RESUMO
BACKGROUND: Breath-holding spells are a benign condition primarily seen in 3% to 5% of healthy children aged between six months and five years. Although no specific treatment is recommended due to its benign nature, iron and piracetam are used in severe or recurrent cases. We planned to compare the heart rate variability (HRV) before and after treatment with 24-hour Holter monitoring in patients receiving iron and piracetam treatment and investigate the treatment's effectiveness. METHODS: Twenty-five patients who applied to the outpatient clinic between 2013 and 2015 due to breath-holding spells were included in the study. The patients who received piracetam and iron therapy and underwent 24-hour rhythm Holter monitoring were evaluated retrospectively. RESULTS: Fourteen (56%) of these patients were evaluated as having cyanotic-type and 11 (44%) patients were assessed as having pale-type breath-holding spells. A significant difference was found only between hourly peak heart rate and total power in the group receiving iron treatment. Significant differences were also found among the minimum heart rate, mean heart rate, the standard deviation of RR intervals, the mean square root of the sum of the squares of their difference between adjacent RR intervals, spectpow, and low frequency before and after the treatment in the patients who started piracetam treatment (P < 0.05). CONCLUSIONS: Our study is critical as it is the first to investigate the effects of treatment options on various HRV in patients with breath-holding spells. There were statistically significant changes in HRV parameters in patients receiving piracetam, and the number of attacks decreased significantly. Piracetam treatment contributes positively to the breath-holding spell with regard to efficacy and HRV, therefore it can be used to treat breath-holding spells.
Assuntos
Suspensão da Respiração , Frequência Cardíaca , Piracetam , Humanos , Frequência Cardíaca/efeitos dos fármacos , Frequência Cardíaca/fisiologia , Suspensão da Respiração/efeitos dos fármacos , Masculino , Feminino , Pré-Escolar , Estudos Retrospectivos , Lactente , Piracetam/farmacologia , Piracetam/administração & dosagem , Piracetam/uso terapêutico , Eletrocardiografia Ambulatorial/efeitos dos fármacos , Resultado do Tratamento , Ferro/administração & dosagem , Ferro/farmacologiaRESUMO
BACKGROUND: Patients at our pediatric outpatient clinic were offered 24-h Holter electrocardiogram (ECG) before and after 3-month period of dietary supplementation with omega-3 fatty acids to monitor the effect on heart rate variability (HRV) and arrhythmias. METHODS: The study included 17 children (mean age: 11.6⯱â¯4.9â¯years) with >1% premature ventricular contractions (PVC) at baseline. 24-h Holter ECG monitoring was performed before and after omega-3 fatty acid supplementation (mean duration: 143â¯days). RESULTS: Compared with 86 age-matched healthy control children, baseline HRV was significantly reduced and mean heart rate was significantly increased in children with frequent PVC. After omega-3-fatty acid supplementation, the mean heart rate decreased from 92.6⯱â¯3.4â¯bpm to 83.9⯱â¯9.9â¯bpm (pâ¯=â¯0.001), while global HRV showed a significant increase [standard deviation of all NN intervals (SDNN): 148.1⯱â¯34.4â¯ms vs. 126.5⯱â¯39.3â¯ms, pâ¯=â¯0.022)]. Enhanced vagal activity was indicated by significantly higher square root of the mean of the sum of the squares of differences between adjacent NN intervals (rMSSD) (42.3⯱â¯12.6 vs. 33.2⯱â¯14.8; pâ¯=â¯0.0003). PVC percentage significantly decreased by 45% (6.9⯱â¯7.0% vs. 12.1⯱â¯8.2%; pâ¯=â¯0.014). CONCLUSIONS: Omega-3-fatty acid supplementation caused a 45% reduction in frequent PVC in children with structurally healthy hearts. This antiarrhythmic effect was likely attributable to improved autonomic function, which is consistent with previous findings in children with obesity, attention deficit disorder, and short stature.
Assuntos
Efeitos Psicossociais da Doença , Suplementos Nutricionais , Eletrocardiografia Ambulatorial/efeitos dos fármacos , Eletrocardiografia Ambulatorial/tendências , Ácidos Graxos Ômega-3/administração & dosagem , Complexos Ventriculares Prematuros/dietoterapia , Adolescente , Antiarrítmicos/administração & dosagem , Criança , Feminino , Frequência Cardíaca/efeitos dos fármacos , Frequência Cardíaca/fisiologia , Humanos , Masculino , Complexos Ventriculares Prematuros/diagnóstico , Complexos Ventriculares Prematuros/fisiopatologiaRESUMO
BACKGROUND: Ivabradine increases the risk of atrial fibrillation (AF). Heart failure (HF) or sinoatrial node (SAN) dysfunction increases the risk of AF, and pulmonary veins (PVs) play a critical role in the pathophysiology of AF. This study investigated the electrophysiologic effects of ivabradine on SANs and PVs in a rabbit model of HF. METHODS AND RESULTS: Conventional microelectrodes were used to simultaneously record the electrical activities and conduction properties of control and HF rabbit SAN-PV preparations before and after perfusion with ivabradine (0.1, 1, or 10 µmol/L), either alone or with isoproterenol (1 µmol/L). HF SANs exhibited a lower beating rate than the control SANs. SAN automaticity exit blocks and SAN-PV conduction blocks were observed in 25% and 50% of samples, respectively, with P < .05 for HF SANs (nâ¯=â¯8) but not for control SANs (nâ¯=â¯6). Delayed afterdepolarization (DAD) was observed in 37.5% of HF PVs but not in control PVs. HF PVs exhibited a faster beating rate and more severe fibrosis than control PVs. Ivabradine reduced the SAN beating rates and increased the occurrences of SAN-PV conduction blocks and PV DADs in control and HF preparations. However, ivabradine induced SAN automaticity exit blocks only in HF preparations. Isoproterenol induced PV burst firing and shifting electrical conduction in control and HF preparations. A combination of isoproterenol and ivabradine (10 µmol/L) in HF preparations resulted in the highest incidences of PV burst firing and SAN-PV electrical shifting. CONCLUSIONS: HF differentially modulates the effects of ivabradine on the electrical activities of SAN and PVs, which may increase PV arrhythmogenesis and contribute to the risk of AF in HF patients.
Assuntos
Potenciais de Ação/efeitos dos fármacos , Eletrocardiografia Ambulatorial/efeitos dos fármacos , Insuficiência Cardíaca/tratamento farmacológico , Frequência Cardíaca/fisiologia , Ivabradina/farmacologia , Veias Pulmonares/fisiopatologia , Nó Sinoatrial/fisiopatologia , Animais , Fármacos Cardiovasculares/farmacologia , Modelos Animais de Doenças , Ecocardiografia , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/fisiopatologia , Frequência Cardíaca/efeitos dos fármacos , Masculino , Veias Pulmonares/efeitos dos fármacos , Coelhos , Nó Sinoatrial/efeitos dos fármacos , Volume Sistólico/efeitos dos fármacos , Volume Sistólico/fisiologiaRESUMO
PURPOSE: Phase Ib study evaluating the effect of apalutamide, at therapeutic exposure, on ventricular repolarization by applying time-matched pharmacokinetics and electrocardiography (ECG) in patients with castration-resistant prostate cancer. Safety of daily apalutamide was also assessed. METHODS: Patients received 240 mg oral apalutamide daily. Time-matched ECGs were collected via continuous 12-lead Holter recording before apalutamide (Day - 1) and on Days 1 and 57 (Cycle 3 Day 1). Pharmacokinetics of apalutamide were assessed on Days 1 and 57 at matched time points of ECG collection. QT interval was corrected for heart rate using Fridericia correction (QTcF). The primary endpoint was the maximum mean change in QTcF (ΔQTcF) from baseline to Cycle 3 Day 1 (steady state). Secondary endpoints were the effect of apalutamide on other ECG parameters, pharmacokinetics of apalutamide and its active metabolite, relationship between plasma concentrations of apalutamide and QTcF, and safety. RESULTS: Forty-five men were enrolled; 82% received treatment for ≥ 3 months. At steady state, the maximum ΔQTcF was 12.4 ms and the upper bound of its associated 90% CI was 16.0 ms. No clinically meaningful effects of apalutamide were reported for heart rate or other ECG parameters. A concentration-dependent increase in QTcF was observed for apalutamide. Most adverse events (AEs) (73%) were grade 1-2 in severity. No patients discontinued due to QTc prolongation or AEs. CONCLUSION: The effect of apalutamide on QTc prolongation was modest and does not produce a clinically meaningful effect on ventricular repolarization. The AE profile was consistent with other studies of apalutamide.
Assuntos
Eletrocardiografia Ambulatorial/efeitos dos fármacos , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/fisiopatologia , Tioidantoínas/administração & dosagem , Idoso , Idoso de 80 Anos ou mais , Antagonistas de Receptores de Andrógenos/administração & dosagem , Antagonistas de Receptores de Andrógenos/efeitos adversos , Antagonistas de Receptores de Andrógenos/farmacocinética , Frequência Cardíaca/efeitos dos fármacos , Ventrículos do Coração/efeitos dos fármacos , Ventrículos do Coração/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias de Próstata Resistentes à Castração/metabolismo , Tioidantoínas/efeitos adversos , Tioidantoínas/farmacocinéticaRESUMO
Background: Fingolimod is a sphingosine-1-phosphate receptor modulator for the treatment of relapsing-remitting multiple sclerosis (RRMS). Despite an established effect on heart rate, the effect of fingolimod on cardiac repolarization is not completely known. Methods: Twenty-seven patients with RRMS underwent 24-hr ambulatory ECG before fingolimod (baseline), at the day of fingolimod initiation (1D) and after three-month treatment (3M). The mean values of RR-interval as well as QT-interval corrected by Bazzet's (QTcBaz) and Fridericia's (QTcFri) formula were compared between baseline, 1D, and 3M over 24-hr period as well as at daytime and nighttime. Results: QTcBaz over 24-hr was shorter at 1D (414 ± 20 ms, p < .001) and at 3M (414 ± 20 ms, p < .001) than at baseline (418 ± 20 ms). In contrast, QTcFri over 24-hr was longer at 1D (410 ± 19 ms, p < .001) but similar at 3M (406 ± 19 ms, p = .355) compared to baseline (407 ± 19 ms). Daytime QTcBaz was shorter at 1D (p < .001) and at 3M (p = .007), whereas daytime QTcFri was longer at 1D (p < .05) but similar at 3M (p = ns) compared to baseline. During the night, changes were observed neither in QTcBaz nor in QTcFri between baseline, 1D, and 3M. Conclusions: Changes in cardiac repolarization after fingolimod initiation were mild and occurred at daytime. Ambiguously, QTcBaz demonstrated shortening, whereas QTcFri showed prolongation in cardiac repolarization after fingolimod initiation. The formula applied for QT-interval correction needs to be taken carefully into account as evaluating pharmacovigilance issues related to fingolimod.
Assuntos
Eletrocardiografia Ambulatorial/efeitos dos fármacos , Cloridrato de Fingolimode/farmacologia , Coração/efeitos dos fármacos , Imunossupressores/farmacologia , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/fisiopatologia , Adulto , Feminino , Coração/fisiologia , Frequência Cardíaca/efeitos dos fármacos , Frequência Cardíaca/fisiologia , Humanos , MasculinoRESUMO
BACKGROUND: We tested the hypothesis that an alpha-glucosidase inhibitor (α-GI), miglitol, is effective in protecting the cardiovascular system in type 2 diabetes mellitus (T2DM). METHODS: We studied 19 hospitalized heart disease patients with T2DM in whom we performed continuous glucose monitoring, Holter electrocardiogram, and ambulatory blood pressure (BP) monitoring simultaneously for 48h. The α-GI miglitol was administered for half of the study period by a cross-over fashion. T-wave alternans (TWA), a marker of future fatal arrhythmic events, was also analyzed by Holter ECG. RESULTS: Of the 19 patients, the measures of glucose variability were significantly lower during miglitol therapy than in control period. BP variability was similar with/without miglitol. However, TWA was significantly lower during the miglitol period compared to control period (63±4.8 vs. 75.8±5.1µV, p=0.032). CONCLUSION: An α-GI, miglitol, can reduce TWA by reducing the fluctuation of glucose in heart disease patients with T2DM.
Assuntos
1-Desoxinojirimicina/análogos & derivados , Arritmias Cardíacas/prevenção & controle , Diabetes Mellitus Tipo 2/tratamento farmacológico , Eletrocardiografia Ambulatorial/efeitos dos fármacos , Inibidores de Glicosídeo Hidrolases/uso terapêutico , 1-Desoxinojirimicina/farmacologia , 1-Desoxinojirimicina/uso terapêutico , Idoso , Glicemia/metabolismo , Pressão Sanguínea , Estudos Cross-Over , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/fisiopatologia , Feminino , Inibidores de Glicosídeo Hidrolases/farmacologia , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Users of antipsychotics (APs) have a risk of sudden cardiac death (SCD). Sudden cardiac death in such patients is thought to be largely due to drug-induced QT prolongation. It has been reported that many subjects with drug-induced torsades de pointes (TdP) have risk alleles associated with subclinical congenital long QT syndrome. METHODS: We investigated the effects of the risk alleles associated with long QT on the QT interval in patients receiving APs using 24-hour Holter electrocardiograms to take into account the circadian fluctuation of QT intervals. We investigated 8 single-nucleotide polymorphisms identified on a GWAS. RESULTS: We found that increased numbers of risk alleles at rs7188697 in NDRG4 and rs11970286 in PLN were the major predictors of an increased maximum QT interval over 24 hours in users of APs. CONCLUSIONS: It could be useful to perform a DNA-based analysis before the initiation of APs to reduce the risk of drug-induced torsades de pointes and SCD.
Assuntos
Antipsicóticos/uso terapêutico , Eletrocardiografia Ambulatorial/efeitos dos fármacos , Variação Genética/genética , Estudo de Associação Genômica Ampla/métodos , Frequência Cardíaca/genética , Esquizofrenia/genética , Adulto , Antipsicóticos/farmacologia , Eletrocardiografia Ambulatorial/tendências , Feminino , Variação Genética/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Esquizofrenia/tratamento farmacológico , Fatores de TempoRESUMO
BACKGROUND: The role of thrombolytic therapy in acute pulmonary embolism patients is still controversial considering the occurrence of arrhythmias. Short-term effects of thrombolytics are well-known whereas long-term effects on cardiac electrophysiology have not been reported before. The objective of our study was to assess the arrhythmic differences in pulmonary embolism patients who received thrombolytics followed by anticoagulation or anticoagulation alone. METHODS: Sixty patients who received thrombolytic therapy followed by anticoagulation (group 1) and 60 patients who received anticoagulation alone (group 2) were included in this retrospective, single-centre observational study. Twenty-four-hour ambulatory electrocardiography was performed 31 ± 9 months after pulmonary embolism hospitalisation in order to compare arrhythmias originating from both ventricles and atria. RESULTS: The age and gender distribution of the patients were statistically similar. Ventricular arrhythmias were found to be the same between t-PA and non t-PA groups. All types of atrial arrhythmias were found to be increased in non t-PA group even though left and right atrial volume indexes were statistically identical between the two groups. CONCLUSION: In long-term pulmonary embolism, follow-up thrombolytic therapy was demonstrated to have atrial antiarrhythmic effects.
Assuntos
Arritmias Cardíacas/fisiopatologia , Eletrocardiografia Ambulatorial/efeitos dos fármacos , Fibrinolíticos/uso terapêutico , Frequência Cardíaca/efeitos dos fármacos , Embolia Pulmonar/tratamento farmacológico , Taquicardia Ventricular/fisiopatologia , Terapia Trombolítica/métodos , Doença Aguda , Idoso , Arritmias Cardíacas/etiologia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Embolia Pulmonar/complicações , Embolia Pulmonar/fisiopatologia , Estudos Retrospectivos , Taquicardia Ventricular/etiologia , Fatores de Tempo , Resultado do TratamentoRESUMO
The QT interval of the electrocardiogram (ECG) is a measure of the duration of the ventricular depolarization and repolarization. In fish as in human, the QT interval is positively correlated with the RR interval of the ECG, a measure of the cardiac cycle length. Urotensin II (UII) is a neuropeptide that has been highly conserved from fish to human, and UII and its receptor (UT) are expressed in cardiovascular tissues including the heart. Although UII exerts potent cardiovascular actions, its possible effects on the QT interval have never been investigated. The goal of the present study was to provide insight into the potential effect of UII on the QT interval in an established in vivo trout model. To this end, the effects of UII on dorsal aortic blood pressure (PDA), RR, QT intervals and corrected QT (QTc) for RR interval, were investigated after intra-arterial (IA) injection of 5, 50 and 100 pmol UII. The effects of UII were compared to those of two structurally UII-related peptides (URPs), URP1 and URP2, and to those of arginine vasotocin (AVT), homolog of the mammalian arginine vasopressin. IA injection of vehicle or 5 pmol UII had no effect on the various parameters. At the 50-pmol dose, UII evoked its usual increase in PDA with a peak value observed 15 min after the injection (+22% from baseline, P<0.001). This hypertensive effect of UII was accompanied by a significant increase in the RR interval (+18%, P<0.001), i.e. a bradycardia, and these effects remained constant until the end of the recording. The highest dose of UII evoked similar hypertensive and bradycardic effects. Of interest, the QT interval did not change during the bradycardic action of UII (50 and 100 pmol) but the QTc interval significantly decreased. In trout pre-treated with urantide, a peptidic antagonist of UT, the hypertensive and bradycardic actions of 50 pmol UII were reduced 3-fold and no change occurred in the QT and QTc intervals. In trout pre-treated with blockers of the autonomic nervous system, the hypertensive effect of UII was maintained but no change appeared in RR, QT and QTc intervals. IA injections of 50 pmol URPs were without action on the preceding parameters. IA administration of 50 pmol AVT provoked quite similar increase in PDA, and elevation of the RR interval to those evoked by IA injection of UII but, in contrast to UII, AVT injection induced a highly significant and sustained prolongation of the QT interval compared to baseline (+7%, P<0.001) without change in QTc. Our results are indicative of a lack of QT interval change during UII-evoked bradycardia but not after AVT-induced bradycardia and suggest for the first time that some compensatory mechanism specific for the UII peptide is working to stabilize the QT interval. Further research is needed to elucidate the mechanism involved in this action of UII. The potential for UII to prevent detrimental prolongation of cardiac ventricular repolarization might be questioned.
Assuntos
Cardiotônicos/intoxicação , Modelos Animais de Doenças , Proteínas de Peixes/intoxicação , Coração/efeitos dos fármacos , Síndrome do QT Longo/induzido quimicamente , Urotensinas/intoxicação , Vasotocina/intoxicação , Animais , Aquicultura , Sistema Nervoso Autônomo/efeitos dos fármacos , Sistema Nervoso Autônomo/fisiologia , Sistema Nervoso Autônomo/fisiopatologia , Bradicardia/induzido quimicamente , Bradicardia/fisiopatologia , Bradicardia/prevenção & controle , Cardiotônicos/administração & dosagem , Cardiotônicos/química , Cardiotônicos/farmacologia , Relação Dose-Resposta a Droga , Eletrocardiografia Ambulatorial/efeitos dos fármacos , Eletrocardiografia Ambulatorial/veterinária , Feminino , Proteínas de Peixes/administração & dosagem , Proteínas de Peixes/química , Proteínas de Peixes/farmacologia , Coração/inervação , Coração/fisiologia , Coração/fisiopatologia , Hipertensão/induzido quimicamente , Hipertensão/fisiopatologia , Hipertensão/prevenção & controle , Injeções Intra-Arteriais , Síndrome do QT Longo/fisiopatologia , Síndrome do QT Longo/prevenção & controle , Masculino , Oncorhynchus mykiss , Fragmentos de Peptídeos/uso terapêutico , Urotensinas/administração & dosagem , Urotensinas/antagonistas & inibidores , Urotensinas/química , Urotensinas/farmacologia , Urotensinas/uso terapêutico , Vasotocina/administração & dosagem , Vasotocina/farmacologiaRESUMO
AIMS: Custirsen (OGX-011/TV-1011), a second-generation antisense oligonucleotide (ASO) that reduces clusterin production, is under investigation with chemotherapy in patients with solid tumours. Custirsen is associated with constitutional symptoms (CS) that may interfere with clinical pharmacology investigations, such as QT interval studies. Experience with other ASOs suggests NSAID premedication may ameliorate CS, but we observed suboptimal outcomes in healthy subjects given custirsen and NSAIDs. We sought to establish a custirsen regimen for future clinical pharmacology studies in healthy subjects. METHODS: Subjects received custirsen (640 mg intravenously over 120 min) with dexamethasone premedication or increasing doses (320, 480, 640 mg over 6 days) of custirsen with dexamethasone premedication, then one full custirsen dose without premedication on day 8. Incidence/severity of adverse events (AEs) and extensive electrocardiogram readings were evaluated. Pharmacokinetic parameters were estimated. RESULTS: AEs included CS, elevated transaminases and prolonged activated partial thromboplastin time (aPTT) that were predominantly grade 1/2. Administration of increasing custirsen doses and dexamethasone premedication reduced the incidence of CS associated with full dose custirsen. Transaminase elevation showed a dose-dependent effect (0% at days 2, 4, 27% at day 6) with the highest custirsen doses. Increasing doses of custirsen may have mitigated the severity but not incidence of aPTT prolongation. Neither regimen was associated with cardiac repolarization changes in QT values or concentration-effect analyses. The custirsen pharmacokinetic profile was consistent with previous experience. CONCLUSION: Escalation of custirsen dose combined with dexamethasone premedication reduced CS associated with full dose custirsen and should be considered in future clinical pharmacology studies of custirsen.
Assuntos
Anti-Inflamatórios/uso terapêutico , Antineoplásicos/efeitos adversos , Dexametasona/uso terapêutico , Oligonucleotídeos Antissenso/efeitos adversos , Tionucleotídeos/efeitos adversos , Adolescente , Adulto , Anti-Inflamatórios/administração & dosagem , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Estudos Cross-Over , Dexametasona/administração & dosagem , Relação Dose-Resposta a Droga , Eletrocardiografia , Eletrocardiografia Ambulatorial/efeitos dos fármacos , Voluntários Saudáveis , Humanos , Infusões Intravenosas , Síndrome do QT Longo/induzido quimicamente , Síndrome do QT Longo/diagnóstico , Masculino , Dose Máxima Tolerável , Oligonucleotídeos Antissenso/administração & dosagem , Oligonucleotídeos Antissenso/farmacocinética , Pré-Medicação , Tionucleotídeos/administração & dosagem , Tionucleotídeos/farmacocinética , Adulto JovemRESUMO
An 88-year-old man was admitted with fatigue, dizziness, and heart palpitations. Both the electrocardiogram and Holter confirmed the existence of sinus bradycardia and sinus arrest. One hour prior to the onset of symptoms, he received levobunolol hydrochloride solution topically. The levobunolol hydrochloride solution was discontinued and the bradycardia resolved. He was diagnosed as having intermittent sinus bradycardia and sinus arrest, induced by topical ß-blocker therapy. Levobunolol hydrochloride solution is an effective therapy for ocular hypertension, probably by reducing aqueous fluid production. However, it can induce cardiac side effects such as bradyarrhythmia and should be used with caution in elderly patients or patients with cardiac disease.
Assuntos
Antagonistas Adrenérgicos beta/efeitos adversos , Bradicardia/induzido quimicamente , Levobunolol/efeitos adversos , Hipertensão Ocular/tratamento farmacológico , Parada Sinusal Cardíaca/induzido quimicamente , Antagonistas Adrenérgicos beta/administração & dosagem , Idoso de 80 Anos ou mais , Bradicardia/diagnóstico , Eletrocardiografia Ambulatorial/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Humanos , Levobunolol/administração & dosagem , Masculino , Soluções Oftálmicas , Parada Sinusal Cardíaca/diagnósticoRESUMO
BACKGROUND: Guanfacine (Intuniv) is a centrally active alpha-2A adrenergic agonist for the new indication of attention-deficit/hyperactivity disorder. QTc (QTcF and QTcNi) was prolonged at both therapeutic (4 mg) and supratherapeutic (8 mg) doses of a thorough QT study even though guanfacine has had a safe clinical history of over 3 million prescriptions for the treatment of hypertension. In an attempt to understand this disparity, retrospective evaluation of the continuous ECG data utilized dynamic beat-to-beat and ECG restitution analyses was performed. METHODS: Sixty healthy subjects using 24-hour Holters were examined in a 3-arm, placebo- and positive-controlled, double-blind crossover study for effects on beat-to-beat QT, TQ, and RR intervals. RESULTS: ECG restitution analyses indicated that, at all time points, a disproportionate effect to increase the TQ interval (rest) occurred more in relationship to each QT interval lengthening resulting in a placebo-adjusted reduced QT/TQ ratio of 21% after 4 mg and 31% after 8 mg (both antiarrhythmic responses). Additionally, the percentage of time and magnitude of stress on the heart, as measured by the upper limits of the QT/TQ ratio, were reduced with guanfacine by 22% to 24%. In contrast to guanfacine, moxifloxacin did not show a significant improvement in any restitution parameters but reflected a trend toward proarrhythmia with an increase in the QT/TQ ratio of up to 11%. CONCLUSION: These results indicate that guanfacine causes a stabilizing effect on cardiac restitution that helps reconcile the clinical evidence for a lack of arrhythmia liability despite apparent increases in typical QT/QTc prolongation measures.
Assuntos
Agonistas de Receptores Adrenérgicos alfa 2/farmacologia , Arritmias Cardíacas/induzido quimicamente , Eletrocardiografia Ambulatorial/efeitos dos fármacos , Eletrocardiografia Ambulatorial/métodos , Guanfacina/farmacologia , Síndrome do QT Longo/induzido quimicamente , Estudos Cross-Over , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Fluoroquinolonas/administração & dosagem , Humanos , Masculino , Moxifloxacina , Valores de Referência , Estudos Retrospectivos , Medição de Risco/métodosAssuntos
Fibrilação Atrial/tratamento farmacológico , Benzazepinas/uso terapêutico , Eletrocardiografia Ambulatorial/efeitos dos fármacos , Idoso , Fibrilação Atrial/diagnóstico , Fibrilação Atrial/fisiopatologia , Benzazepinas/farmacologia , Eletrocardiografia Ambulatorial/tendências , Feminino , Hospitalização/tendências , Humanos , IvabradinaRESUMO
BACKGROUND: Standing invoked change in QT interval has been identified as a promising autonomic maneuver for the assessment of QT/QTc prolongation in patients with underlying heart abnormalities or as a positive control in healthy volunteers for drug studies. Criticism for its more widespread use is the high variability in reported results and the need for a more standardized methodology with defined normal ranges. METHODS: Forty healthy male subjects underwent continuous ECG collection on the day before dosing in a double-blind, placebo-controlled, randomized, single ascending dose trial. A brisk supine to standing (3 minutes) response was conducted at three time points. Results were grouped by treatment cohort or assessed as a pooled group at each time point. Maximum time and median change from baseline (ΔTmax QTcF, ΔQTcF) were calculated for each individual over sequential 30-second periods staggered by 5 seconds. RESULTS: Maximum ΔQTcF at all time points and in all groups was significant (i.e., the lower bound of 90% CI was > 5 milliseconds) which is the ICH E14 regulatory requirement for a positive control. Variability of the time to maximum response was also reduced 9-fold by the third time period. CONCLUSIONS: Standing invoked ΔQTcF can be utilized to validate the sensitivity of a study for assessment of the QT interval effect of drugs in early development. The methodology may be used to further improve its diagnostic use of long QT syndromes by reducing the variability and allowing adequate definition of normal limits.
Assuntos
Antiarrítmicos/farmacologia , Eletrocardiografia Ambulatorial/efeitos dos fármacos , Eletrocardiografia Ambulatorial/métodos , Frequência Cardíaca/fisiologia , Postura , Adolescente , Adulto , Estudos de Coortes , Relação Dose-Resposta a Droga , Método Duplo-Cego , Humanos , Masculino , Pessoa de Meia-Idade , Decúbito Dorsal , Fatores de Tempo , Adulto JovemRESUMO
BACKGROUND: Previous studies have demonstrated the presence of autonomic dysfunction in human immunodeficiency virus (HIV)-infected patients. However, the data in those receiving combination antiretroviral therapy (cART) are conflicting. The aim of this study was to assess the autonomic function using heart rate variability (HRV) and heart rate turbulence (HRT) analysis in HIV-infected patients receiving cART. METHODS: Eighty-one HIV-infected patients receiving cART and 42 control subjects were enrolled in the study. The HRV and HRT parameters were assessed on 24-hour digital Holter electrocardiogram recordings. RESULTS: Baseline characteristics were comparable between HIV-infected and control subjects, except the higher fasting glucose and triglyceride and lower high-density lipoprotein cholesterol observed in HIV-infected patients. All components of HRV were significantly reduced in HIV-infected patients. After adjustment with biochemical parameters, most of the HRV parameters were still significantly reduced in HIV-infected patients. However, HRV parameters reflecting vagal activity were no longer different between 2 groups. In addition, HRT parameters did not differ between HIV-infected and control subjects. The standard deviation of normal-to-normal intervals significantly correlated with CD4 lymphocyte counts in HIV-infected patients but did not with protease inhibitors therapy. CONCLUSIONS: We demonstrated the overall decrease in HRV in HIV-infected patients receiving cART. The metabolic disturbance observed in HIV-infected patients possibly accounted for decreased vagal activity.
Assuntos
Antirretrovirais/uso terapêutico , Infecções por HIV/tratamento farmacológico , Frequência Cardíaca/efeitos dos fármacos , Adulto , Antirretrovirais/metabolismo , Terapia Antirretroviral de Alta Atividade/métodos , Glicemia/efeitos dos fármacos , Creatinina/metabolismo , Eletrocardiografia Ambulatorial/efeitos dos fármacos , Eletrocardiografia Ambulatorial/métodos , Feminino , Infecções por HIV/metabolismo , Humanos , Metabolismo dos Lipídeos/efeitos dos fármacos , MasculinoAssuntos
Arritmias Cardíacas/induzido quimicamente , Frequência Cardíaca/efeitos dos fármacos , Nicotina/efeitos adversos , Fumar/efeitos adversos , Adulto , Morte Súbita Cardíaca/etiologia , Eletrocardiografia Ambulatorial/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Sistema Nervoso Simpático/efeitos dos fármacosRESUMO
BACKGROUND: In the long QT syndrome (LQTS) the effects of beta-blocker treatment on prevention of cardiac events differs according to the genotype. We aimed to assess the effect of beta-blocker treatment on QT/QTc duration in Type 1 LQTS (LQT1) and Type 2 LQTS (LQT2) patients. METHODS: 24-hour digital Holter ECG were recorded before and after beta-blocking therapy initiation in LQT1 (n = 30) and LQT2 patients (n = 16). QT duration was measured on consecutive 1-minute averaged QRS-T complexes leading to up to 1440 edited QT-RR pairs for each recording. We computed subject- and treatment-specific log/log QT/RR relationships which were used to correct the QT intervals. The QT duration was also evaluated at predefined heart rates and after correction using Bazett and Fridericia coefficients. RESULTS: At baseline, individual QT/RR coefficients were higher in LQT2 than in LQT1 patients (0.53 ± 0.10 vs. 0.40 ± 0.11, P < 0.001) and QT1000 was longer in LQT2 than in LQT1 patients (521 ± 38 vs. 481 ± 39 ms, P < 0.01). Beta-blockers significantly prolonged the mean RR interval (from 827 ± 161 to 939 ± 197 ms, P < 0.0001). The individual QT/RR coefficients were not significantly modified by beta-blockers. Beta-blocker treatment was associated with a prolongation of the QT1000 interval (from 481 ± 39 to 498 ± 43 ms, P < 0.01) in LQT1 patients but with a shortening in LQT2 patients (from 521 ± 38 to 503 ± 32 ms, P < 0.01). CONCLUSIONS: The effect of beta-adrenergic blockade on QTc duration is different in LQT1 and LQT2 patients. Our data suggest that, in LQT1 patients, the well-known positive effect of beta-blockade might be associated with a prolongation of QTc duration. The mechanisms of beta-blockade protection may be different in LQT1 and in LQT2 patients.
Assuntos
Antagonistas Adrenérgicos beta/administração & dosagem , Eletrocardiografia Ambulatorial/efeitos dos fármacos , Síndrome do QT Longo/tratamento farmacológico , Síndrome do QT Longo/genética , Síndrome de Romano-Ward/tratamento farmacológico , Síndrome de Romano-Ward/genética , Adulto , Análise de Variância , Estudos de Coortes , Bases de Dados Factuais , Relação Dose-Resposta a Droga , Esquema de Medicação , Eletrocardiografia/efeitos dos fármacos , Eletrocardiografia Ambulatorial/métodos , Feminino , Seguimentos , Predisposição Genética para Doença , Genótipo , Frequência Cardíaca/efeitos dos fármacos , Humanos , Síndrome do QT Longo/diagnóstico , Masculino , Pessoa de Meia-Idade , Medição de Risco , Síndrome de Romano-Ward/diagnóstico , Resultado do TratamentoRESUMO
OBJECTIVE: To investigate the influence of acid reflux on chest pain and ischemic events and the effects of cardiac drugs on acid reflux in patients with coronary artery disease (CAD) and refractory chest pain. METHODS: Simultaneous 24-hour esophageal pH monitoring and 24-hour continuous electrocardiogram (ECG) (Holter) results were obtained for 64 patients. Ischemic events and cardiac drug prescriptions were compared between the patients with and without gastroesophageal reflux disease (GERD). Patients fulfilling the GERD criteria received 14-day therapy with omeprazole at a dose of 20 mg bid. The results of the 24-hour pH monitoring, Holter and the SF-36 questionnaire were compared before treatment and again after two weeks of therapy. RESULTS: GERD was identified in 38 (69%) patients, with 49% of all chest pain occurring in association with acid reflux. A higher incidence (p=0.033) and longer duration (p=0.040) of ischemic events were observed in the GERD (+) patients. More frequent combined use of cardiac drugs was found in the GERD (+) patients. However, fewer ischemic events and greater total SF-36 survey scores were noted after PPI therapy in the GERD (+) patients. CONCLUSION: Acid reflux is common in patients with CAD and refractory chest pain. Refractory chest pain in patients with CAD can be partially noncardiac chest pain (NCCP) secondary to acid reflux. The combined use of common cardiac drugs may predispose or aggravate GERD. Short-term proton pump inhibitor (PPI) therapy not only restores a normal esophageal pH, but also significantly improves the general health-related quality of life (HRQL) of patients.
Assuntos
Dor no Peito/epidemiologia , Doença da Artéria Coronariana/epidemiologia , Refluxo Gastroesofágico/epidemiologia , Medição da Dor/métodos , Dor Intratável/epidemiologia , Adulto , Idoso , Dor no Peito/diagnóstico , Dor no Peito/tratamento farmacológico , Doença da Artéria Coronariana/diagnóstico , Doença da Artéria Coronariana/tratamento farmacológico , Eletrocardiografia Ambulatorial/efeitos dos fármacos , Eletrocardiografia Ambulatorial/métodos , Feminino , Refluxo Gastroesofágico/diagnóstico , Refluxo Gastroesofágico/tratamento farmacológico , Humanos , Masculino , Pessoa de Meia-Idade , Medição da Dor/efeitos dos fármacos , Dor Intratável/diagnóstico , Dor Intratável/tratamento farmacológico , Inibidores da Bomba de Prótons/farmacologia , Inibidores da Bomba de Prótons/uso terapêuticoRESUMO
PURPOSE: Brentuximab vedotin (ADCETRIS®), an antibody-drug conjugate, comprises an anti-CD30 antibody conjugated by a protease-cleavable linker to a microtubule-disrupting agent, monomethyl auristatin E (MMAE). In vitro studies showed that MMAE does not interfere with hERG K+ channels at clinically relevant concentrations. In pivotal phase 2 clinical trials in patients with relapsed or refractory Hodgkin lymphoma and systemic anaplastic large cell lymphoma, brentuximab vedotin has shown substantial efficacy and an acceptable safety profile. This phase 1 open-label study was designed to evaluate the effect of brentuximab vedotin on the duration of cardiac ventricular repolarization. METHODS: Patients with CD30-positive hematologic malignancies were treated with 1.8 mg/kg brentuximab vedotin by intravenous infusion every 3 weeks for up to 16 cycles. The primary endpoint was the change from baseline to Cycle 1 Days 2, 3, and 4 in the duration of ventricular repolarization using Fridericia's corrected QT interval (QTcF). RESULTS: There was no clinically meaningful change from baseline in the duration of ventricular repolarization as measured by QTcF in the 46 evaluable patients out of 52 total patients treated with brentuximab vedotin. There was no evidence of treatment-emergent cardiac safety abnormalities. Brentuximab vedotin was generally well tolerated with a response rate and an adverse event profile consistent with prior studies. CONCLUSION: There is no significant prolongation of the QT/QTc interval with brentuximab vedotin in patients with CD30-positive hematologic malignancies.
Assuntos
Antineoplásicos/efeitos adversos , Coração/efeitos dos fármacos , Neoplasias Hematológicas/tratamento farmacológico , Imunoconjugados/efeitos adversos , Antígeno Ki-1/metabolismo , Síndrome do QT Longo/induzido quimicamente , Adulto , Idoso , Antineoplásicos/sangue , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Brentuximab Vedotin , Cardiotoxinas/efeitos adversos , Cardiotoxinas/uso terapêutico , Hipersensibilidade a Drogas/imunologia , Eletrocardiografia Ambulatorial/efeitos dos fármacos , Feminino , Coração/fisiopatologia , Ventrículos do Coração/efeitos dos fármacos , Ventrículos do Coração/fisiopatologia , Neoplasias Hematológicas/sangue , Neoplasias Hematológicas/metabolismo , Neoplasias Hematológicas/fisiopatologia , Doença de Hodgkin/sangue , Doença de Hodgkin/tratamento farmacológico , Doença de Hodgkin/metabolismo , Doença de Hodgkin/fisiopatologia , Humanos , Imunoconjugados/sangue , Imunoconjugados/farmacocinética , Imunoconjugados/uso terapêutico , Antígeno Ki-1/sangue , Síndrome do QT Longo/fisiopatologia , Masculino , Pessoa de Meia-Idade , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/fisiopatologia , Índice de Gravidade de Doença , Adulto JovemRESUMO
BACKGROUND: In parallel thorough QT (TQT) studies, it has been speculated that either baseline correction should be omitted, under the assumption that it only adds noise to the data, or a time-averaged baseline instead of a time-matched baseline correction should be considered in order to reduce the study variability. OBJECTIVE: This study characterized the assumptions and implications of different baseline correction approaches in parallel TQT studies submitted for regulatory review. DATA AND METHODS: 57 parallel TQT studies conducted between 2002 and 2009 in 5591 healthy volunteers were evaluated. Only moxifloxacin and placebo arms, including their baselines, were considered. The options of using no baseline correction, time-averaged baseline correction, and time-matched baseline correction were examined and compared. RESULTS: QTc values exhibited a diurnal pattern, with longer QTc intervals during sleep preserved when correcting for a time-averaged baseline. Post-dose and baseline QTc values were highly correlated (mean ρ = 0.80, range 0.56-0.98 and mean ρ = 0.79, range 0.50-0.96 in the placebo and moxifloxacin groups, respectively). The variability of raw QTc values was substantially larger than that of baseline-adjusted QTc values. The difference in the point estimate of QTc differences between moxifloxacin and placebo differed by up to ± 4 ms between the time-averaged and the time-matched baseline corrections. Statistical tests indicate that assumptions of time-averaged baseline and no baseline correction are not appropriate. CONCLUSIONS: Baseline correction in parallel TQT studies leads to more precise QTc estimates. Because of possible inaccuracy introduced by time-averaged baseline correction, the time-matched baseline correction appears to be preferable for a parallel TQT study to both reduce the intrinsic variability due to circadian patterns and obtain more accurate point estimates.