Molecular Basis of Chronopharmaceutics

Ohdo, Shigehiro; Koyanagi, Satoru; Matsumoto, Naoya; Hamdan, Ahmed M.

doi:10.1002/jps.22656

Cited by 31 publications

(32 citation statements)

References 106 publications

(166 reference statements)

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“…3B; Table S1). Furthermore, the effects of rivaroxaban on prolongation of thrombin generation lag time and prolongation of the time to the peak of thrombin generation were significantly greater than those of apixaban for all measured parameters (E max , AUC 0-12 , AUC [12][13][14][15][16][17][18][19][20][21][22][23][24] , and AUC 0-24 ; Figs 4 and 5; Table S1). At time points 36 h and 48 h after the last dose of rivaroxaban (equivalent to 24 h and 36 h after the last dose of apixaban), the inhibitory effects of rivaroxaban on the peak and time to peak of thrombin generation were significantly greater than those of apixaban (Table S2).…”

Section: Thrombin Generationmentioning

confidence: 92%

“…During the time period 0-12 h after the last dose of rivaroxaban and the morning dose of apixaban, the inhibitory effects of rivaroxaban on ETP relative to baseline were significantly greater than those of apixaban (AUC 0-12 , 6.36 h for rivaroxaban and 8.69 h for apixaban; Table S1). In the time period 12-24 h after the last dose of rivaroxaban and 0-12 h after the last (evening) dose of apixaban (AUC [12][13][14][15][16][17][18][19][20][21][22][23][24] ), the effects of rivaroxaban and apixaban on inhibition of ETP were similar (Table S1). Rivaroxaban also showed significantly greater suppression of the peak of thrombin generation during the 0-24-h dosing interval (AUC 0-24 , 6.59 h for rivaroxaban and 7.84 h for apixaban; Fig.…”

Section: Thrombin Generationmentioning

confidence: 92%

“…AUC 0-12 represents the time period 0-12 h after the last dose of rivaroxaban and the morning dose of apixaban, AUC [12][13][14][15][16][17][18][19][20][21][22][23][24] represents the time periods 12-24 h after the last dose of rivaroxaban and 0-12 h after the evening dose of apixaban and AUC 0-24 represents the 24-h time period after the last dose of rivaroxaban and the morning dose of apixaban. Relative changes from baseline were investigated for all PD parameters, except anti-FXa activity, for which absolute values were evaluated.…”

Section: Pd Assessmentsmentioning

confidence: 99%

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Dissociation between the pharmacokinetics and pharmacodynamics of once‐daily rivaroxaban and twice‐daily apixaban: a randomized crossover study

Kreutz

Persson

Kubitza

et al. 2017

Journal of Thrombosis and Haemostasis

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In this crossover study the anticoagulant effects of rivaroxaban and apixaban were compared. Healthy volunteers received rivaroxaban 20 mg once daily or apixaban 5 mg twice daily. Rivaroxaban was associated with more prolonged inhibition of thrombin generation than apixaban. Rivaroxaban induced a clear prolongation of prothrombin time and activated partial thromboplastin time. Summary BackgroundThe anticoagulant actions of the oral direct activated factor Xa inhibitors, rivaroxaban and apixaban, have not previously been directly compared. ObjectivesTo compare directly the steady‐state pharmacokinetics and anticoagulant effects of rivaroxaban and apixaban at doses approved for stroke prevention in patients with non‐valvular atrial fibrillation. MethodsTwenty‐four healthy Caucasian male volunteers were included in this open‐label, two‐period crossover, phase 1 study (EudraCT number: 2015‐002612‐32). Volunteers were randomized to receive rivaroxaban 20 mg once daily or apixaban 5 mg twice daily for 7 days, followed by a washout period of at least 7 days before they received the other treatment. Plasma concentrations and anticoagulant effects were measured at steady state and after drug discontinuation. ResultsOverall exposure was similar for both drugs: the geometric mean area under the plasma concentration–time curve for the 0–24‐h interval was 1830 μg h L−1 for rivaroxaban and 1860 μg h L−1 for apixaban. Rivaroxaban was associated with greater inhibition of endogenous thrombin potential (geometric mean area under the curve relative to baseline during the 0–24‐h interval: 15.5 h versus 17.5 h) and a more pronounced maximal prolongation relative to baseline of prothrombin time (PT) (1.66‐fold versus 1.14‐fold) and activated partial thromboplastin time (APTT) (1.43‐fold versus 1.16‐fold) at steady state than apixaban. ConclusionsDespite similar exposure to both drugs, rivaroxaban 20 mg once daily was associated with greater and more sustained inhibition of thrombin generation than apixaban 5 mg twice daily. Sensitive PT and APTT assays can be used to estimate the anticoagulant effects of rivaroxaban.

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Section: Thrombin Generationmentioning

confidence: 92%

Section: Thrombin Generationmentioning

confidence: 92%

Section: Pd Assessmentsmentioning

confidence: 99%

See 1 more Smart Citation

Dissociation between the pharmacokinetics and pharmacodynamics of once‐daily rivaroxaban and twice‐daily apixaban: a randomized crossover study

Kreutz

Persson

Kubitza

et al. 2017

Journal of Thrombosis and Haemostasis

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“…The master clock in the suprachiasmatic nuclei of the anterior hypothalamus in mammals is entrained to a 24-hour period by the daily light/ dark cycle. The master clock, in turn, synchronizes circadian oscillators in other brain regions and many peripheral tissues through neural and/or hormonal signals (Ohdo et al, 2011;Paul and Etienne, 2011). Synchronized oscillators in peripheral tissues drive energy metabolism, cell division, hormonal secretion, and immune response (Matsuo et al, 2003;Ishida et al, 2005;Shimba et al, 2005;Hashiramoto et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

Molecular Mechanism Regulating 24-Hour Rhythm of Dopamine D3 Receptor Expression in Mouse Ventral Striatum

et al. 2013

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The dopamine D3 receptor (DRD3) in the ventral striatum is thought to influence motivation and motor functions. Although the expression of DRD3 in the ventral striatum has been shown to exhibit 24-hour variations, the mechanisms underlying the variation remain obscure. Here, we demonstrated that molecular components of the circadian clock act as regulators that control the 24-hour variation in the expression of DRD3. The transcription of DRD3 was enhanced by the retinoic acid-related orphan receptor a (RORa), and its activation was inhibited by the orphan receptor REV-ERBa, an endogenous antagonist of RORa. The serum or dexamethasone-induced oscillation in the expression of DRD3 in cells was abrogated by the downregulation or overexpression of REV-ERBa, suggesting that REV-ERBa functions as a regulator of DRD3 oscillations in the cellular autonomous clock. Chromatin immunoprecipitation assays of the DRD3 promoter indicated that the binding of the REVERBa protein to the DRD3 promoter increased in the early dark phase. DRD3 protein expression varied with higher levels during the dark phase. Moreover, the effects of the DRD3 agonist 7-hydroxy-N,N-dipropyl-2-aminotetralin (7-OH-DPAT)-induced locomotor hypoactivity were significantly increased when DRD3 proteins were abundant. These results suggest that RORa and REV-ERBa consist of a reciprocating mechanism wherein RORa upregulates the expression of DRD3, whereas REV-ERBa periodically suppresses the expression at the time of day when REV-ERBa is abundant. Our present findings revealed that a molecular link between the circadian clock and the function of DRD3 in the ventral striatum acts as a modulator of the pharmacological actions of DRD3 agonists/antagonists.

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“…[1][2][3][4] The circadian clock systems also affect the efficacy of medication by influencing the pharmacokinetics and/or pharmacodynamics of the drug. [5][6][7] The efficacy of various drugs varies according to the dosing time. 8) It is important to consider the chronopharmacological profiles of each drug in order to provide effective medication.…”

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confidence: 99%

Chronopharmacological Analysis of Antidepressant Activity of a Dual-Action Serotonin Noradrenaline Reuptake Inhibitor (SNRI), Milnacipran, in Rats

Kawai

Machida

Ishibashi

et al. 2018

Biological & Pharmaceutical Bulletin

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Biological rhythms are thought to be related to the pathogenesis and therapy of various diseases including depression. Here we investigated the influence of circadian rhythms on the antidepressant activity of the dual-action serotonin-noradrenaline reuptake inhibitor (SNRI) milnacipran. Rats administered milnacipran in the morning (8:00 a.m.; zeitgeber time [ZT]1) or in the evening (8:00 p.m.; ZT13) were analyzed in a forced swim test (FST). At ZT1, the rats' immobility was reduced and the swimming was increased, whereas at ZT13, their climbing was increased. These results suggest that the serotonergic and noradrenergic systems are preferentially affected at ZT1 and ZT13, respectively by milnacipran. We analyzed the plasma and brain levels of milnacipran after administration, and there were no differences between ZT1 and ZT13. The circadian rhythm of monoamine neurotransmitters was analyzed in several brain regions. The serotonin turnover showed rhythms with a peak during ZT18-ZT22 in hippocampus. The noradrenaline turnover showed rhythms with a peak during ZT22-ZT2. There was a difference of approx. 4 h between the serotonergic and noradrenergic systems. This time difference might be one of the factors that affect the action of milnacipran and contribute to the dosing time-dependent behavioral pattern in the FST.Key words circadian rhythm; antidepressant; forced swim test; milnacipran; serotonin; noradrenaline Many physiological functions have a rhythm with a period of 24 h. In mammals, circadian clock systems govern almost all organs, and they affect the pathophysiology of various diseases such as cancer, cardiovascular diseases, and psychiatric diseases.1-4) The circadian clock systems also affect the efficacy of medication by influencing the pharmacokinetics and/or pharmacodynamics of the drug.5-7) The efficacy of various drugs varies according to the dosing time.8) It is important to consider the chronopharmacological profiles of each drug in order to provide effective medication.Depression is one of the diseases thought to be affected by the circadian system. Depressive symptoms relate to the chronotype, 9) the symptoms of the depression show diurnal variations, 10) certain types of depression are developed according to the length of daylight, 11) and the modification of the circadian systems is sometimes effective for treating patients.12-14) The monoamine hypothesis proposes that the reduction of monoamine systems in the brain causes depression. However, the interactions between the circadian system and various pathophysiologies are not yet thoroughly understood.Many therapeutic drugs have been developed for depression, and various drugs such as tricyclic antidepressants, selective serotonin reuptake inhibitors (SSRIs), and serotoninnoradrenaline reuptake inhibitors (SNRIs) are currently used in clinical settings. Most of these drugs modify the monoaminergic systems in the brain to exert their antidepressant activity.In rodent models used to assess the effectiveness of antidepressants, the forced swim te...

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Molecular Basis of Chronopharmaceutics

Cited by 31 publications

References 106 publications

Dissociation between the pharmacokinetics and pharmacodynamics of once‐daily rivaroxaban and twice‐daily apixaban: a randomized crossover study

Dissociation between the pharmacokinetics and pharmacodynamics of once‐daily rivaroxaban and twice‐daily apixaban: a randomized crossover study

Molecular Mechanism Regulating 24-Hour Rhythm of Dopamine D3 Receptor Expression in Mouse Ventral Striatum

Chronopharmacological Analysis of Antidepressant Activity of a Dual-Action Serotonin Noradrenaline Reuptake Inhibitor (SNRI), Milnacipran, in Rats

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