chronopharmacology

BACKGROUND: Chronopharmacology takes into account, among other things, the circadian rhythm, a recurring, daily rhythm of biological functions that is significantly influenced by the day-night rhythm. Daily rhythm, diseases, and therapies influence each other: the circadian rhythm, among other factors, could influence the effect of pharmacological and nonpharmacological therapies, especially in urological oncology. AIM: This article focuses on the question of the optimal time for therapeutic interventions and considers relevant basics of chronobiological principles depending on possible biomarkers that could be targets of a future therapeutic approach...

Clock genes, circadian pacemaker resides in the paired suprachiasmatic nuclei (SCN), control various circadian rhythms in many biological processes such as physiology and behavior. Clock gene regulates many diseases such as cancer, immunological dysfunction, metabolic syndrome and sleep disorders etc. Chronotherapy is especially relevant, when the risk and/or intensity of the symptoms of disease vary predicably over time as exemplified by allergic rhinitis, arthritis, asthma, myocardial infarction, congestive heart failure, stroke, and peptic ulcer disease...

Introduction: The master clock, which is located in the suprachiasmatic nucleus (SCN), harmonizes clock genes present in the liver to synchronize life rhythms and bioactivity with the surrounding environment. The reversed feeding disrupts the expression of clock genes in the liver. Recently, a novel role of PPAR- γ as a regulator in correlating circadian rhythm and metabolism was demonstrated. This study examined the influence of PPAR- γ agonist pioglitazone (PG) on the mRNA expression profile of principle clock genes and inflammation-related genes in the mouse liver disrupted by reverse feeding...

Various in vitro model systems have been established over the last decades to understand physiological processes, the causalities of diseases and the response of humans to environmental and industrial chemicals or therapeutic drugs. Common to all is a limited biological significance due to the impairment of functionality, for instance by the lack of physiological 3D tissue architecture or the loss of fundamental regulatory mechanisms including the circadian rhythm. The circadian rhythm is an adaption of living organisms to rhythmic environmental changes of the day-night cycle and coordinates behavior as well as various crucial physiological processes in a 24-hour pattern...

The circadian system is an innate clock mechanism that governs biological processes on a near 24-hour cycle. Circadian rhythm disruption (i.e., misalignment of circadian rhythms), which results from the lack of synchrony between the master circadian clock located in the suprachiasmatic nuclei (SCN) and the environment (i.e., exposure to day light) or the master clock and the peripheral clocks, has been associated with increased risk of and unfavorable cancer outcomes. Growing evidence supports the link between circadian disruption and increased prevalence and mortality of genitourinary cancers (GU) including prostate, bladder, and renal cancer...

Liver homeostasis is strongly influenced by the circadian clock, an evolutionarily conserved mechanism synchronising physiology and behaviour across a 24-hour cycle. Disruption of the clock has been heavily implicated in the pathogenesis of metabolic dysfunction including non-alcoholic fatty liver (NAFL) and non-alcoholic steatohepatitis (NASH). Furthermore, many of the current NASH drug candidates specifically target pathways known to be under circadian control including fatty acid synthesis and signalling via the farnesoid X receptor, fibroblast growth factor 19 and 21, peroxisome proliferator-activated receptor α and γ, glucagon-like peptide 1, and the thyroid hormone receptor...

Dosing time-dependency of pharmacokinetics (or chronopharmacokinetics) has been long recognized. Studies in recent years have revealed that daily rhythmicity in expression of drug-metabolizing enzymes and transporters (DMETs) are key factors determining chronopharmacokinetics. In this article, we briefly summarize current knowledge with respect to circadian mechanisms of DMETs and discuss how rhythmic DMETs are translated to drug chronoeffects. More importantly, we present our perspectives on pharmacokinetics-based chronotherapy...

Glycolysis is considered a main metabolic pathway in highly proliferative cells, including endothelial, epithelial, immune, and cancer cells. Although oxidative phosphorylation (OXPHOS) is more efficient in ATP production per mole of glucose, proliferative cells rely predominantly on aerobic glycolysis, which generates ATP faster compared to OXPHOS and provides anabolic substrates to support cell proliferation and migration. Cellular metabolism, including glucose metabolism, is under strong circadian control...

The pharmacodynamics of hypertension medications can be significantly affected by circadian rhythms in the biological mechanisms of the 24 h blood pressure (BP) pattern. Hypertension guidelines fail to recommend the time of day when patients, including those who require treatment with multiple medications, are to ingest BP-lowering therapy. We conducted a systematic review of published prospective trials that investigated hypertension medications for ingestion-time differences in BP-lowering, safety, patient adherence, and markers of target organ pathology...

An often overlooked element of pulmonary vascular disease is time. Cellular responses to time, which are regulated directly by the core circadian clock, have only recently been elucidated. Despite an extensive collection of data regarding the role of rhythmic contribution to disease pathogenesis (such as systemic hypertension, coronary artery, and renal disease), the roles of key circadian transcription factors in pulmonary hypertension remain understudied. This is despite a large degree of overlap in the pulmonary hypertension and circadian rhythm fields, not only including shared signaling pathways, but also cell-specific effects of the core clock that are known to result in both protective and adverse lung vessel changes...

The objective of the optimization of pharmacotherapy compliant with the basic rules of clinical pharmacology is its maximum individualization, ensuring paramount effectiveness and security of the patient's therapy. Thus, multiple factors that are decisive in terms of uniqueness of treatment of the given patient must be taken into consideration, including, but not limited to, the patient's age, sex, concomitant diseases, special physiological conditions (e.g., pregnancy, lactation, extreme age groups), polypharmacotherapy and polypragmasia (particularly related to increased risk of drug interactions), and patient's phenotypic response to the administered drug with possible genotyping...

BACKGROUND: Intrinsic rhythms in host and cancer cells play an imperative role in tumorigenesis and anticancer therapy. Circadian medicine in cancer is principally reliant on the control of growth and development of cancer cells or tissues by targeting the molecular clock and implementing time-of-day-based anticancer treatments for therapeutic improvements. In recent years, based on extensive high-throughput studies, we witnessed the arrival of several drugs and drug-like compounds that can modulate circadian timekeeping for therapeutic gain in cancer management...

Migration of leukocytes from the skin to lymph nodes (LNs) via afferent lymphatic vessels (LVs) is pivotal for adaptive immune responses1,2 . Circadian rhythms have emerged as important regulators of leukocyte trafficking to LNs via the blood3,4 . Here, we demonstrate that dendritic cells (DCs) have a circadian migration pattern into LVs, which peaks during the rest phase in mice. This migration pattern is determined by rhythmic gradients in the expression of the chemokine CCL21 and of adhesion molecules in both mice and humans...

Adrenal insufficiency (AI) is characterized by higher mortality and morbidity compared with the general population. Conventional replacement steroid therapy, currently recommended for the treatment of AI, is associated with increased frequency of metabolic comorbidities due to daily overexposure. By contrast, dual-release hydrocortisone is associated with a decreased risk of metabolic comorbidities, providing an adequate release of hydrocortisone and mimicking the physiological profile of cortisol. These favorable effects are due to a reduced daily steroid exposure that does not affect the expression of the clock genes which are involved in metabolic pathways and are regulated by the normal physiological circadian rhythm of endogenous cortisol...

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...

This paper takes a critical look at the role of chronobiology in society today, with particular reference to its entanglements with health and medicine and whether or not this amounts to the (bio)medicalisation of our bodily rhythms. What we have here, we show, is a complex unfolding storyline, within and beyond medicine. On the one hand, the promises and problems of these circadian, infradian and ultradian rhythms for our health and well-being are now increasingly emphasised. On the other hand, a variety of new rhythmic interventions and forms of governance are now emerging within and beyond medicine, from chronotherapies and chronopharmacology to biocompatible school and work schedules, and from chronodiets to the optimisation of all we do according to our 'chronotypes'...

The objective of chronotherapy is to optimize medical treatments taking into account the body's circadian rhythms. Chronotherapy is referred to and practiced in two different ways: (1) to alter the sleep-wake rhythms of patients to improve the sequels of several pathologies; (2) to take into account the circadian rhythms of patients to improve therapeutics. Even minor dysfunction of the biological clock can greatly affect sleep/wake physiology causing excessive diurnal somnolence, increase in sleep onset latency, phase delays or advances in sleep onset, frequent night awakenings, reduced sleep efficiency, delayed and shortened rapid eye movement sleep, or increased periodic leg movements...

Background : Empagliflozin is an SGLT2 inhibitor approved for use in patients with diabetes mellitus type 2 (DMT2) with or without other cardiovascular disease. Empagliflozin is taken once daily without rationale on the optimal timing for administration. This study aimed to determine the chronopharmacological effects of morning vs evening administration of empagliflozin (10 mg) in healthy Egyptian adults, by investigating the pharmacokinetics and pharmacodynamics parameters of empagliflozin depending on the intake time...

The pharmacokinetics (PK) - absorption, distribution, metabolism, and elimination - and pharmacodynamics (PD) of hypertension medications can be significantly affected by circadian rhythms. As a consequence, the time when blood pressure (BP) lowering medications are ingested, with reference to the staging of all involved circadian rhythms modulating PK and PD, can affect their duration of action, magnitude of effect on features of the 24 h BP profile, and safety. We conducted a systematic and comprehensive review of published prospective human trials that investigated individual hypertension medications of all classes and their combinations for ingestion-time differences in BP-lowering, safety, patient adherence, and markers of hypertension-associated target organ pathology of the kidney and heart...

The paired suprachiasmatic nuclei (SCN) is the circadian pacemaker in mammals. Clock genes ultimately regulates a vast array of circadian rhythms involved in biological, physiological and behavioral process. The clock genes are closely related to sleep disorders, metabolic syndromes, and cancer diseases. Monitoring rhythm, overcoming rhythm disruption, and manipulating rhythm from the perspective of the clock genes play an important role to improve chronopharmacotherapy. Such an approach should be achieved by overcoming the new challenges in drug delivery systems that match the circadian rhythm (Chrono-DDS)...