Drug-Induced QT Prolongation in Women During the Menstrual Cycle

Rodríguez, I.; Kilborn, Michael J.; Liu, Xiao Ke; Pezzullo, John C.; Woosley, Raymond L.

doi:10.1001/jama.285.10.1322

Cited by 284 publications

(220 citation statements)

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“…Thus, P4 may not be able to further impair the blocked trafficking of the mutated HERG channels in the inherited LQTS patients. For this reason, our results may also explain why the incidence of arrhythmias is not higher in pregnancy than in other periods in the life of the LQTS patients (3,13).…”

Section: Discussionmentioning

confidence: 60%

“…6 -4.5 nmol/liter during the preovulatory phase to 10.5-80 nmol/liter during the luteal phase (1). It was reported that P4 at Ͻ100 nmol/liter, which is comparable with that occurring during the luteal phase, had no significant effect on the QT interval (2)(3)(4). However, recent studies show that P4 may shorten the action potential duration or QT interval (5).…”

mentioning

confidence: 98%

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Progesterone Impairs Human Ether-a-go-go-related Gene (HERG) Trafficking by Disruption of Intracellular Cholesterol Homeostasis

Soong

et al. 2011

Journal of Biological Chemistry

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The prolongation of QT intervals in both mothers and fetuses during the later period of pregnancy implies that higher levels of progesterone may regulate the function of the human ether-ago-go-related gene (HERG) potassium channel, a key ion channel responsible for controlling the length of QT intervals. Here, we studied the effect of progesterone on the expression, trafficking, and function of HERG channels and the underlying mechanism. Treatment with progesterone for 24 h decreased the abundance of the fully glycosylated form of the HERG channel in rat neonatal cardiac myocytes and HERG-HEK293 cells, a cell line stably expressing HERG channels. Progesterone also concentration-dependently decreased HERG current density, but had no effect on voltage-gated L-type Ca Progesterone (P4) 2 is an important steroid hormone involved in the female menstrual cycle, pregnancy, and embryogenesis. In the normal menstrual cycle, P4 levels increase from 0.6 -4.5 nmol/liter during the preovulatory phase to 10.5-80 nmol/liter during the luteal phase (1). It was reported that P4 at Ͻ100 nmol/liter, which is comparable with that occurring during the luteal phase, had no significant effect on the QT interval (2-4). However, recent studies show that P4 may shorten the action potential duration or QT interval (5). This is probably because P4 at this level enhances the rapid component of the delayed rectifier K ϩ current and inhibits L-type Ca 2ϩ currents (6). If pregnancy occurs, P4 levels are initially maintained at the luteal level, but may increase to 1 mol/liter at term (7). Elevated levels of P4 are important for the implantation of the embryo and the maintenance of a conducive environment for the embryo. At such a high level, the corrected QT interval is significantly prolonged (8, 9). This explains why pregnant women are more susceptible to ventricular arrhythmias during pregnancy, labor, and delivery (10 -12). However, it is interesting to note that in the patients with inherited long QT syndrome (LQTS) the risk for cardiac events is not higher during pregnancy than during other periods in life (10, 13). These findings suggest that the mechanisms for pregnancy-induced cardiac events in normal healthy women are different from those in the patients with inherited LQTS.In the fetus, the P4 level was reported to be very high (ϳ4.5 mol/liter) in umbilical cord vein during late stages of pregnancy (7). At this stage, longer QT and corrected QT intervals were reported in fetal magnetocardiography and noninvasive fetal electrocardiography (14, 15). More importantly, the rate of sudden death is higher in the uterus than at most other times in the human life cycle. Although the major reasons remain unknown, several studies of newborns suggest that QT prolongation and the increased risk of ventricular arrhythmias may account for the significant mortality (16,17). This may be the same for stillbirth as several case reports indicate that LQTS is one cause for otherwise unexplained fetal demise (18).The human ether-a-go-go-related gene (HE...

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Section: Discussionmentioning

confidence: 60%

mentioning

confidence: 98%

Progesterone Impairs Human Ether-a-go-go-related Gene (HERG) Trafficking by Disruption of Intracellular Cholesterol Homeostasis

Soong

et al. 2011

Journal of Biological Chemistry

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“…Insbesondere können Östrogene zu einer Verlänge-rung der QT-Strecke führen. Wie Rodriguez und Mitarbeiter unter der Behandlung mit QT-Intervall-verlängernden Medikamenten zeigen konnten, tritt dieser Effekt besonders in der ersten Zyklushälfte auf [73]. Zwar sterben Frauen statistisch gesehen immer noch seltener am plötzlichen Herztod, das Risiko einer QTVerlängerung unter der Behandlung mit AP ist für Frauen und hier besonders in der ersten Zyklushälfte, aber deutlich erhöht [7].…”

Section: Qtc-zeitverlängerung Und Herzrhythmusstörungenunclassified

Neuere Antipsychotika

et al. 2007

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In this review we investigate whether sex differences exist for side effects of second-generation antipsychotics. Results are based on a MEDLINE search for the years 1974 through 2005. Even if pharmacokinetics differ between females and males, significantly higher plasma levels for women have been demonstrated only for olanzapine and clozapine. Hyperprolactinaemia is mainly induced by treatment with risperidone and amisulpride, and there is evidence for more pronounced prolactin levels in females. Most studies reviewed indicate that clozapine and olanzapine are associated with more body weight gain, once more especially in female patients. Furthermore, the few published studies indicate that metabolic syndrome is more frequent in females and there are likely no gender-specific differences between the new antipsychotic medications concerning frequency and degree of acute or chronic movement disturbance. The risk of QT prolongation with torsades de pointes arrhythmia is again higher in females. In conclusion, there is some evidence of sex differences in the side effects of second-generation antipsychotics. For better understanding of the basic mechanisms in sex differences, future studies with a primary focus on this topic are required. More specific data will help to determine how these differences shall affect clinical management.

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“…Dieser geschlechtsspezifische Unterschied lässt sich am isolierten Kaninchenherzen nachweisen [45]. Ferner unterliegt die Sensibilität der weiblichen Herzreizleitung einer Zyklusabhängigkeit [46]. Bei Frauen ist nicht nur die Herzreizleitung, sondern auch das zentrale Nervensystem für bestimmte Nebenwirkungen empfindlicher.…”

Section: Geschlechtsspezifische Unterschiede In Der Pharmakodynamik Uunclassified

Geschlechtsspezifische Unterschiede in der Pharmakokinetik und -dynamik von Arzneimitteln

Thürmann

2005

Bundesgesundheitsbl - Gesundheitsf - Gesundheitsschutz

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Following the negative experience with thalidomide, women were excluded from participation in clinical trials with new pharmaceutical agents as far as possible, especially from phase I studies. However, in the early 1990s a body of evidence accumulated suggesting clinically relevant gender-related differences in the efficacy and safety of drugs. Gender-related differences have been shown for the metabolism and the effects of drugs. Gender differences have been described especially for the enzymes of the cytochrome P 450 family, but also for phase II reactions and most recently for P-glycoprotein. Most of these differences observed are only of minor clinical relevance, however may result in an increased rate of adverse drug reactions. Further differences may be based on different receptor/target sensitivities, e. g. the increased sensitivity for drug-induced torsade de pointes arrhythmia in women. In addition, in complex diseases such as heart failure, men and women may develop different mechanisms of counter- regulation requiring different therapeutic approaches. Population-based approaches demonstrate gender differences in the incidence of adverse drug reactions.

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Drug-Induced QT Prolongation in Women During the Menstrual Cycle

Abstract: Menstrual cycle and sex differences exist in QTc responses to ibutilide, with the greatest increase in QTc corresponding to the first half of the menstrual cycle.

Cited by 284 publications

References 20 publications

Progesterone Impairs Human Ether-a-go-go-related Gene (HERG) Trafficking by Disruption of Intracellular Cholesterol Homeostasis

Progesterone Impairs Human Ether-a-go-go-related Gene (HERG) Trafficking by Disruption of Intracellular Cholesterol Homeostasis

Neuere Antipsychotika

Geschlechtsspezifische Unterschiede in der Pharmakokinetik und -dynamik von Arzneimitteln

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