QT interval prolongation by non-cardiovascular drugs: issues and solutions for novel drug development

Crumb, William J.; Cavero, Icilio

doi:10.1016/s1461-5347(99)00172-8

Cited by 113 publications

(67 citation statements)

References 34 publications

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“…The principle underlying mechanism for drug-induced LQTS is inhibition of cardiac I Kr (Roden, 1998;Crumb and Cavero, 1999). Therefore, understanding the molecular determinants of drug binding to HERG could have a major impact in the identification of new compounds without this undesirable side effect.…”

Section: Discussionmentioning

confidence: 99%

Structural Determinants of HERG Channel Block by Clofilium and Ibutilide

et al. 2004

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Block of human ether-a-go-go related gene (HERG) Kϩ channels by a variety of medications has been linked to acquired long QT syndrome, a disorder of cardiac repolarization that predisposes to lethal arrhythmias. The drug-binding site is composed of residues that face into the central cavity of the channel. Two aromatic residues located on the S6 domain (Tyr652 and Phe656) are particularly important structural determinants of drug block. The role of pore helix residues (Thr623, Ser624, Val625) is less clear. In this study, we compared the pharmacological properties of two structurally related compounds, ibutilide and clofilium. Both compounds are charged amines with a single phenyl ring. Clofilium, a chlorobenzene derivative, is a potent blocker of HERG channels, but has a remarkably slower time course for recovery from block than ibutilide, a methanesulfonanilide. The difference in the rate of recovery from block can be explained simply by variation in drug trapping. There is little recovery from clofilium block with D540K HERG channels that permit untrapping at hyperpolarized potentials. Alanine-scanning mutagenesis of the S6 domain and a portion of the pore helix revealed that the binding site residues were the same for both compounds. However, S624A, located at the base of the pore helix, was the only HERG mutation that enabled rapid recovery from clofilium block. In summary, the pore helix residues are important components of the HERG drug binding site, and may be particularly important for drugs with polar substituents, such as a halogen (e.g., clofilium) or a methanesulfonamide (e.g., ibutilide).

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Section: Discussionmentioning

confidence: 99%

Structural Determinants of HERG Channel Block by Clofilium and Ibutilide

et al. 2004

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“…LQT also can be acquired as a side effect of treatment with commonly used medications, including some antiarrhythmic, antihistamine, antibiotic, psychoactive, and gastrointestinal prokinetic agents (6, 7). Although drug-induced LQT theoretically could result from reduction of any voltage-gated K ϩ current that contributes to ventricular repolarization, all known drugs with this side effect preferentially block I Kr (1,8,9). It is unclear why so many structurally diverse compounds block HERG channels, but this undesirable side effect now is recognized as a major hurdle in the development of new and safe drugs (9, 10).…”

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confidence: 99%

“…Although drug-induced LQT theoretically could result from reduction of any voltage-gated K ϩ current that contributes to ventricular repolarization, all known drugs with this side effect preferentially block I Kr (1,8,9). It is unclear why so many structurally diverse compounds block HERG channels, but this undesirable side effect now is recognized as a major hurdle in the development of new and safe drugs (9,10). Previous studies have characterized single residues of HERG that when mutated altered the sensitivity of the channel to block by the methanesulfonanilide antiarrhythmic drug dofetilide.…”

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confidence: 99%

A structural basis for drug-induced long QT syndrome

Mitcheson

Chen

Lin

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

864

540

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L ong QT syndrome (LQT) is an abnormality of cardiac muscle repolarization that predisposes affected individuals to a ventricular arrhythmia that can degenerate into ventricular fibrillation and cause sudden death (1). The cellular mechanism of the lengthened QT interval recorded on the body surface electrocardiogram is prolonged ventricular action potentials. Recent genetic discoveries have determined that the molecular mechanism of inherited LQT is mutations in one of several genes [e.g., HERG (2), KCNE2 (3)] that encode ion channel subunits important for normal repolarization of the ventricle. HERG encodes the pore-forming subunits of channels that conduct the rapid delayed rectifier K ϩ current (I Kr ; refs. 4 and 5). LQT also can be acquired as a side effect of treatment with commonly used medications, including some antiarrhythmic, antihistamine, antibiotic, psychoactive, and gastrointestinal prokinetic agents (6, 7). Although drug-induced LQT theoretically could result from reduction of any voltage-gated K ϩ current that contributes to ventricular repolarization, all known drugs with this side effect preferentially block I Kr (1,8,9). It is unclear why so many structurally diverse compounds block HERG channels, but this undesirable side effect now is recognized as a major hurdle in the development of new and safe drugs (9, 10). Previous studies have characterized single residues of HERG that when mutated altered the sensitivity of the channel to block by the methanesulfonanilide antiarrhythmic drug dofetilide. However, these residues are believed to alter drug binding by an allosteric effect related to the loss of inactivation gating (11). A more recent study found that mutation of a Phe located in the S6 domain of HERG decreased block by dofetilide and quinidine (12). However, it is unlikely that a single residue could confer drug sensitivity. Thus, despite the obvious clinical importance of HERG channel block to acquired LQT, the structural basis of the high-affinity drug binding site has not been adequately characterized. Materials and Methods Mutagenesis and Channel Expression in Oocytes.Mutations were introduced into the HERG K ϩ channel (13) by using sitedirected mutagenesis as described previously (14). Complementary RNAs for injection into oocytes were prepared with SP6 Cap-Scribe (Boehringer Mannheim) after linearization of the expression construct with EcoRI. Isolation and maintenance of Xenopus oocytes and cRNA injection were performed as described previously (14-16).Voltage Clamp. The two-microelectrode voltage clamp technique (17) was used to record membrane currents in oocytes 2-4 days after cRNA injection as previously described (18). To attenuate endogenous chloride currents, Cl Ϫ was replaced with Mes (2-[N-morpholino]ethanesulfonic acid) in the external solution that contained 96 mM NaMes͞2 mM KMes͞2 mM CaMes 2 ͞5 mM Hepes͞1 mM MgCl 2 adjusted to pH 7.6 with methane sulfonic acid. In some experiments, KMes was increased to 96 mM with a similar reduction in NaMes.MK-499 was supplied by Me...

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“…are associated with cardiovascular adverse effects, such as ventricular fibrillation, prolongation of the QT interval, upright posture hypotension, which may result in a higher incidence of sudden unexplained death in schizophrenia patients than in the normal population. The increased toxicity is due to the adverse effects of drugs on the markedly abnormal cardiac autonomic nervous system and ventricular repolarization [2]. The QT interval represents the time of ventricular depolarization and repolarization and is caused by transmembrane flow of ions (e.g.…”

Section: Discussionmentioning

confidence: 99%

“…Johnson and Johnson launched paliperidone under the trade name of Invega in the end of 2006. The poor absolute oral bioavailability (only 28%) and the high daily dose of Invega may lead to an increased risk of side effects [2]. Consequently, it is very important to search for new derivatives of paliperidone for the treatment of schizophrenia with higher oral bioavailability and lower side effects [3].…”

mentioning

confidence: 99%

Studies on the Acute Toxicity, Pharmacokinetics and Pharmacodynamics of Paliperidone Derivatives – Comparison to Paliperidone and Risperidone in Mice and Rats

Sun¹,

Su²,

Cheng³

et al. 2010

Basic Clin Pharma Tox

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The objective of this study was to investigate the acute toxicity, pharmacokinetics and pharmacodynamics of paliperidone derivatives (PDs) compared with paliperidone and risperidone. The i.g. LD 50 and i.v. maximum tolerated doses of PD1, PD5 and PD6 were greater than those of paliperidone and risperidone in mice. Pharmacokinetic study showed that PDs were quickly metabolized to paliperidone to take effect in the treatment of schizophrenia in rats after i.g. administration. Only traces of the parent substances were found. Pharmacodynamic study showed that PDs significantly reduced MK-801-induced hyperlocomotion in mice. The electrocardiogram (ECG) was recorded at 0,5,10,15,20, 25, 30, 45 and 60 min. in anaesthetized rats after i.v. injection of 0.21, 0.59, 1.69 lmol ⁄ kg drugs. Heart rate reduction had a linear relation with dose after i.v. injection of PDs, paliperidone and risperidone. No significant change in the ECG parameters was found in all groups after administration of the low dose. Although the reductions in heart rate and the corrected QT interval (QTc) were observed in all drugs at the high dose, PD5 and PD6 were associated with smaller effects on the ECG parameters than other compounds, including paliperidone and risperidone. Therefore, PD5 and PD6 could be potential candidates for the treatment of schizophrenia.Risperidone, 3-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidin]ethyl}-6,7,8,9-tetrahydro-2-methyl-4H-pyrido-[1,2-a]py rimidine-4-one, is a serotonin 5-HT 2 and dopamine D 2 receptor antagonist and widely used in the treatment of schizophrenia as an atypical antipsychotic drug. In human beings, risperidone is mainly metabolized to 9-hydroxyrisperidone by cytochrome P450 in the liver [1]. Because of its antipsychotic activity, 9-hydroxyrisperidone has been reported under the name of paliperidone for the treatment of schizophrenia. Johnson and Johnson launched paliperidone under the trade name of Invega in the end of 2006. The poor absolute oral bioavailability (only 28%) and the high daily dose of Invega may lead to an increased risk of side effects [2]. Consequently, it is very important to search for new derivatives of paliperidone for the treatment of schizophrenia with higher oral bioavailability and lower side effects [3]. A series of paliperidone derivatives (PDs) were synthesized ( fig. 1) and their physical and chemical properties are listed in table 1.Among patients with schizophrenia, accelerated heart disease is a major cause of sudden death and the risk of dying from cardiovascular disease is two to three times higher than in the general population [4]. Numerous antipsychotic drugs are well-documented for their effects on the QT interval [5]. Prolongation of the QT interval by risperidone has also been reported in a clinical study [6]. In vitro electrophysiological studies showed that supra-therapeutic doses of risperidone induced the prolongation of ventricular repolarization in a dose-related and reverse use-dependent manner, which prolonged the terminal repolariza...

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QT interval prolongation by non-cardiovascular drugs: issues and solutions for novel drug development

Cited by 113 publications

References 34 publications

Structural Determinants of HERG Channel Block by Clofilium and Ibutilide

Structural Determinants of HERG Channel Block by Clofilium and Ibutilide

A structural basis for drug-induced long QT syndrome

Studies on the Acute Toxicity, Pharmacokinetics and Pharmacodynamics of Paliperidone Derivatives – Comparison to Paliperidone and Risperidone in Mice and Rats

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