Extent of asleep blood pressure reduction by hypertension medications is ingestion-time dependent: Systematic review and meta-analysis of published human trials

Hermida, Ramón C.; Mojón, Artemio; Hermida-Ayala, Ramón G.; Smolensky, Michael H.; Fernández, José R.

doi:10.1016/j.smrv.2021.101454

Cited by 26 publications

(26 citation statements)

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“…Our results show that further refinement can be achieved considering circadian oscillations in the expression of drug targets and associated pathway components. The correct timing of drug dose has been a largely underappreciated factor in established therapeutic schemes for most diseases [ 63 ], improving therapeutic outcomes as in hypertension [ 64 ]. This becomes particularly important in cancer treatment, where the therapeutic window of most drugs is generally narrow and there is a need to optimize therapeutic outcomes minimizing the associated side effects [ 65 ].…”

Section: Discussionmentioning

confidence: 99%

Timing of Novel Drug 1A-116 to Circadian Rhythms Improves Therapeutic Effects against Glioblastoma

et al. 2021

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The Ras homologous family of small guanosine triphosphate-binding enzymes (GTPases) is critical for cell migration and proliferation. The novel drug 1A-116 blocks the interaction site of the Ras-related C3 botulinum toxin substrate 1 (RAC1) GTPase with some of its guanine exchange factors (GEFs), such as T-cell lymphoma invasion and metastasis 1 (TIAM1), inhibiting cell motility and proliferation. Knowledge of circadian regulation of targets can improve chemotherapy in glioblastoma. Thus, circadian regulation in the efficacy of 1A-116 was studied in LN229 human glioblastoma cells and tumor-bearing nude mice. Methods. Wild-type LN229 and BMAL1-deficient (i.e., lacking a functional circadian clock) LN229E1 cells were assessed for rhythms in TIAM1, BMAL1, and period circadian protein homolog 1 (PER1), as well as Tiam1, Bmal1, and Rac1 mRNA levels. The effects of 1A-116 on proliferation, apoptosis, and migration were then assessed upon applying the drug at different circadian times. Finally, 1A-116 was administered to tumor-bearing mice at two different circadian times. Results. In LN229 cells, circadian oscillations were found for BMAL1, PER1, and TIAM1 (mRNA and protein), and for the effects of 1A-116 on proliferation, apoptosis, and migration, which were abolished in LN229E1 cells. Increased survival time was observed in tumor-bearing mice when treated with 1A-116 at the end of the light period (zeitgeber time 12, ZT12) compared either to animals treated at the beginning (ZT3) or with vehicle. Conclusions. These results unveil the circadian modulation in the efficacy of 1A-116, likely through RAC1 pathway rhythmicity, suggesting that a chronopharmacological approach is a feasible strategy to improve glioblastoma treatment.

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Section: Discussionmentioning

confidence: 99%

Timing of Novel Drug 1A-116 to Circadian Rhythms Improves Therapeutic Effects against Glioblastoma

et al. 2021

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“…The augmented reduction of the asleep SBP mean by the bedtime/evening treatment schedule was greater for individuals at highest CVD risk, i.e., non-dipper (8.30 mmHg [6.39, 10.21], P < 0.01), diabetic, chronic kidney disease (CKD), and previous CVD-event patients (7.99 mmHg [3.03, 12.95], P < 0.01), than uncomplicated (absence of such diagnoses/medical history) lower CVD risk hypertensive patients (4.20 mmHg [3.09, 5.31], P < 0.01). Furthermore, none of the ABPM-based hypertension monotherapy trials reported the conventional morning-time treatment schedule to be more beneficial than the bedtime/evening treatment one; 51 (82.3%) of the 62 ABPM-based trials disclosed significantly enhanced advantages of the bedtime/evening schedule of treatment, while the other 11 (17.7%) trials showed non-inferiority of it in comparison to the morning one ( Hermida et al., 2021b , 2021c ).…”

Section: Circadian Rhythms As Mediators Of Cardiovascular Ddimentioning

confidence: 99%

“…Studies show that the PD of therapies are not solely dependent on the rhythm-influenced PK but also different rhythms that affect the: (i) concentration of the circulating drug free-fraction and the receptor number/conformation and second messengers/signaling pathways of their cell/tissue targets, which for antihypertension medications include directly or indirectly the blood vessels of the general circulation and the heart, brain, and kidney tissues; and (ii) mechanisms precisely organized in time that regulate the 24 h BP pattern, particularly the ANS and RAAS ( Smolensky et al., 2017a ). Thus, it should not be surprising that the time, with reference to the staging of deterministic circadian rhythms, when BP-lowering drugs are ingested impacts the extent of the beneficial effect exerted in normalizing the 24 h BP profile of hypertension and also the risk for adverse effects ( Hermida et al., 2021b , 2021c ).…”

Section: Circadian Rhythms As Mediators Of Cardiovascular Ddimentioning

confidence: 99%

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Pharmacogenomics and circadian rhythms as mediators of cardiovascular drug-drug interactions

Geng

Madonna

Hermida

et al. 2021

Current Research in Pharmacology and Drug Discovery

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This article summarizes the current literature and documents new evidence concerning drug-drug interactions (DDI) stemming from pharmacogenomic and circadian rhythm determinants of therapies used to treat common cardiovascular diseases (CVD), such as atherosclerosis and hypertension. Patients with CVD often have more than one pathophysiologic condition, namely metabolic syndromes, hypertension, hyperlipidemia, and hyperglycemia, among others, which necessitate polytherapeutic or polypharmaceutic management. Interactions between drugs, drugs and food/food supplements, or drugs and genetic/epigenetic factors may have adverse impacts on the cardiovascular and other systems of the body. The mechanisms underlying cardiovascular DDI may involve the formation of a complex pharmacointeractome, including the absorption, distribution, metabolism, and elimination of drugs, which affect their respective bioavailability, efficacy, and/or harmful metabolites. The pharmacointeractome of cardiovascular drugs is likely operated with endogenous rhythms controlled by circadian clock genes. Basic and clinical investigations have improved the knowledge and understanding of cardiovascular pharmacogenomics and pharmacointeractomes, and additionally they have presented new evidence that the staging of deterministic circadian rhythms, according to the dosing time of drugs, e.g., upon awakening vs. at bedtime, cannot only differentially impact their pharmacokinetics and pharmacodynamics but also mediate agonistic/synergetic or antagonistic DDI. To properly manage CVD patients and avoid DDI, it is important that clinicians have sufficient knowledge of their multiple risk factors, i.e., age, gender, and life style elements (like diet, smoking, psychological stress, and alcohol consumption), and comorbidities, such as diabetes, hypertension, dyslipidemia, and depression, and the potential interactions between genetic or epigenetic background of their prescribed therapeutics.

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“…Thus, in PD models that include BP circadian rhythm, a baseline BP function must be established prior to estimating PD parameters, as was early described by Hempel et al [ 18 ]. Moreover, previous works indicate that not only the pharmacodynamics is altered by mechanisms of circadian variation but also the pharmacokinetic processes, mainly those administered orally [ 19 ]. However, circadian variation has not been included in PK models of antihypertensive medications.…”

Section: Introductionmentioning

confidence: 99%

Dosing time optimization of antihypertensive medications by including the circadian rhythm in pharmacokinetic-pharmacodynamic models

2022

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Blood pressure (BP) follows a circadian variation, increasing during active hours, showing a small postprandial valley and a deeper decrease during sleep. Nighttime reduction of 10–20% relative to daytime BP is defined as a dipper pattern, and a reduction of less than 10%, as a non-dipper pattern. Despite this BP variability, hypertension’s diagnostic criteria and therapeutic objectives are usually based on BP average values. Indeed, studies have shown that chrono-pharmacological optimization significantly reduces long-term cardiovascular risk if a BP dipper pattern is maintained. Changes in the effect of antihypertensive medications can be explained by circadian variations in their pharmacokinetics (PK) and pharmacodynamics (PD). Nevertheless, BP circadian variation has been scarcely included in PK-PD models of antihypertensive medications to date. In this work, we developed PK-PD models that include circadian rhythm to find the optimal dosing time (Ta) of first-line antihypertensive medications for dipper and non-dipper patterns. The parameters of the PK-PD models were estimated using global optimization, and models were selected according to the lowest corrected Akaike information criterion value. Simultaneously, sensitivity and identifiability analysis were performed to determine the relevance of the parameters and establish those that can be estimated. Subsequently, Ta parameters were optimized to maximize the effect on BP average, BP peaks, and sleep-time dip. As a result, all selected models included at least one circadian PK component, and circadian parameters had the highest sensitivity. Furthermore, Ta with which BP>130/80 mmHg and a dip of 10–20% are achieved were proposed when possible. We show that the optimal Ta depends on the therapeutic objective, the medication, and the BP profile. Therefore, our results suggest making chrono-pharmacological recommendations in a personalized way.

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Extent of asleep blood pressure reduction by hypertension medications is ingestion-time dependent: Systematic review and meta-analysis of published human trials

Cited by 26 publications

References 90 publications

Timing of Novel Drug 1A-116 to Circadian Rhythms Improves Therapeutic Effects against Glioblastoma

Timing of Novel Drug 1A-116 to Circadian Rhythms Improves Therapeutic Effects against Glioblastoma

Pharmacogenomics and circadian rhythms as mediators of cardiovascular drug-drug interactions

Dosing time optimization of antihypertensive medications by including the circadian rhythm in pharmacokinetic-pharmacodynamic models

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