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  • 1
    Electronic Resource
    Electronic Resource
    Gene-Specific Therapy for Long QT Syndrome (1997)
    Oxford, UK : Blackwell Publishing Ltd
    Annals of noninvasive electrocardiology 2 (1997), S. 0 
    Details
    ISSN: 1542-474X
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Background: One form of the hereditary long QT syndrome (LQT-3) has recently been shown to be caused by the SCN5A mutation of the human cardiac sodium channel. Cellular studies have suggested that type lb antiarrhythmics may be potentially therapeutic via preferential blockade of the resulting abnormal late inward sodium current. To test this hypothesis, we implemented a pilot study to evaluate the potential for long-term, gene-specific therapy in patients with this disease.Methods and Results: The effects of short-term intravenous lidocaine and oral tocainide were studied in three siblings: two carriers of the SCN5A mutation; and one noncarrier. The two carriers had prolonged QT intervals at baseline, 531 ms, and 566 ms, which markedly shortened with intravenous lidocaine to 438 and 482 ms, respectively. Tocainide-induced correction of the QT interval was similar in both carriers. The noncarrier did not have any significant change in the QT with either drug. One carrier was then placed on outpatient therapy with oral tocainide, and has demonstrated persistent normalization of the QT interval and T wave morphology during the past 10 months.Conclusion: This is the first demonstration of long-term outpatient treatment in LQT-3 using oral tocainide during a 10-month period. QT shortening was achieved by both intravenous lidocaine and oral tocainide, with no adverse affects. The predominant effect was a reduction in the QT onset interval, suggesting that blockade of the mutant sodium current allows repolarization to begin at an earlier time during the action potential.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1111/j.1542-474X.1997.tb00336.x
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  • 2
    Electronic Resource
    Electronic Resource
    Safety and Efficacy of Flecainide in Subjects with Long QT-3 Syndrome (ΔKPQ Mutation): A Randomized, Double-Blind, Placebo-Controlled Clinical Trial (2005)
    350 Main Street , Malden , MA 02148 , USA , and 9600 Garsington Road , Oxford OX4 2XG , UK . : Blackwell Publishing, Inc.
    Annals of noninvasive electrocardiology 10 (2005), S. 0 
    Details
    ISSN: 1542-474X
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Background: We conducted a study of chronic therapy with flecainide versus placebo in a small group of LQT-3 patients with the ΔKPQ deletion to evaluate the safety and efficacy of flecainide in this genetic disorder. In vitro studies have shown that flecainide provides correction of the impaired inactivation associated with the ΔKPQ deletion. Methods: A randomized, double-blind, placebo-controlled clinical trial was conducted with flecainide and placebo in six male LQT-3 subjects with the ΔKPQ deletion. Results: The lowest possible dose of flecainide associated with at least a 40 ms reduction in the QTc interval was determined in an initial open-label, dose-ranging investigation using one-fourth or half of the recommended maximal antiarrhythmic flecainide dose. QTc reduction was achieved with a flecainide dose of 1.5 mg/kg per day in 4 subjects and with 3.0 mg/kg per day in 2 subjects. Subjects were randomized to four 6-month alternating periods of flecainide and placebo therapy based on the open-label dose findings. Average QTc values during placebo and flecainide therapies were 534 ms and 503 ms, respectively, with an adjusted reduction in QTc of −27.1 ms (95% confidence interval: −36.8 ms to −17.4 ms; P 〈 0.001) at a mean flecainide blood level of 0.11 ±0.05 μg/ml. Minimal prolongation in QRS occurred (mean: +2.5 ms), and there were no major adverse cardiac effects. Conclusions: Chronic low-dose flecainide significantly shortens the QTc interval in LQT-3 subjects with the ΔKPQ mutation. No major adverse drug effects were observed with flecainide during this trial, but the sample size is not large enough to evaluate the safety of flecainide therapy in patients with this mutation.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1111/j.1542-474X.2005.00077.x
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  • 3
    Electronic Resource
    Electronic Resource
    Novel Compound Heterozygous Mutations in the KCNQ1 Gene Associated with Autosomal Recessive Long QT Syndrome (Jervell and Lange-Nielsen syndrome) (2003)
    350 Main Street , Malden , MA 02148 , USA , and 9600 Garsington Road , Oxford OX4 2DQ , UK . : Blackwell Science Inc
    Annals of noninvasive electrocardiology 8 (2003), S. 0 
    Details
    ISSN: 1542-474X
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Background: The Jervell and Lange-Nielsen syndrome (JLNS) is the autosomal recessive form of long QT syndrome (LQTS)—a familial cardiac disorder that causes syncope, seizures, and sudden death from ventricular arrhythmias, specifically torsade de pointes. JLNS is associated with sensorineural deafness and has been shown to occur with homozygous mutations in KCNQ1 or KCNE1 in JLNS families in which QTc prolongation is inherited as a dominant trait. This study investigated the molecular pathology of a family with clinical evidence of JLNS. Methods and Results: Single-strand conformation polymorphism, denaturing high performance liquid chromatography, and DNA sequencing analyses were used to screen for KCNQ1 mutations. Novel compound heterozygous nonsense mutations R518X/Q530X in the C-terminus of KCNQ1 were identified in both affected dizygotic twins; both the parents and a sibling each carried only one of the mutant alleles and were asymptomatic with modestly prolonged QTc intervals (0.46, 0.50, and 0.45 seconds, respectively). These two nonsense mutations lead to premature termination of C-terminus with truncation of the postulated assembly domain. Conclusion: Novel compound heterozygous nonsense mutations in C-terminus of KCNQ1 can cause JLNS.               A.N.E 2003;8(3):246-250
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1542-474X.2003.08313.x
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