Incidence of Cardiac Arrhythmias During Intravenous Pentamidine Therapy in HIV-Infected Patients

Eisenhauer, Michael D.; Eliasson, Arn H.; Taylor, Allen J.; Coyne, Philip E.; Wortham, Dale C.

doi:10.1378/chest.105.2.389

Cited by 77 publications

(42 citation statements)

References 29 publications

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“…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). We believe that this slow time course is consistent with a pentamidine-induced decrease in the expression of functional hERG channels in the heart, rather than a direct blocking effect of the drug, since QT prolongation by direct hERG channel blockers such as dofetilide are evident immediately upon administration (Lande et al, 1998).…”

Section: Discussionmentioning

confidence: 99%

Pentamidine-Induced Long QT Syndrome and Block of hERG Trafficking

Kuryshev¹,

Ficker²,

Wang³

et al. 2004

J Pharmacol Exp Ther

250

167

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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.

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Section: Discussionmentioning

confidence: 99%

Pentamidine-Induced Long QT Syndrome and Block of hERG Trafficking

Kuryshev¹,

Ficker²,

Wang³

et al. 2004

J Pharmacol Exp Ther

250

167

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“…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

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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 .

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“…These included non- sedating antihistamines, 2 classic as well as atypical antipsychotics, 6 tricyclic and tetracyclic antidepressants, 7 ketanserin, 8 cisapride, 3,9 halofantrine, 10 pentamidine, 11 macrolide antibiotics (erythromycin and clarithromycin), 12,13 fluoroquinolones, 14 cotrimoxazole, 15 glibenclamide, 16 and probucol. 17 A patient was defined as a current user if the index date fell between the dispensing date and the theoretical end date of the prescription.…”

Section: Methodsmentioning

confidence: 99%

QTc-prolonging drugs and hospitalizations for cardiac arrhythmias

Bruin

Hoes

Leufkens

2003

The American Journal of Cardiology

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Cardiac arrhythmia as an adverse effect of noncardiac drugs has been an issue of growing importance during the past few years. In this population-based study, we evaluated the risk for serious cardiac arrhythmias during the use of several noncardiac QTc-prolonging drugs in day-to-day practice, and subsequently focused on several specific groups of patients who could be extremely vulnerable for drug-induced arrhythmias. We performed a case-control study in which patients (cases), hospitalized for nonatrial cardiac arrhythmias from 1987 to 1998, were compared with their matched controls regarding current use of QTc-prolonging drugs. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using multivariate conditional logistic regression, adjusting for potential confounding factors. Data were obtained from the PHARMO record linkage system. We identified 501 cases, 39 of whom used QTcprolonging drugs. A statistically nonsignificant increased risk for arrhythmias (OR 1.2, 95% CI 0.8 to 1.9) was observed in patients who received QTc-prolonging drugs. A clearly increased risk of arrhythmias was, however, found in patients with a history of asthma (OR 9.9, 95% CI 1.0 to 100) and in patients using potassiumlowering drugs (OR 5.3, 95% CI 1.1 to. 25.9). Our data do not suggest that there is a strong overall association between the use of QTc-prolonging drugs and hospitalization for cardiac arrhythmias in the population at large. However, there appears to be clinically relevant associations of patients with a history of asthma and patients taking potassium-lowering drugs. The use of QTc-prolonging drugs should therefore be either avoided or monitored closely in these specific patients. ᮊ2003 by Excerpta Medica, Inc.(Am J Cardiol 2003;91:59 -62) C ardiac arrhythmias as an adverse effect of noncardiac drugs has been an issue of growing importance in medical science during the last few years, resulting in regulatory action concerning several drugs. 1 Because of the seriousness of this adverse effect, regulatory action has sometimes already been taken after a few case reports, before the actual risk has been quantified in large population-based studies.For only a few of all QTc-prolonging drugs, studies have unequivocally shown a causal relation between the use of the drugs and the occurrence of cardiac arrhythmias. The use of antihistamines has been associated with an increased risk for cardiac arrhythmias. 2 In contrast, no increased risk for serious rhythm disorders was observed in patients who took cisapride, 3 although its use has been linked to the occurrence of cardiac arrhythmias in several case reports. 4,5 In this population-based study, we evaluated the risk for serious cardiac arrhythmias and the use of several noncardiac QTc-prolonging drugs in day-to-day practice. Subsequently, we focused on several specific groups of patients who may be quite vulnerable to druginduced arrhythmias.

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Incidence of Cardiac Arrhythmias During Intravenous Pentamidine Therapy in HIV-Infected Patients

Cited by 77 publications

References 29 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

QTc-prolonging drugs and hospitalizations for cardiac arrhythmias

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