol (Paris) 23 :341–346.
-
25
Anonymous, 2005. Medicines and QT prolongation. Australian Adverse Drug Reactions Bulletin 24 :1–4.
-
26
Champeroux P, Viaud K, Amrani AIE, Fowler JSL, Martel E, LeGuennec J-Y, Richard S, 2005. Prediction of the risk of torsade de pointes using the model of isolated canine Purkinje fibres. Br J Pharmacol 144 :376–385.
-
27
Gintant GA, Limbris JT, McDermott JS, Wegner CD, Cox BF, 2001. The canine Purkinje fiber: an in vitro model system for acquired long QT syndrome and drug-induced arrhythmogenesis. J Cardiovasc Pharmacol 37 :607–618.
-
28
Roden DM, 1998. Taking the “idio” out of “idiosyncratic” predicting torsades de pointes. PACE 21 :1029–1034.
-
29
Milberg P, Eckhardt L, Bruns HJ, Biertz J, Ramtin S, Reinsch N, Fleisher D, Kirchhof P, Fabritz L, Breithardt G, Haverkamp W, 2002. Divergent proarrhythmic potential of macrolide antibiotics despite similar QT prolongation: fast phase 3 repolarization prevents early afterdeploarization and torsades de pointes. J Pharmacol Exp Ther 303 :218–225.
-
30
Looareesuwan S, White NJ, Chanthavanich P, Edwards G, Nicholl DD, Bunch C, Warrell DA, 1986. Cardiovascular toxicity and distribution kinetics of intravenous chloroquine. Br J Clin Pharmacol 22 :31–36.
-
31
Diaz ME, O’Neill SC, Eisner DA, 2004. Sarcoplasmic reticulum calcium content fluctuation is the key to cardiac alternans. Circ Res 94 :650–656.
-
32
Shin DD, Brandimarte F, De Luca L, Sabbah HN, Fonarow GC, Filippatos G, Komajda M, Gheorghiade M, 2007. Review of current and investigational pharmacologic agents for acute heart failure syndromes. Am J Cardiol 99 :4A–23A.
-
33
Daenas C, Hatziefthimiou AA, Gourgoulianis KI, Molyvdas PA, 2006. Azithromycin has a direct relaxant effect on precontracted airway smooth muscle. Eur J Pharmacol 553 :280–287.
-
34
Tamargo J, De Miguel B, Tejerina MT, 1982. A comparison of josamycin with macrolides and related antibiotics on isolated rat atria. Eur J Pharmacol 80 :285–293.
-
35
Main BW, Means JR, Rinkema LE, Smith WC, Sarazan RD, 1996. Cardiovascular effects of the macrolide antibiotic tilmicosin, administered alone and in combination with propranolol or dobutamine, in conscious unrestrained dogs. J Vet Pharmacol Ther 19 :225–232.
| Past two years | Past Year | Past 30 Days | |
|---|---|---|---|
| Abstract Views | 138 | 104 | 12 |
| Full Text Views | 415 | 4 | 1 |
| PDF Downloads | 117 | 3 | 1 |
Azithromycin/Chloroquine Combination Does Not Increase Cardiac Instability despite an Increase in Monophasic Action Potential Duration in the Anesthetized Guinea Pig
Anthony A. Fossa
Anthony A. Fossa
Pfizer Global Research and Development, Departments of Translational and Molecular Medicine, Safety Pharmacology, Drug Metabolism and Biostatistics, Groton, Connecticut
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Todd Wisialowski
Todd Wisialowski
Pfizer Global Research and Development, Departments of Translational and Molecular Medicine, Safety Pharmacology, Drug Metabolism and Biostatistics, Groton, Connecticut
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J. Neil Duncan
J. Neil Duncan
Pfizer Global Research and Development, Departments of Translational and Molecular Medicine, Safety Pharmacology, Drug Metabolism and Biostatistics, Groton, Connecticut
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Shibing Deng
Shibing Deng
Pfizer Global Research and Development, Departments of Translational and Molecular Medicine, Safety Pharmacology, Drug Metabolism and Biostatistics, Groton, Connecticut
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Michael Dunne
Michael Dunne
Pfizer Global Research and Development, Departments of Translational and Molecular Medicine, Safety Pharmacology, Drug Metabolism and Biostatistics, Groton, Connecticut
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Prolongation of the electrocardiogram QT interval by some, but not all drugs, has been associated with increased incidence of sudden cardiac death. Current preclinical regulatory assays cannot discriminate the arrhythmia liability of these drugs. Consequently, many new medications that prolong the QT interval are not developed despite their potential therapeutic benefit. Alternans (action potential duration alternations) is a measure of cardiac instability in humans and animals associated with the onset of ventricular fibrillation. Due to potential arrhythmia risk from observed QT prolongation, alternans was assessed in the anesthetized guinea pig after azithromycin or chloroquine alone and after combination treatment at clinically relevant concentrations proposed for the management of malaria. Chloroquine alone, but not azithromycin, caused a profound increase in action potential duration but with only minimal effects on alternans (~10 ms). Azithromycin alone and in combination with chloroquine showed no increase in alternans beyond vehicle baseline responses indicating no additional arrhythmia liability.
Author Notes
ProCite
RefWorks
Reference Manager
BibTeX
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-
1
Anonymous, 2005. ICH S7B: The nonclinical evaluation of the potential for delayed ventricular repolarization (QT interval prolongation) by human pharmaceuticals. London, 25 May 2005. CPMP/ICH/423/02. http://www.emea.eu.int/pdfs/human/ich/042302en.pdf
-
2
Anonymous, 2005. ICH E14: The clinical evaluation of QT/QTc interval prolongation and proarrhythmic potential for non-antiarrhythmic drugs. London, 25 May 2005. CPMP/ICH/2/04. http://www.emea.eu.int/pdfs/human/ich/000204en.pdf
-
3
Owens RC Jr, 2004. QT prolongation with antimicrobial agents: understanding the significance. Drugs 64 :1091–1124.
-
4
Shah RR, 2005. Drugs, QT interval prolongation and ICH E14. Drug Saf 28 :115–125.
-
5
Finlayson K, Witchel HJ, McCulloch J, Sharkey J, 2004. Acquired QT interval prolongation and HERG: implications for drug discovery and development. Eur J Pharmacol 500 :129–142.
-
6
Fermini B, Fossa AA, 2003. The impact of drug-induced QT interval prolongation on drug development and discovery. Nature Reviews 2 :439–447.
-
7
Redfern WS, Carlsson L, Davis AS, Lynch WG, MacKenzie I, Palethorpe S, Siegl PK, Strang I, Sullivan AT, Wallis R, Camm AJ, Hammond TG, 2003. Relationships between preclinical cardiac electrophysiology, clinical QT interval prolongation and torsade de pointes for a broad range of drugs: evidence for a provisional safety margin in drug development. Cardiovasc Res 58 :32–45.
-
8
Ohrt C, Willingmyre GD, Lee P, Knirsch C, Milhous W, 2002. Assessment of azithromycin in combination with other anti-malarials drugs against Plasmodium falciparum in vitro. Animicrob Agent Chemother 46 :2518–2524.
-
9
Dunne MW, Singh N, Shukla M, Valecha N, Bhattacharyya PC, Dev V, Patel K, Mohapatra MK, Lakhani J, Benner R, Lele C, Patki K, 2005. A multicenter study of azithromycin, alone and in combination with chloroquine, for the treatment of acute uncomplicated Plasmodium falciparum malaria in India. J Infect Dis 191 :1582–1588.
-
10
Traebert M, Dumotier B, Meister L, Hoffman P, Dominguez-Estevez M, Suter W, 2004. Inhibition of hERG K+ currents by antimalarial drugs in stably transfected HEK293 cells. Eur J Pharmacol 484 :41–48.
-
11
Touze J-E, Heno P, Fourcade L, Deharo J-C, Thomas G, Bohan S, Paule P, Riviere P, Kouassi E, Buguet A, 2002. The effects of antimalarial drugs on ventricular repolarization. Am J Trop Med 67 :54–60.
-
12
Thomsen MB, Beekman JDM, Attevelt NJM, Takahara A, Sugiyama A, Chiba K, Vos MA, 2006. No proarrhythmic properties of the antibiotics moxifloxacin or azithromycin in aneaesthetized dogs with chronic-AV block. Br J Pharmacol 149 :1039–1048.
-
13
Bustos MDG, Gay F, Diquet B, Thomare P, Warot D, 1994. The pharmacokinetics and electrocardiographic effects of chloroquine in healthy subjects. Trop Med Parasitol 45 :83–86.
-
14
Walker ML, Rosenbaum DS, 2003. Repolarization alternans: implications for the mechanism and prevention of sudden cardiac death. Cardiovasc Res 57 :599–614.
-
15
Gilmour RF Jr, 2003. A novel approach to identifying antiar-rhythmic drug targets. Drug Disc Today 8 :162–167.
-
16
Karagueuzian HS, Chen PS, 1999. Graded response and restitution hypotheses of ventricular vulnerability to fibrillation: insights into the mechanism of initiation of fibrillation. J Electrocardiol 32 :S87–S91.
-
17
Fossa AA, Wisialowski T, Wolfgang E, Wang E, Avery M, Raunig DL, Fermini B, 2004. Differential effect of HERG blocking agents on cardiac electrical alternans in the guinea pig. Eur J Pharmacol 486 :209–221.
-
18
Fossa AA, Gorczyca W, Wisialowski T, Yasgar A, Wang E, Crimin K, Volberg W, Zhou J, 2007. Electrical alternans and hemodynamics in the anesthetized guinea pig can discriminate the cardiac safety of antidepressants. J Pharmacol Toxicol Methods 55 :78–85.
-
19
Wisialowski T, Crimin K, Engtrakul J, O’Donnell J, Fermini B, Fossa AA, 2006. Differentiation of arrhythmia risk of the antibacterials moxifloxacin, erythromycin and telithromycin based on analysis of monophasic action potential duration alternans and cardiac instability. J Pharmacol Exp Ther 318 :352–359.
-
20
Cook JA, Randinitis EJ, Bramson CR, Wesche DL, 2006. Lack of a pharmacokinetic interaction between azithromycin and chloroquine. Am J Trop Med Hyg 74 :407–412.
-
22
Pastore JM, Rosenbaum DS, 2000. Role of structural barriers in the mechanism of alternans-induced reentry. Circ Res 87 :1157–1163.
-
23
Demaziere J, Fourcade JMN, Bussiuil CTA, Adeleine P, Meyer SM, Saissy JM, 1995. The hazards of chloroquine self prescription in West Africa. Clin Toxicol 33 :369–370.
-
24
Fauchier JP, Lanfranchi J, Ginies G, Raynaud R, 1974. Syncope through multifocal ventricular tachycardia during treatment with chloroquine. Study of the hisian electrogram and treatment by verapamil. Ann Cardiol Angeiol (Paris) 23 :341–346.
-
25
Anonymous, 2005. Medicines and QT prolongation. Australian Adverse Drug Reactions Bulletin 24 :1–4.
-
26
Champeroux P, Viaud K, Amrani AIE, Fowler JSL, Martel E, LeGuennec J-Y, Richard S, 2005. Prediction of the risk of torsade de pointes using the model of isolated canine Purkinje fibres. Br J Pharmacol 144 :376–385.
-
27
Gintant GA, Limbris JT, McDermott JS, Wegner CD, Cox BF, 2001. The canine Purkinje fiber: an in vitro model system for acquired long QT syndrome and drug-induced arrhythmogenesis. J Cardiovasc Pharmacol 37 :607–618.
-
28
Roden DM, 1998. Taking the “idio” out of “idiosyncratic” predicting torsades de pointes. PACE 21 :1029–1034.
-
29
Milberg P, Eckhardt L, Bruns HJ, Biertz J, Ramtin S, Reinsch N, Fleisher D, Kirchhof P, Fabritz L, Breithardt G, Haverkamp W, 2002. Divergent proarrhythmic potential of macrolide antibiotics despite similar QT prolongation: fast phase 3 repolarization prevents early afterdeploarization and torsades de pointes. J Pharmacol Exp Ther 303 :218–225.
-
30
Looareesuwan S, White NJ, Chanthavanich P, Edwards G, Nicholl DD, Bunch C, Warrell DA, 1986. Cardiovascular toxicity and distribution kinetics of intravenous chloroquine. Br J Clin Pharmacol 22 :31–36.
-
31
Diaz ME, O’Neill SC, Eisner DA, 2004. Sarcoplasmic reticulum calcium content fluctuation is the key to cardiac alternans. Circ Res 94 :650–656.
-
32
Shin DD, Brandimarte F, De Luca L, Sabbah HN, Fonarow GC, Filippatos G, Komajda M, Gheorghiade M, 2007. Review of current and investigational pharmacologic agents for acute heart failure syndromes. Am J Cardiol 99 :4A–23A.
-
33
Daenas C, Hatziefthimiou AA, Gourgoulianis KI, Molyvdas PA, 2006. Azithromycin has a direct relaxant effect on precontracted airway smooth muscle. Eur J Pharmacol 553 :280–287.
-
34
Tamargo J, De Miguel B, Tejerina MT, 1982. A comparison of josamycin with macrolides and related antibiotics on isolated rat atria. Eur J Pharmacol 80 :285–293.
-
35
Main BW, Means JR, Rinkema LE, Smith WC, Sarazan RD, 1996. Cardiovascular effects of the macrolide antibiotic tilmicosin, administered alone and in combination with propranolol or dobutamine, in conscious unrestrained dogs. J Vet Pharmacol Ther 19 :225–232.
| Past two years | Past Year | Past 30 Days | |
|---|---|---|---|
| Abstract Views | 138 | 104 | 12 |
| Full Text Views | 415 | 4 | 1 |
| PDF Downloads | 117 | 3 | 1 |