Safety pharmacology in focus: New methods developed in the light of the ICH S7B guidance document

Curtis, Michael J.

doi:10.1016/j.vascn.2006.05.002

Cited by 21 publications

(9 citation statements)

References 26 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…VR is determined by the duration of the cardiac action potential as a result of the activities of many membrane ion channels and transporters. In this guideline are descriptions of in vitro (patch clamp) and in vivo electrophysiology studies for competition binding protocols in which test substances are studied for their ability to displace a hERG channel blocker (human Ether‐a‐go‐go Related Gene) 61, 62. The hERG gene encodes a potassium ion channel responsible for the repolarizing I Kr current in the cardiac action potential.…”

Section: Drug Discovery: How Does This Work?mentioning

confidence: 99%

Pharmacokinetics in Drug Discovery

Ruiz-Garcı́a

Bermejo

Moss

et al. 2008

Journal of Pharmaceutical Sciences

150

View full text Add to dashboard Cite

Section: Drug Discovery: How Does This Work?mentioning

confidence: 99%

Pharmacokinetics in Drug Discovery

Ruiz-Garcı́a

Bermejo

Moss

et al. 2008

Journal of Pharmaceutical Sciences

150

View full text Add to dashboard Cite

“…* pϽ0.05, * * pϽ0.01, * * * pϽ0.001 vs. control. 10.7Ϯ2.8% in the 10-mM group (pϾ0.05), 11.3Ϯ5.5% in the 30-mM group (pϾ0.05), 47.0Ϯ2.3% in the 100-mM group (pϽ0.01) and 53.7Ϯ2.5% in the 300-mM group (pϽ0.001); the corresponding fractional blocks of I tail were 1.1Ϯ3.0% (pϾ0.05), 17.1Ϯ3.3% ( pϾ0.05), 32.7Ϯ1.9% ( pϽ0.05) and 56.0Ϯ2.4% (pϽ0.001), respectively. Thus, compared with the control, 100-mM SC and 300-mM SC had statistically significant inhibitory effects on I step and I tail (Fig.…”

Section: Inhibition Of Herg Kmentioning

confidence: 99%

“…[6][7][8][9] Regulatory guidelines [CPMP/986/96 (1997) and ICH S7B (2005)] recommend the use of preclinical in vivo and in vitro (in which a broad range of concentrations should be used) studies to detect the QT-prolonging effects and arrhythmogenic potential of new chemical entities. [10][11][12] The HERG assay (which tests I Kr ) is one of the recommended in vitro models for the detection of potential drug-induced long QT. 11) Sophocarpine (SC) is a dehydroderivative of the bis-quinolizidine alkaloid matrine.…”

mentioning

confidence: 99%

HERG K+ Channel Blockade by the Novel Antiviral Drug Sophocarpine

Zhao

Fang

et al. 2008

Biological & Pharmaceutical Bulletin

View full text Add to dashboard Cite

Torsade de pointes (TdP) arrhythmia is a potentially fatal form of ventricular arrhythmia that occurs under conditions in which cardiac repolarization is delayed (as indicated by prolonged QT intervals in electrocardiograph recordings).1-3) A likely mechanism for QT interval prolongation and TdP arrhythmias is blockade of the rapid component of the cardiac delayed rectifier K ϩ current (I Kr ), which is encoded by human ether-à-go-go-related gene (HERG). 1,4,5) More than 100 non-cardiovascular drugs can induce TdP arrhythmias or QT interval prolongations in electrocardiograms. [6][7][8][9] Regulatory guidelines [CPMP/986/96 (1997) and ICH S7B (2005)] recommend the use of preclinical in vivo and in vitro (in which a broad range of concentrations should be used) studies to detect the QT-prolonging effects and arrhythmogenic potential of new chemical entities. [10][11][12] The HERG assay (which tests I Kr ) is one of the recommended in vitro models for the detection of potential drug-induced long QT. 11)Sophocarpine (SC) is a dehydroderivative of the bis-quinolizidine alkaloid matrine. 13) In China, it has entered clinical development as an injection solution with a superior inhibitory effect on Coxsackie B virus that should result in improved efficacy in the treatment of viral myocarditis. [14][15][16][17] The inhibitory actions of several matrine-type alkaloids on I Kr have recently been reported. 18,19) We investigated the effects of SC on HERG-encoded K ϩ channels to assess the risk of this drug causing cardiac arrhythmia associated with QT interval prolongation.We set out to establish: (i) the effects of SC on the amplitude, concentration dependence and kinetics of currents conducted by HERG channels stably expressed in human embryonic kidney (HEK293) cells. This was done using a wholecell patch clamp method; and (ii) the effects of SC on HERG protein levels in HEK293 cells. This was achieved using Western blot analysis and immunofluorescence methods. MATERIALS AND METHODS HERG-Expressing Cell LinesExperiments were performed on HEK293 cells that stably expressed the wild-type HERG gene (provided by Professor Zhi-Guo Wang, Montreal Heart Institute, Montreal, Canada). Cells were maintained in Dulbecco's Modified Eagle's Medium (DMEM, Hyclone) supplemented with 10% (v/v) fetal calf serum (FCS, Gibco) and 200-mM geneticin (G-418, Gibco) at 37°C in a humidified atmosphere of 5% CO 2 .Sophocarpine SC (Dushun Ltd., Ningxia, China) was dissolved in deionized water to obtain a 10-mM stock solution, which was stored at Ϫ20°C.Electrophysiological Recordings HERG currents were measured using the whole-cell configuration of the patch clamp technique. 8,9,20) Heat-polished patch pipettes had final resistances of 2-4 MW when filled with a pipette solution containing (in mM): 130 KCl, 1 MgCl 2 · 6H 2 O, 10 HEPES, 5 Mg-ATP, 5 EGTA and 0.1 guanosine triphosphate (GTP) (pH 7.3 with KOH). The extracellular solution contained (in mM): 136 NaCl, 5.4 KCl, 5 HEPES, 1 MgCl 2 · 6H 2 O, 1 CaCl 2 and 10 glucose (pH 7.4 with NaOH). The f...

show abstract

“…Ex-vivo assays: These are listed as follow up repolarization assays in ICHS7B and EMEA guidance documents [43], and are conducted to obtain mechanistic insight often when hERG screening results are discrepant from the results of in vivo experiments [46]. These typically include studies to assess the effects of drug candidates on cardiac Purkinje fibers [47], studies on isolated cardiomyocytes either using electrophysiological recording of evoked action potentrials [48] and studies on ECG's and monophasic action potentials on Langendorff perfused isolated heart preparations [49,50].…”

Section: Predicting Cardiac Arrhythmiasmentioning

confidence: 99%

hERG (KCNH2 or Kv11.1) K+ Channels: Screening for Cardiac Arrhythmia Risk

Bowlby¹,

Peri²,

Zhang³

et al. 2008

CDM

View full text Add to dashboard Cite

Testing new compounds for pro-arrhythmic potential has focused in recent years on avoiding activity at the hERG K+ channel, as hERG block is a common feature of many pro-arrhythmic compounds associated with Torsades de Pointes in humans. Blockers of hERG are well known to prolong cardiac action potentials and lead to long QT syndrome, and activators, although rarer, can lead to short QT syndrome. The most reliable assays of hERG utilize stable cell lines, and include ligand binding, Rb+ flux and electrophysiology (both automated and manual). These assays can be followed by measurement of activity at other ion channels contributing to cardiac contractility and detailed action potential/repolarization measurements in cardiac tissue. An integrated risk assessment for pro-arrhythmic potential is ultimately required, as the constellation of ion channel activities and potencies, along with the mechanism/kinetics of ion channel block, may ultimately be the best predictor of cardiac risk in vivo.

show abstract

Safety pharmacology in focus: New methods developed in the light of the ICH S7B guidance document

Cited by 21 publications

References 26 publications

Pharmacokinetics in Drug Discovery

Pharmacokinetics in Drug Discovery

HERG K+ Channel Blockade by the Novel Antiviral Drug Sophocarpine

hERG (KCNH2 or Kv11.1) K+ Channels: Screening for Cardiac Arrhythmia Risk

Contact Info

Product

Resources

About