Recurrent Ventricular Tachycardia Due to Pentamidine-Induced Cardiotoxicity

Bibler, Mark R.; Chou, Te-Chuan; Toltzis, Robert J.; Wade, Patricia A.

doi:10.1378/chest.94.6.1303

Cited by 62 publications

(24 citation statements)

References 14 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…These doses result in peak serum levels that range from about 1 to 5 M (Sands et al, 1985;Conte et al, 1986;Lidman et al, 1994), similar to the concentrations required for inhibition of hERG trafficking in vitro. Prolongation of the QT interval on the electrocardiogram and the development of TdP tachycardias are well documented adverse events associated with pentamidine treatment (Wharton et al, 1987;Bibler et al, 1988;Girgis et al, 1997;Kroll and Gettes, 2002). However, QT prolongation is not immediately evident in these patients and generally takes several days to develop (Stein et al, 1991;Eisenhauer et al, 1994;Otsuka et al, 1997).…”

Section: Discussionmentioning

confidence: 99%

“…In the United States, it is used in the treatment of Pneumocystis carinii pneumonia, a common opportunistic infection in patients who have contracted the human immunodeficiency virus or in patients immunosuppressed during chemotherapy (Sands et al, 1985;Goa and Campoli-Richards, 1987). Therapy with pentamidine is often accompanied by prolongation of the QT interval on the electrocardiogram (ECG) and, in some instances, by torsades de pointes (TdP) tachycardias that can degenerate into ventricular fibrillation and cause sudden cardiac death (Wharton et al, 1987;Bibler et al, 1988;Girgis et al, 1997).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Pentamidine-Induced Long QT Syndrome and Block of hERG Trafficking

Kuryshev¹,

Ficker²,

Wang³

et al. 2004

J Pharmacol Exp Ther

251

167

View full text Add to dashboard Cite

The diamidine pentamidine is used to treat leishmaniasis, trypanosomiasis, and Pneumocystis carinii pneumonia. Treatment may be accompanied by prolongation of the QT interval of the electrocardiogram and torsades de pointes tachycardias. Up to now, it has been thought that therapeutic compounds causing QT prolongation are associated with direct block of the cardiac potassium channel human ether a-go-go-related gene (hERG), which encodes the ␣ subunit of cardiac I Kr currents. We show that pentamidine has no acute effects on currents produced by hERG, KvLQT1/mink, Kv4.3, or SCNA5. Cardiac calcium currents and the guinea pig cardiac action potential were also not affected. After overnight exposure, however, pentamidine reduced hERG currents and inhibited trafficking and maturation of hERG with IC 50 values of 5 to 8 M similar to therapeutic concentrations. Surface expression determined in a chemiluminescence assay was reduced on exposure to 10, 30, and 100 M pentamidine by about 30, 40, and 70%, respectively. These effects were specific for hERG since expression of hKv1.5, KvLQT1/minK, and Kv4.3 was not altered. In isolated guinea pig ventricular myocytes, 10 M pentamidine prolonged action potential duration APD 90 from 374.3 Ϯ 57.1 to 893.9 Ϯ 86.2 ms on overnight incubation. I Kr tail current density was reduced from 0.61 Ϯ 0.09 to 0.39 Ϯ 0.04 pA/pF. We conclude that pentamidine prolongs the cardiac action potential by block of hERG trafficking and reduction of the number of functional hERG channels at the cell surface. We propose that pentamidine, like arsenic trioxide, produces QT prolongation and torsades de pointes in patients by inhibition of hERG trafficking.

show abstract

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Pentamidine-Induced Long QT Syndrome and Block of hERG Trafficking

Kuryshev¹,

Ficker²,

Wang³

et al. 2004

J Pharmacol Exp Ther

251

167

View full text Add to dashboard Cite

show abstract

“…The fourth category of compounds (cimetidine, pentamidine, and arsenic trioxide) was relatively ineffective at blocking I HERG . Despite these observations, both pentamidine (Wharton et al, 1987;Bibler et al, 1988;Eisenhauer et al, 1994) and arsenic trioxide (Ohnishi et al, 2000;Barbey and Soignet, 2001;Unnikrishnan et al, 2001) have been associated with cardiac repolarization delays (QT lengthening) and TdP-like arrhythmias in patients. Recent reports have suggested that although these drugs may not interfere with I HERG directly, they may nevertheless cause reductions in I HERG via interference with trafficking of HERG proteins to the membrane (Ficker et al, 2004;Cordes et al, 2005;Kuryshev et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

“…Several "negative control" compounds, including lovastatin, chlorpheniramine, and cimetidine, were also evaluated under similar conditions. Two compounds in particular, arsenic trioxide and pentamidine, had little or no effect on I HERG , although both of these compounds have been associated with long QT syndromes and TdP-like arrhythmias in patients (Wharton et al, 1987;Bibler et al, 1988;Stein et al, 1991;Eisenhauer et al, 1994;Ohnishi et al, 2000;Barbey and Soignet, 2001;Unnikrishnan et al, 2001). Thus, to further evaluate the potential for these compounds to influence cardiac repolarization and cause arrhythmias, we also examined their influence in the isolated perfused (Langendorff) rabbit heart model.…”

mentioning

confidence: 99%

Comparative Evaluation of HERG Currents and QT Intervals following Challenge with Suspected Torsadogenic and Nontorsadogenic Drugs

Katchman

Koerner

Tosaka

et al. 2005

J Pharmacol Exp Ther

137

View full text Add to dashboard Cite

The purpose of the present study was to comparatively evaluate human HERG currents and QT intervals following challenge with suspected torsadogenic and nontorsadogenic drugs. Various concentrations of 14 different drugs were initially evaluated in terms of their relative potency to block I HERG in stably transfected human embryonic kidney cells. Four general categories of drugs were identified: high-potency blockers (IC 50 Ͻ 0.1 M) included lidoflazine, terfenadine, and haloperidol; moderatepotency blockers (0.1 M Ͻ IC 50 Ͻ 1 M) included sertindole, thioridazine, and prenylamine; low-potency blockers (IC 50 Ͼ 1 M) included propafenone, loratadine, pyrilamine, lovastatin, and chlorpheniramine; and ineffective blockers (IC 50 Ͼ 300 M) included cimetidine, pentamidine, and arsenic trioxide. All measurements were performed using similar conditions and tested acute drug effects only (Ͻ30 min of drug exposure per measurement). Since two of the drugs that were ineffective I HERG blockers, arsenic trioxide and pentamidine, have been associated with cardiac repolarization delays (QT interval lengthening) and torsades de pointes ventricular arrhythmias in patients, we chose to evaluate them further using the isolated perfused rabbit heart model. Neither arsenic trioxide nor pentamidine had any significant effect on QT intervals in this model, even at relatively high (micromolar) concentrations. Similar results were obtained for loratadine in this model. When the hearts were challenged with a known torsadogenic drug such as cisapride, significant QT lengthening was rapidly induced. These results demonstrate that arsenic trioxide and pentamidine are essentially devoid of direct acute effects on cardiac repolarization or inhibition of I HERG .

show abstract

“…Pentamidine is an antiprotozoal compound, used in the treatment of trypanosomiasis, leishmaniasis, and Pneumocystis carinii pneumonia, that causes drug-induced or acquired long QT syndrome (acLQTS) in clinical use (Sands et al, 1985;Wharton et al, 1987;Bibler et al, 1988;Girgis et al, 1997;Nacher et al, 2001;Burchmore et al, 2002). acLQTS produces electrocardiographic abnormalities that have been associated with syncope, torsades de pointes arrhythmias, and sudden cardiac death (Kannankeril et al, 2010) and are most often caused by direct block of the cardiac potassium current I Kr /hERG, which is crucial for terminal repolarization in human heart (Sanguinetti and TristaniFirouzi, 2006).…”

Section: Introductionmentioning

confidence: 99%

Molecular Determinants of Pentamidine-Induced hERG Trafficking Inhibition

Dennis¹,

Wang²,

Wan³

et al. 2011

Mol Pharmacol

View full text Add to dashboard Cite

Pentamidine is an antiprotozoal compound that clinically causes acquired long QT syndrome (acLQTS), which is associated with prolonged QT intervals, tachycardias, and sudden cardiac arrest. Pentamidine delays terminal repolarization in human heart by acutely blocking cardiac inward rectifier currents. At the same time, pentamidine reduces surface expression of the cardiac potassium channel I Kr /human ether à -gogo-related gene (hERG). This is unusual in that acLQTS is caused most often by direct block of the cardiac potassium current I Kr /hERG. The present study was designed to provide a more complete picture of how hERG surface expression is disrupted by pentamidine at the cellular and molecular levels. Using biochemical and electrophysiological methods, we found that pentamidine exclusively inhibits hERG export from the endoplasmic reticulum to the cell surface in a heterologous expression system as well as in cardiomyocytes. hERG trafficking inhibition could be rescued in the presence of the pharmacological chaperone astemizole. We used rescue experiments in combination with an extensive mutational analysis to locate an interaction site for pentamidine at phenylalanine 656, a crucial residue in the canonical drug binding site of terminally folded hERG. Our data suggest that pentamidine binding to a folding intermediate of hERG arrests channel maturation in a conformational state that cannot be exported from the endoplasmic reticulum. We propose that pentamidine is the founding member of a novel pharmacological entity whose members act as small molecule antichaperones.

show abstract

Recurrent Ventricular Tachycardia Due to Pentamidine-Induced Cardiotoxicity

Cited by 62 publications

References 14 publications

Pentamidine-Induced Long QT Syndrome and Block of hERG Trafficking

Pentamidine-Induced Long QT Syndrome and Block of hERG Trafficking

Comparative Evaluation of HERG Currents and QT Intervals following Challenge with Suspected Torsadogenic and Nontorsadogenic Drugs

Molecular Determinants of Pentamidine-Induced hERG Trafficking Inhibition

Contact Info

Product

Resources

About