Pentavalent antimonial-induced torsade de pointes

Ortega-Carnicer, Julián; Alcázar, Roberto; Torre, M. de la; Benezet, Javier

doi:10.1016/s0022-0736(97)80023-4

Cited by 21 publications

(12 citation statements)

References 6 publications

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“…Shimizu & Antzelevitch (1999) have shown that low external calcium and ryanodine could suppress negative T wave and alternans, and give rise to torsade de pointes. Reduced entry of calcium could therefore account for torsade de pointes that have been described during antileishmanian treatment with Sb in man (Ortega‐Canicer et al ., 1997; Takur et al ., 1998) and explain death of guinea‐pigs in the first days of Sb treatment. Although no histological studies have been performed on hearts from Sb(III)‐treated guinea‐pigs (which appeared normal upon excision), cells death and/or increased fibrosis might account for the reduced yield of cells upon isolation and might contribute to the reduced amplitude of the ECG waves that was noticed on all the leads that were used in this study.…”

Section: Discussionmentioning

confidence: 99%

“…However, Lu & Liu (1963) estimated that 70–90% of deaths resulting from antimony therapy were due to cardiac intoxication and therefore treatment switched to Sb(V) to reduce the cardiovascular risk. Sb(V) is better tolerated but has been repeatedly reported to have threatening effects in human close to those described for Sb(III): hypotension, modifications of the electrocardiogram (ECG) including T wave flattening and/or inversion and prolonged corrected QT interval eventually leading to ST segment changes and P, R and T wave amplitude reductions, torsade de pointes and sudden death (Chulay et al ., 1985; Hepburn et al ., 1994; Ortega‐Canicer et al ., 1997; Takur et al ., 1998; Ribeiro et al ., 1999). These effects are related to the dose and duration of the treatment.…”

Section: Introductionmentioning

confidence: 99%

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Antimony‐induced cardiomyopathy in guinea‐pig and protection by L‐carnitine

Álvarez

Malécot

Gannier

et al. 2005

British J Pharmacology

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1 Antimony (Sb) is the mainstay for the treatment of Leishmaniasis. It has serious, often lethal, cardiovascular side effects. The objective of this study was to examine the effects of Sb treatment upon the electrocardiogram (ECG), myocyte contractility (assessed by monitoring sarcomere length during field stimulation), whole-cell action potential (AP) and calcium current (I Ca ) of the guinea-pig and to evaluate L-carnitine as a cardioprotective agent. 2 Guinea-pigs received daily injections of either saline, Sb(V), Sb(III), L-carnitine or L-carnitine with Sb(III). Eight lead ECGs were recorded under halothane anaesthesia every 4 days. At the end of each treatment regime, animals were killed and ventricular myocytes were enzymatically isolated. 3 Treatment with Sb(V) for 26 days prolonged the QT interval of the ECG. Treatment with Sb(III) was lethal within 2 days for B50% of the animals. The survivors showed ECG alterations similar to those described in man: T wave flattening and/or inversion, depression of the ST segment, and elongation of RR and QT intervals. Their ventricular myocytes showed impaired contraction responses to changes in stimulus frequency, elongated AP and reduced I Ca . 4 Combined treatment with L-carnitine and Sb(III) delayed mortality. Prior treatment with L-carnitine followed by combined treatment with L-carnitine and Sb(III) reduced mortality to o10% over 12 days and these animals showed normal ECG. Their myocytes showed normal contractility and AP. 5 It is concluded that L-carnitine has a preventive cardioprotective role against antimony-induced cardiomyopathy. The mechanism of action of L-carnitine may be to counter oxidative stress caused by Sb(III).

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Antimony‐induced cardiomyopathy in guinea‐pig and protection by L‐carnitine

Álvarez

Malécot

Gannier

et al. 2005

British J Pharmacology

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“…Although pentavalent antimony compounds have proven to be very effective, drug use is often limited in patients because of toxic side effects, such as nausea, abdominal pain, chemical pancreatitis, renal toxicity, and electrocardiographic abnormalities, which are especially worrisome (Guerin et al, 2002). The cardiotoxicity of pentavalent antimony compounds, which may include inversion of the STsegment on the electrocardiogram, QTc prolongation, torsade de pointes arrhythmias, and sudden cardiac arrest (Chulay et al, 1985;Ortega-Carnicer et al, 1997;Thakur, 1998;Berhe et al, 2001;Cesur et al, 2002), severely limits pro-longed treatment courses in patients, particularly when high concentrations are indicated to combat and overcome resistance. Although antimonial compounds have been used in the treatment of leishmaniasis for at least 100 years, their precise mechanism of action remains unknown.…”

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confidence: 99%

Antimony-Based Antileishmanial Compounds Prolong the Cardiac Action Potential by an Increase in Cardiac Calcium Currents

Kuryshev¹,

Wang²,

Wible³

et al. 2006

Mol Pharmacol

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Antimonial agents are a mainstay for the treatment of leishmaniasis, a group of protozoal diseases that includes visceral leishmaniasis, or Kala Azar. Chemotherapy with trivalent potassium antimony tartrate (PAT) and, more importantly, pentavalent antimony-carbohydrate complexes, such as sodium stibogluconate (SSG), has been reported to prolong the QT interval and produce life-threatening arrhythmias. PAT is chemically related to As 2 O 3 , which alters cardiac excitability by inhibition of human ether a-go-go related gene (hERG) trafficking and an increase of cardiac calcium currents. In this study, we report that PAT does not block hERG currents on short-term exposure but reduces current density on long-term exposure (IC 50 , 11.8 M) and inhibits hERG maturation on Western blots (IC 50 , 62 M). Therapeutic concentrations of 0.3 M PAT increase cardiac calcium currents from Ϫ4.8 Ϯ 0.7 to Ϫ7.3 Ϯ 0.5 pA/pF at 10 mV. In marked contrast, pentavalent SSG, the drug of choice for the treatment of leishmaniasis, did not affect hERG/I Kr or any other cardiac potassium current at therapeutic concentrations. However, both cardiac sodium and calcium currents were significantly increased on long-term exposure to 30 M SSG in isolated guinea pig ventricular myocytes. We propose that the increase in calcium currents from Ϫ3.2 Ϯ 0.3 to Ϫ5.1 Ϯ 0.3 pA/pF at 10 mV prolongs APD 90 from 464 Ϯ 35 to 892 Ϯ 64 ms. Our data suggest that conversion of Sb(V) into active Sb(III) in patients produces a common mode of action for antimonial drugs, which define a novel compound class that increases cardiac risk not by a reduction of hERG/I Kr currents but-for the first time-by an increase in cardiac calcium currents.

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“…Recent studies suggest that elevations of amylase and lipase are common, and that a subset of patients suffer clinically significant pancreatitis. Nonetheless, these side‐effects rarely lead to discontinuation of the drug [2–4].…”

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confidence: 99%

“…Nevertheless, serious side‐effects, such as atrial and ventricular arrhythmia, atrial fibrillation, ventricular tachycardia, ventricular fibrillation, and torsade de pointes, are rare. Torsade de pointes induced by pentavalent antimony, followed by sudden death, has been observed [3–5]. Arrhythmias and sudden death have been reported with doses greater than 20 mg/kg body weight/day [1].…”

mentioning

confidence: 99%