The Additive Effects of the Active Component of Grapefruit Juice (Naringenin) and Antiarrhythmic Drugs on HERG Inhibition

Lin, Congrong; Ke, X.; Ranade, Vasant; Somberg, John C.

doi:10.1159/000111923

Cited by 29 publications

(18 citation statements)

References 60 publications

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“…Notably, quinidine shows strong anti-HCV activity at concentrations ranging from 10 to 25 μM (Fig. 3B), overlapping with the drug's therapeutic range of 6-10 μM in human plasma (36). Etazolate, which showed little-to-no cytotoxicity to Huh-7.5 cells and effected an ∼150-fold inhibition of HCV RNA levels at 30 μM (Fig.…”

Section: Effect Of Selected Inhibitors On Hcv Rna Levels and Infectiomentioning

confidence: 82%

A cell protection screen reveals potent inhibitors of multiple stages of the hepatitis C virus life cycle

Chockalingam

Simeon

Rice

et al. 2010

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

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The hepatitis C virus (HCV) life cycle involves multiple steps, but most current drug candidates target only viral replication. The inability to systematically discover inhibitors targeting multiple steps of the HCV life cycle has hampered antiviral development. We present a simple screen for HCV antivirals based on the alleviation of HCV-mediated cytopathic effect in an engineered cell linen4mBid. This approach obviates the need for a secondary screen to avoid cytotoxic false-positive hits. Application of our screen to 1280 compounds, many in clinical trials or approved for therapeutic use, yielded >200 hits. Of the 55 leading hits, 47 inhibited one or more aspects of the HCV life cycle by >40%. Six compounds blocked HCV entry to levels similar to an antibody (JS-81) targeting the HCV entry receptor CD81. Seven hits inhibited HCV replication and/or infectious virus production by >100-fold, with one (quinidine) inhibiting infectious virus production by 450-fold relative to HCV replication levels. This approach is simple and inexpensive and should enable the rapid discovery of new classes of HCV life cycle inhibitors.cell death | drug | high throughput | rescue | virus assembly H epatitis C virus (HCV) infection is a major public health problem, putting~180 million infected individuals worldwide (3% of the world's population) at risk for developing cirrhosis, hepatocellular carcinoma, and liver failure. Chronic hepatitis C is a leading cause for liver transplantation in the Western world. The current standard IFN-based therapy is costly, time-consuming, riddled with serious side effects, and cures only ∼50% of patients infected with the most common genotype. Although it is anticipated that small molecules that effectively inhibit the HCV life cycle can complement or even replace IFN therapy, no anti-HCV drugs have yet been approved for human use. Efforts to develop HCV antivirals mostly target only viral replication due to widespread dependence on the HCV replicon model (1-4), which effectively reproduces the RNA replication aspects of the HCV life cycle but does not allow screens to identify inhibitors of entry or infectious virus assembly and release.The identification of a genotype 2a isolate of HCV that reproduces the entire viral life cycle in cell culture (5-7) promised to accelerate the discovery of antivirals targeting all aspects of HCV growth in a more true-to-life model system. Several recent reports describe systems that can in principle screen for inhibitors targeting different steps of the HCV life cycle via the prevention of the spread of cell culture-derived hepatitis C virus (HCVcc) infection in a cell monolayer (8-11). Very recently, one such screen based on a colorimetric readout following immunostaining with an anti-E2 antibody identified inhibitors of multiple stages of the HCV life cycle (12). Although effective, this approach is labor-intensive and not readily amenable to high-throughput application, requiring antibodies and 12 washing steps in addition to a secondary screen to assess drug ...

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Section: Effect Of Selected Inhibitors On Hcv Rna Levels and Infectiomentioning

confidence: 82%

A cell protection screen reveals potent inhibitors of multiple stages of the hepatitis C virus life cycle

Chockalingam

Simeon

Rice

et al. 2010

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

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“…However, in this study, methadone does show a concentration effect inhibition of IKr in oocytes with HERG overexpression on the cell membrane. We are measuring a relative difference in drug effects, which this model does well, as reported with the effects of naringenin and antiarrhythmic drugs on HERG inhibition [44], or with regard to the assessment of extracellular acidification and hyperkalemia [45]. Using patch clamp techniques with cardiac myocytes is a superior model for biophysical studies, but for pharmacologic comparison of drugs that inhibit IKr in the oocytes, the oocytes model is adequate for comparative studies.…”

Section: Discussionmentioning

confidence: 99%

The Effects of Chiral Isolates of Methadone on the Cardiac Potassium Channel IKr

et al. 2008

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Objectives: Methadone is a synthetic opioid, an analgesic and an antiaddictive. QT prolongation as well as torsade de pointes ventricular tachycardia and death have been reported with methadone. Methadone’s proarrhythmic toxicity is related to the inhibition of cardiac IKr channel and prolongation of the action potential. We hypothesized that the 2 isomers of methadone may have different effects on the IKr channel. Methods: The effects of the isomers on IKr were evaluated by using an oocytes system with heterogeneously expressed human ether-a-go-go-related gene (HERG) using the 2 electrode voltage clamp technique. r- and s-methadone were obtained by employing chiral high-performance liquid chromatography, separating methadone into 2 isolates, with optical rotations of –141 and +143 degrees. Results: At concentrations of 0.01, 0.03, 0.1, 1 and 3 mM, r/s-methadone produced a dose-dependent inhibition of HERG by 17 ± 5, 23 ± 4, 40 ± 4, 57 ± 3, 69 ± 3 and 80 ± 1%, respectively. The IC₅₀ of r/s-methadone was 0.21 ± 0.02 mM. At 0.1, 0.3 and 1 mM, s-methadone reduced HERG current by 50 ± 4, 76 ± 5 and 87 ± 5%, respectively, while r-methadone reduced HERG current by 26 ± 4, 53 ± 3 and 77 ± 3%, respectively. Conclusions: There was a significant difference (p < 0.01) in the percentage of current inhibition between r- and s-methadone, at 0.1 and 0.3 mM (52% reduction). Thus, r-methadone may be a safer agent due to less QT effect.

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“…The list of such drugs is available at www.crediblemeds.org and it should be given to the patient and/or family members. Herbal medicines including liquorice20) and grapefruit21) should be avoided. The effect of oral contraceptives seems to be neutral 22).…”

Section: Life-style Modificationmentioning

confidence: 99%

Management of Patients with Long QT Syndrome

Cho

2016

Korean Circ J

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Long QT syndrome (LQTS) is a rare cardiac channelopathy associated with syncope and sudden death due to torsades de pointes and ventricular fibrillation. Syncope and sudden death are frequently associated with physical and emotional stress. Management of patients with LQTS consists of life-style modification, β-blockers, left cardiac sympathetic denervation (LCSD), and implantable cardioverter-defibrillator (ICD) implantation. Prohibition of competitive exercise and avoidance of QT-prolonging drugs are important issues in life-style modification. Although β-blockers are the primary treatment modality for patients with LQTS, these drugs are not completely effective in some patients. Lifelong ICD implantation in young and active patients is associated with significant complications. LCSD is a relatively simple and highly effective surgical procedure. However, LCSD is rarely used.

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The Additive Effects of the Active Component of Grapefruit Juice (Naringenin) and Antiarrhythmic Drugs on HERG Inhibition

Cited by 29 publications

References 60 publications

A cell protection screen reveals potent inhibitors of multiple stages of the hepatitis C virus life cycle

A cell protection screen reveals potent inhibitors of multiple stages of the hepatitis C virus life cycle

The Effects of Chiral Isolates of Methadone on the Cardiac Potassium Channel IKr

Management of Patients with Long QT Syndrome

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