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The subject of this article are patients with ankylosing spondylitis and the possibilities of improving the control of morning pain and stiffness characteristic of the disease by applying the principles of chronopharmacology. Chronopharmacology uses knowledge of biological rhythms to develop an optimal pharmacotherapeutic plan. The aim was to study and summarize the modern medical literature on the subject by means of the methods of analysis of the information obtained by keywords in specialized electronic medical databases. In conclusion, it can be said that the results of the study of the available literature show the importance of applying the principles of chronopharmacology to achieve optimal pain control, manage morning stiffness and improve therapeutic results in patients with ankylosing spondylitis. [ABSTRACT FROM AUTHOR]

The time of day that drugs are given and for them to be effective is highly dependent upon the biological clock or an oscillation that is available in mammals in the suprachiasmatic nucleus (SCN) of the hypothalamus that mainly controls the homeostatic system like appetite, hormonal levels, slep and activity, and many other bodily functions with the 24-hour cycles in all living organisms. Hence, several drugs alter the 24-hour rhythms of biochemical, behavioural and physiological processes. This is where chronopharmacology plays a role in optimizing or maintaining the effectiveness of a drug with variations in the pharmacological actions over biological timings and endogenous periodicities. Currently, chronopharmacology is applied in different treatments viz., oncology, asthma therapy, hypertension, strokes, sleep apnea, G.I. tract disorders and allergies. [ABSTRACT FROM AUTHOR]

Chronopharmacology is a multidisciplinary field that investigates the impact of biological rhythms on drug effects and responses. It aims to optimize drug therapy by considering the timing and rhythm characteristics of biological events. Chronopharmacology focuses on designing drug dosing schedules that align with the body's natural biological rhythms, enhancing drug efficacy and safety while reducing adverse reactions. This approach holds significant promise in pharmacology and drug therapy, as it can revolutionize medication administration and patient care. Chronotherapeutics involves timing interventions such as surgery, physical agents, and psychotherapy to minimize toxicity and enhance treatment efficacy. It benefits translational medicine by considering underlying circadian rhythms in drug pharmacology, including pharmacokinetics and pharmacodynamics, as well as patients' physiology and disease pathology. Recent research focuses on targeting treatments toward rhythm-generating biologic timing systems to improve outcomes. Chronopharmacology has shown potential advantages in treating disorders such as peptic ulcer disease, cancer, allergic rhinitis, and rheumatoid arthritis. Challenges for chronopharmacology include lack of translation research, variability in therapeutic responses, replication of findings, optimized drug dosing schedules, clinical implementation, clock disruption, and standardization of chronopharmacological guidelines. In terms of pharmacology and medication therapy, chronopharmacology has a lot of promise. This strategy has the potential to change medicine administration and enhance patient care by utilizing biological rhythms and optimizing drug dose schedules. To fully realize the promise of chronopharmacology in clinical practice, additional study and validation of findings are required. [ABSTRACT FROM AUTHOR]

Copyright of Kranion is the property of Publicidad Permanyer SLU and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

The majority of a mammal's physiology and behavior are time-dependent due to an innate "circadian" clock. Consequently, it is not unexpected that numerous facets of In pharmacology and medicine, the discovery of the biological clock has challenged some long-held beliefs and theories. The only way to cure diseases brought on by disruptions or dysregulation of the biological clock is to reset it. Numerous natural and lifestyle factors cause the clock to become deregulate. This review sheds light on the several chronotherapeutic medicines that have been identified and tested recently. The 24-hour clocks are also used to drive oscillations in toxicology and pharmacology.Circadian pharmacokinetics are based on daily fluctuations in the quantity of proteins required for medication absorption or metabolism; circadian pharmacodynamics are based on daily fluctuations in the physiological systems that these drugs target. The majority of bodily cells have these clocks, although they are arranged hierarchically. It's interesting to note that while some elements of physiology and behavior are directly regulated by a "slave" oscillator located in different brain areas or bodily tissues, others are regulated by a "master clock" located in the suprachiasmatic nuclei of the hypothalamus. [ABSTRACT FROM AUTHOR]

Clinical hypertension trials typically rely on homeostatic principles, including single time-of-day office blood pressure (BP) measurements (OBPM), rather than circadian chronopharmacological principles, including ambulatory monitoring (ABPM) done around-the-clock to derive the asleep systolic BP (SBP) mean and sleep-time relative SBP decline – jointly the strongest prognosticators of cardiovascular disease (CVD) risk and true definition of hypertension – to qualify participants and assess outcomes. Eight chronopharmacological elements are indispensable for design and conduct of hypertension medication trials, mainly those on ingestion-time differences in effects, and also a means of rating quality of investigations. Accordingly, we highlight the findings and shortcomings of: (i) 155 such ingestion-time trials, 83.9% finding at-bedtime/evening treatment more beneficial than conventional upon-awakening/morning treatment; (ii) HOPE and ONTARGET CVD outcomes investigations assessing in the former add-on ramipril at-bedtime and in the latter telmisartan, ramipril, or both in combination in the morning; and (iii) pragmatic TIME CVD outcomes trial. Failure to incorporate chronopharmacological principals – including ABPM to derive asleep SBP and SBP dipping to qualify subjects as hypertensive and assess CVD risk – results in deficient study design, dubious findings, and unnecessary medical controversy at the expense of advances in patient care. [ABSTRACT FROM AUTHOR]

Today's challenge for precision medicine involves the integration of the impact of molecular clocks on drug pharmacokinetics, toxicity, and efficacy toward personalized chronotherapy. Meaningful improvements of tolerability and/or efficacy of medications through proper administration timing have been confirmed over the past decade for immunotherapy and chemotherapy against cancer, as well as for commonly used pharmacological agents in cardiovascular, metabolic, inflammatory, and neurological conditions. Experimental and human studies have recently revealed sexually dimorphic circadian drug responses. Dedicated randomized clinical trials should now aim to issue personalized circadian timing recommendations for daily medical practice, integrating innovative technologies for remote longitudinal monitoring of circadian metrics, statistical prediction of molecular clock function from single-timepoint biopsies, and multiscale biorhythmic mathematical modelling. Importantly, chronofit patients with a robust circadian function, who would benefit most from personalized chronotherapy, need to be identified. Conversely, nonchronofit patients could benefit from the emerging pharmacological class of chronobiotics targeting the circadian clock. [ABSTRACT FROM AUTHOR]

Copyright of Actualités Pharmaceutiques is the property of Elsevier B.V. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Mammalians' circadian pacemaker resides in the paired suprachiasmatic nuclei (SCN). SCN control biological rhythms such as the sleep-wake rhythm and homeostatic functions of steroid hormones and their receptors. Alterations in these biological rhythms are implicated in the outcomes of pathogenic conditions such as depression, diabetes, and cancer. Chronotherapy is about optimizing treatment to combat risks and intensity of the disease symptoms that vary depending on the time of day. Thus, conditions/diseases such as allergic rhinitis, arthritis, asthma, myocardial infarction, congestive heart failure, stroke, and peptic ulcer disease, prone to manifest severe symptoms depending on the time of day, would be benefited from chronotherapy. Monitoring rhythm, overcoming rhythm disruption, and manipulating the rhythms from the viewpoints of underlying molecular clocks are essential to enhanced chronopharmacotherapy. New drugs focused on molecular clocks are being developed to improve therapeutics. In this review, we provide a critical summary of literature reports concerning (a) the rationale/mechanisms for time-dependent dosing differences in therapeutic outcomes and safety of antitumor drugs, (b) the molecular pathways underlying biological rhythms, and (c) the possibility of pharmacotherapy based on the intra- and inter-individual variabilities from the viewpoints of the clock genes. [Display omitted] [ABSTRACT FROM AUTHOR]

It is estimated that 2% to 3% of the population are currently prescribed systemic or topical glucocorticoid treatment. The potent anti-inflammatory action of glucocorticoids to deliver therapeutic benefit is not in doubt. However, the side effects associated with their use, including central weight gain, hypertension, insulin resistance, type 2 diabetes (T2D), and osteoporosis, often collectively termed iatrogenic Cushing's syndrome , are associated with a significant health and economic burden. The precise cellular mechanisms underpinning the differential action of glucocorticoids to drive the desirable and undesirable effects are still not completely understood. Faced with the unmet clinical need to limit glucocorticoid-induced adverse effects alongside ensuring the preservation of anti-inflammatory actions, several strategies have been pursued. The coprescription of existing licensed drugs to treat incident adverse effects can be effective, but data examining the prevention of adverse effects are limited. Novel selective glucocorticoid receptor agonists and selective glucocorticoid receptor modulators have been designed that aim to specifically and selectively activate anti-inflammatory responses based upon their interaction with the glucocorticoid receptor. Several of these compounds are currently in clinical trials to evaluate their efficacy. More recently, strategies exploiting tissue-specific glucocorticoid metabolism through the isoforms of 11β-hydroxysteroid dehydrogenase has shown early potential, although data from clinical trials are limited. The aim of any treatment is to maximize benefit while minimizing risk, and within this review we define the adverse effect profile associated with glucocorticoid use and evaluate current and developing strategies that aim to limit side effects but preserve desirable therapeutic efficacy. [ABSTRACT FROM AUTHOR]

Approximately one-third of patients with epilepsy are drug-refractory, necessitating novel treatment approaches. Chronopharmacology, which adjusts pharmacological treatment to physiological variations in seizure susceptibility and drug responsiveness, offers a promising strategy to enhance efficacy and tolerance. This narrative review provides an overview of the biological foundations for rhythms in seizure activity, clinical implications of seizure patterns through case reports, and the potential of chronopharmacological strategies to improve treatment. Biological rhythms, including circadian and infradian rhythms, play an important role in epilepsy. Understanding seizure patterns may help individualize treatment decisions and optimize therapeutic outcomes. Altering drug concentrations based on seizure risk periods, adjusting administration times, and exploring hormone therapy are potential strategies. Large-scale randomized controlled trials are needed to evaluate the efficacy and safety of differential and intermittent treatment approaches. By tailoring treatment to individual seizure patterns and pharmacological properties, chronopharmacology offers a personalized approach to improve outcomes in patients with epilepsy. [ABSTRACT FROM AUTHOR]

Circadian rhythm influences the pharmacokinetics and pharmacodynamics of a number of drugs and affects their therapeutic efficacy and toxicity depending on the time of day they are administered. Chronopharmacology is a method for incorporating knowledge about circadian rhythm into pharmacotherapy. Chronotherapy, which is the clinical application of chronopharmacology, is particularly relevant when the risk and/or severity of symptoms of a disease change in a predictable manner over time. Chronotherapy has potential benefits in the treatment of many diseases. Although a considerable amount of knowledge about chronopharmacology and chronotherapy has been accumulated, its therapeutic application in clinical practice remains limited in terms of therapy optimization. Resolution of these issues will improve our ability to deliver adequate drug treatment. We propose four approaches for promoting chronotherapy-based drug treatment in clinical practice: targeting drug development and regulatory authorities; education about chronotherapy; drug information for both health professionals and consumers; and a chronotherapy network. [ABSTRACT FROM AUTHOR]

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. Dosing time influences the effectiveness and toxicity of many drugs. The pharmacodynamics of medications as well as pharmacokinetics influences chronopharmacological phenomena. To escape from host immunity in the tumor microenvironment, cancer cells have acquired several pathways. Immune checkpoint therapy targeting programmed death 1 (PD-1) and its ligand (PD-L1) interaction had been approved for the treatment of patients with several types of cancers. Circadian expression of PD-1 is identified on tumor associated macrophages (TAMs), which is rationale for selecting the most appropriate time of day for administration of PD-1/PD-L1 inhibitors. The therapies for chronic kidney disease (CKD) are urgently needed because of a global health problem. The mechanism of the cardiac complications in mice with CKD had been related the GRP68 in circulating monocytes and serum accumulation of retinol. Development of a strategy to suppress retinol accumulation will be useful to prevent the cardiac complications of CKD. Therefore, we introduce an overview of the dosing time-dependent changes in therapeutic outcome and safety of drug for immune-related diseases.

The circadian clock is involved in the pathogenesis of nonalcoholic steatohepatitis (NASH), and the target pathways of many NASH candidate drugs are controlled by the circadian clock. However, the application of chronopharmacology in NASH is little considered currently. Here, the time-dependent effect of REV-ERBα agonist SR9009 on diet-induced NASH and microbiota was investigated. C57BL/6J mice were fed a high-cholesterol and high-fat diet (CL) for 12 weeks to induce NASH and then treated with SR9009 either at Zeitgeber time 0 (ZT0) or ZT12 for another 6 weeks. Pharmacological activation of REV-ERBα by SR9009 alleviated hepatic steatosis, insulin resistance, liver inflammation, and fibrosis in CL diet-induced NASH mice. These effects were accompanied by improved gut barrier function and altered microbial composition and function in NASH mice, and the effect tended to be stronger when SR9009 was injected at ZT0. Moreover, SR9009 treatment at different time points resulted in a marked difference in the composition of the microbiota, with a stronger effect on the enrichment of beneficial bacteria and the diminishment of harmful bacteria when SR9009 was administrated at ZT0. Therefore, the time-dependent effect of REV-ERBα agonist on NASH was partly associated with the microbiota, highlighting the potential role of microbiota in the chronopharmacology of NASH and the possibility of discovering new therapeutic strategies for NASH. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: The objective was to investigate if metformin pharmacokinetics is modulated by time-of-day in humans using empirical and mechanistic pharmacokinetic modelling techniques on a large clinical dataset. This study also aimed to generate and test hypotheses on the underlying mechanisms, including evidence for chronotype-dependent interindividual differences in metformin plasma and efficacy-related tissue concentrations. Methods: A large clinical dataset consisting of individual metformin plasma and urine measurements was analysed using a newly developed empirical pharmacokinetic model. Causes of daily variation of metformin pharmacokinetics and interindividual variability were further investigated by a literature-informed mechanistic modelling analysis. Results: A significant effect of time-of-day on metformin pharmacokinetics was found. Daily rhythms of gastrointestinal, hepatic and renal processes are described in the literature, possibly affecting drug pharmacokinetics. Observed metformin plasma levels were best described by a combination of a rhythm in GFR, renal plasma flow (RPF) and organic cation transporter (OCT) 2 activity. Furthermore, the large interindividual differences in measured metformin concentrations were best explained by individual chronotypes affecting metformin clearance, with impact on plasma and tissue concentrations that may have implications for metformin efficacy. Conclusions/interpretation: Metformin's pharmacology significantly depends on time-of-day in humans, determined with the help of empirical and mechanistic pharmacokinetic modelling, and rhythmic GFR, RPF and OCT2 were found to govern intraday variation. Interindividual variation was found to be partly dependent on individual chronotype, suggesting diurnal preference as an interesting, but so-far underappreciated, topic with regard to future personalised chronomodulated therapy in people with type 2 diabetes. [ABSTRACT FROM AUTHOR]

Copyright of Journal of Faculty of Pharmacy of Ankara University / Ankara Üniversitesi Eczacilik Fakültesi Dergisi is the property of Ankara University and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Approximately one-third of patients with epilepsy are drug-refractory, necessitating novel treatment approaches. Chronopharmacology, which adjusts pharmacological treatment to physiological variations in seizure susceptibility and drug responsiveness, offers a promising strategy to enhance efficacy and tolerance. This narrative review provides an overview of the biological foundations for rhythms in seizure activity, clinical implications of seizure patterns through case reports, and the potential of chronopharmacological strategies to improve treatment. Biological rhythms, including circadian and infradian rhythms, play an important role in epilepsy. Understanding seizure patterns may help individualize treatment decisions and optimize therapeutic outcomes. Altering drug concentrations based on seizure risk periods, adjusting administration times, and exploring hormone therapy are potential strategies. Large-scale randomized controlled trials are needed to evaluate the efficacy and safety of differential and intermittent treatment approaches. By tailoring treatment to individual seizure patterns and pharmacological properties, chronopharmacology offers a personalized approach to improve outcomes in patients with epilepsy.

Chronotherapy for hypertension has been a topic of debate over the past decade. A number of studies up to 2019 suggested that prescribing drugs in the evening has advantages compared to morning, both in terms of normalization of blood pressure and its circadian rhythm, as well as in terms of the risk of adverse outcomes. Some of these studies were not designed for such an analysis, and some have significant limitations that make their interpretation difficult. The results of the HARMONY and TIME studies published in the last 2 years did not confirm any advantage of taking drugs in the evening compared to the morning, but showed its safety. Selection of antihypertensive therapy should be guided by antihypertensive efficacy, duration and stability of the effect, as well as medical adherence. Therefore, a single intake of double or triple fixed-dose combination of long-acting agents at hours convenient for the patient is optimal.

Chronopharmacology of arterial hypertension impacts the long-term cardiovascular risk of hypertensive subjects. Therefore, clinical and computational studies have proposed optimizing antihypertensive medications' dosing time (Ta). However, the causes and mechanisms underlying the Ta- dependency antihypertensive effect have not been elucidated. Here we propose using a Ta- dependent effect model to understand and predict the antihypertensive effect of valsartan and aspirin throughout the day in subjects with grade I or II essential hypertension. The model based on physiological regulation mechanisms includes a periodic function for each parameter that changes significantly after treatment. Circadian variations of parameters depending on the dosing time allowed the determination of regulation mechanisms dependent on the circadian rhythm that were most relevant for the action of each drug. In the case of valsartan, it is the regulation of vasodilation and systemic vascular resistance. In the case of aspirin, the antithrombotic effect generates changes in the sensitivity of systemic vascular resistance and heart rate to changes in physical activity. Dosing time-dependent models predict a more significant effect on systemic vascular resistance and blood pressure when administering valsartan or aspirin at bedtime. However, circadian dependence on the regulation mechanisms showed different sensitivity of their circadian parameters and shapes of functions, presenting different phase shifts and amplitude. Therefore, different mechanisms of action and pharmacokinetic properties of each drug can generate different profiles of Ta-dependence of antihypertensive effect and optimal dosing times. [ABSTRACT FROM AUTHOR]

Chronopharmacology of arterial hypertension impacts the long-term cardiovascular risk of hypertensive subjects. Therefore, clinical and computational studies have proposed optimizing antihypertensive medications’ dosing time (Ta). However, the causes and mechanisms underlying the Ta-dependency antihypertensive effect have not been elucidated. Here we propose using a Ta- dependent effect model to understand and predict the antihypertensive effect of valsartan and aspirin throughout the day in subjects with grade I or II essential hypertension. The model based on physiological regulation mechanisms includes a periodic function for each parameter that changes significantly after treatment. Circadian variations of parameters depending on the dosing time allowed the determination of regulation mechanisms dependent on the circadian rhythm that were most relevant for the action of each drug. In the case of valsartan, it is the regulation of vasodilation and systemic vascular resistance. In the case of aspirin, the antithrombotic effect generates changes in the sensitivity of systemic vascular resistance and heart rate to changes in physical activity. Dosing time-dependent models predict a more significant effect on systemic vascular resistance and blood pressure when administering valsartan or aspirin at bedtime. However, circadian dependence on the regulation mechanisms showed different sensitivity of their circadian parameters and shapes of functions, presenting different phase shifts and amplitude. Therefore, different mechanisms of action and pharmacokinetic properties of each drug can generate different profiles of Ta-dependence of antihypertensive effect and optimal dosing times.

Caffeine is the globally consumed psychoactive substance and the drug of choice for the treatment of apnea of prematurity (AOP), but its therapeutic effects are highly variable among preterm infants. Many of the molecular underpinnings of the marked individual response have remained elusive yet. Interestingly, the significant association between Clock gene polymorphisms and the response to caffeine therapy offers an opportunity to advance our understanding of potential mechanistic pathways. In this review, we delineate the functions and mechanisms of human circadian rhythms. An up-to-date advance of the formation and ontogeny of human circadian rhythms during the perinatal period are concisely discussed. Specially, we summarize and discuss the characteristics of circadian rhythms in preterm infants. Second, we discuss the role of caffeine consumption on the circadian rhythms in animal models and human, especially in neonates and preterm infants. Finally, we postulate how circadian-based therapeutic initiatives could open new possibilities to promote precision caffeine therapy for the AOP management in preterm infants. [ABSTRACT FROM AUTHOR]

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. Dosing time influences the effectiveness and toxicity of many drugs. The pharmacodynamics of medications as well as pharmacokinetics influences chronopharmacological phenomena. To escape from host immunity in the tumor microenvironment, cancer cells have acquired several pathways. Immune checkpoint therapy targeting programmed death 1 (PD-1) and its ligand (PD-L1) interaction had been approved for the treatment of patients with several types of cancers. Circadian expression of PD-1 is identified on tumor associated macrophages (TAMs), which is rationale for selecting the most appropriate time of day for administration of PD-1/PD-L1 inhibitors. The therapies for chronic kidney disease (CKD) are urgently needed because of a global health problem. The mechanism of the cardiac complications in mice with CKD had been related the GRP68 in circulating monocytes and serum accumulation of retinol. Development of a strategy to suppress retinol accumulation will be useful to prevent the cardiac complications of CKD. Therefore, we introduce an overview of the dosing time-dependent changes in therapeutic outcome and safety of drug for immune-related diseases. [ABSTRACT FROM AUTHOR]

In many medical settings, medications are typically administered in the morning or evening, aligning with patients' daily routines. This practice does not stem from chronotherapy, which involves scheduling drug administration to enhance its effectiveness, but rather from the way clinical operations are structured. The timing of drug administration can significantly affect a medication's effectiveness and side effects, with the impact varying by up to ten times based on circadian rhythms. Disorders such as major depression, bipolar disorder, and schizophrenia are linked to disruptions in these rhythms. Recent studies have found that circadian dysfunctions, including genetic and neurohumoral changes, underlie many psychiatric conditions. Issues such as an altered glucocorticoid rhythm due to impaired HPA axis function, disturbed melatonin balance, and sleep disturbances have been noted in psychotic disorders. Furthermore, mood disorders have been associated with changes in the expression of circadian rhythm genes such as Clock , Bmal1 , and Per . Considering that the absorption, biodistribution, effects on target organs, half-life, metabolism, and elimination of drugs are all influenced by the body's circadian rhythms, this narrative review explores the optimal timing of medication administration to maximize efficacy and minimize side effects in the treatment of psychiatric disorders. By closely monitoring circadian variations in cortisol, melatonin, and key clock genes, as well as by deepening our understanding of the metabolisms and pharmacokinetics of antipsychotic medications, we propose a chronotherapy approach for psychiatric patients that could significantly enhance patient care.

We previously reported that brotizolam, but not suvorexant, delayed recovery from isoflurane anesthesia in mice. However, the effects of hypnotics may be altered by the circadian rhythm. Locomotor activity was measured using sighted (ICR and C57BL/6J) and blind (FVB/N and C3H/HeN) mice, and the effects of hypnotics on isoflurane anesthesia were compared during the light and dark periods. In sighted mice, recovery induced by brotizolam was delayed in the light period, while that by suvorexant was delayed in the dark period. In C57BL/6J mice, delayed recovery induced by brotizolam was marked, and that by suvorexant was observed in the light and dark periods. Locomotor activity was low in the last 6 h of the dark period in blind mice, and was similar to that in the light period. In blind mice, delayed recovery induced by brotizolam was identical in both periods, while suvorexant did not influence recovery from isoflurane anesthesia. These results suggest that the effects of hypnotics on isoflurane anesthesia are altered by the circadian rhythm and that daily light–dark stimuli may be required for the chronopharmacological effects of hypnotics.

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. Despite this, there has been little consideration of the application of chronopharmacology in NASH, a strategy whereby the timing of drug delivery is informed by biological rhythms in order to maximise efficacy and tolerability. Chronopharmacology has been shown to have significant clinical benefits in a variety of settings including cardiovascular disease and cancer therapy. The rationale for its application in NASH is therefore compelling. However, no clinical trials in NASH have specifically explored the impact of drug timing on disease progression and patient outcomes. This may contribute to the wide variability in reported outcomes of NASH trials and partly explain why even late-phase trials have stalled because of a lack of efficacy or safety concerns. In this opinion piece, we describe the potential for chronopharmacology in NASH, discuss how the major NASH drug candidates are influenced by circadian biology, and encourage greater consideration of the timing of drug administration in the design of future clinical trials. [ABSTRACT FROM AUTHOR]

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. Among the search-retried 155 trials, 17 published between 1991 and 2020 totaling 1,508 hypertensive participants concerned the differential ingestion-time dependent effects of 14 unique dual-combination therapies. All but one (94.1%) of the trials, involving 98.5% of the total number of investigated individuals, reported clinically and statistically significant benefits – including enhanced reduction of asleep BP without induction of sleep-time hypotension, reduced prevalence of BP non-dipping, decreased adverse effects, improved kidney function, and reduced cardiac pathology – when dual-combination hypertension medications were ingested at-bedtime/evening rather than upon-waking/morning. A systematic and comprehensive review of the literature published in the past three decades reveals no single dual-combination hypertension trial reported significantly better benefit of the still conventional, yet unjustified by medical evidence, upon-waking/morning hypertension treatment scheme. [ABSTRACT FROM AUTHOR]

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 systematic review yielded 155 trials published between 1976 and 2020 – totaling 23,972 hypertensive individuals – that evaluated 37 different single and 14 dual-combination therapies. The vast (83.9%) majority of them reported clinically and statistically significant benefits – including enhanced reduction of asleep BP mean without induced sleep-time hypotension, reduced prevalence of the higher cardiovascular risk non-dipper 24 h BP profile, decreased incidence of adverse effects, improved kidney function, and reduced cardiac pathology – when hypertension medications are ingested at-bedtime/evening rather than upon-waking/morning. Nonetheless, the findings and conclusions of some past conducted trials are inconsistent, often due to disparities and deficiencies of the investigative protocols. Accordingly, we developed a quality assessment method based upon the eight items identified as crucial according to the recently published guidelines of the International Society for Chronobiology and the American Association for Medical Chronobiology and Chronotherapeutics for the design and conduct of human clinical trials on ingestion-time differences of hypertension medications. Among the most frequent deficiencies are: absence or miscalculation of minimum required sample size (83.2%), incorrect choice of primary BP endpoint (53.6%), and inappropriate arbitrary and unrepresentative clock hours chosen for tested treatment times (53.6%). The inability of the very small proportion (16.1%) of trials to verify the advantages of the at-bedtime/evening treatment strategy is likely explained by deficiencies of their study design and conduct. Nonetheless, regardless of the quality score of the 155 trials retrieved by our systematic review, it is most noteworthy that no single published prospective randomized trial reported significantly enhanced BP-lowering, safety, compliance, or other benefits of the unjustified by medical evidence, yet still most recommended, upon-waking/morning hypertension treatment-time scheme. [ABSTRACT FROM AUTHOR]

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. Methods: An open label, sequential, two‐way crossover trial comprised of two periods with a washout period of 7 days. All participants received a single oral dose of empagliflozin (JARDIANCE ®; 10 mg film coated tablet) in the evening, and after a seven-day washout period, the morning. Pharmacokinetics parameters (primary endpoints: t max (h), C max (ng/ml), AUC 0-t (ng.h/ml); secondary endpoints: AUC 0 to ∞(ng.h/ml)) were assessed. Method validation was done prior to injection in LC/MS/MS and samples were processed by Liquid-Liquid extraction. The pharmacodynamic profile (UGE 0-24) was determined after method validation (glucose hexokinase method). Results: T max increased by 35% in the evening phase compared to the morning phase, while C max decreased by -6.5% in the evening dose compared to the morning dose. Additionally, AUC 0 to ∞ increased in the evening phase by 8.25% compared to the morning phase. The mean cumulative amount of glucose excreted (UGE ( 0-24)) increased by 43% in the evening dose compared to the morning dose Conclusion: Despite the difference in pharmacokinetics parameters between evening and morning doses, C max, AUC 0-t, AUC 0-∞, didn’t differ on the bioequivalence level. In addition, as UGE ( 0-24) didn’t statistically differ, thus, we can conclude that there is no statistical significance between the morning and evening doses. Trial registration: Clinal Trials.gov, ID: NCT03895229 (registered on 29 th March 2019).

Circadian rhythms are generated by an endogenously organized timing system that drives daily rhythms in behavior, physiology and metabolism. In mammals, the suprachiasmatic nucleus (SCN) of the hypothalamus is the locus of a master circadian clock. The SCN is synchronized to environmental changes in the light:dark cycle by direct, monosynaptic innervation via the retino-hypothalamic tract. In turn, the SCN coordinates the rhythmic activities of innumerable subordinate clocks in virtually all bodily tissues and organs. The core molecular clockwork is composed of a transcriptional/post-translational feedback loop in which clock genes and their protein products periodically suppress their own transcription. This primary loop connects to downstream output genes by additional, interlocked transcriptional feedback loops to create tissue-specific 'circadian transcriptomes'. Signals from peripheral tissues inform the SCN of the internal state of the organism and the brain's master clock is modified accordingly. A consequence of this hierarchical, multilevel feedback system is that there are ubiquitous effects of circadian timing on genetic and metabolic responses throughout the body. This overview examines landmark studies in the history of the study of circadian timing system, and highlights our current understanding of the operation of circadian clocks with a focus on topics of interest to the neuroscience community.

Physiological functions of cardiovascular system (CVS) are exhibiting circadian patterns regulated by complex system of endogenous factors. Preserving this rhythmicity is important for its normal function, whereas disturbing the synchronization with natural day–night cycle can increase the risk of cardiovascular damage. Cardiovascular pathophysiology also follows cyclic variation; time susceptibility and period with maximum risk associated with elevated blood pressure (BP) can be predicted. Given this rhythmic nature, significant changes in efficacy between morning and evening administration of the drug may occur; appropriate timing of pharmacological intervention in therapy of hypertension may affect the efficacy of the treatment.

Abstract Molecular clocks help organisms to adapt important physiological functions to periodically changing conditions in the environment. These include the adaption of the 24 h sleep-wake rhythm to changes of day and night. The circadian clock is known to act as a key regulator in processes of health and disease in different organs. The knowledge on the circadian clock led to the development of chronopharmacology and chronotherapy. These fields aim to investigate how efficiency of medication and therapies can be improved based on circadian clock mechanisms. In this review we aim to highlight the role of the circadian clock in oral tissues and its potential in the different fields of dentistry including oral and maxillofacial surgery, restorative dentistry, endodontics, periodontics and orthodontics to trigger the evolving field of chronodentistry.

Circadian rhythms describe physiological systems that repeat themselves with a cycle of approximately 24 h. Our understanding of the cellular and molecular origins of these oscillations has improved dramatically, allowing us to appreciate the significant role these oscillations play in maintaining physiological homeostasis. Circadian rhythms allow living organisms to predict and efficiently respond to a dynamically changing environment, set by repetitive day/night cycles. Since circadian rhythms underlie almost every aspect of human physiology, it is unsurprising that they also influence the response of a living organism to disease, stress, and therapeutics. Therefore, not only do the mechanisms that maintain health and disrupt homeostasis depend on our internal circadian clock, but also the way drugs are perceived and function depends on these physiological rhythms. We present a holistic view of the therapeutic process, discussing components such as disease state, pharmacokinetics, and pharmacodynamics, as well as adverse reactions that are critically affected by circadian rhythms. We outline challenges and opportunities in moving toward personalized medicine approaches that explore and capitalize on circadian rhythms for the benefit of the patient. [ABSTRACT FROM AUTHOR]

The importance of circadian rhythm dysfunctions in the pathophysiology of neurological diseases has been highlighted recently. Chronopharmacology principles imply that tailoring the timing of treatments to the circadian rhythm of individual patients could optimize therapeutic management. According to these principles, chronopharmacology takes into account the individual differences in patients' clocks, the rhythmic changes in the organism sensitivity to therapeutic and side effects of drugs, and the predictable time variations of disease. This review examines the current literature on chronopharmacology of neurological diseases focusing its scope on epilepsy, Alzheimer and Parkinson diseases, and neuropathic pain, even if other neurological diseases could have been analyzed. While the results of the studies discussed in this review point to a potential therapeutic benefit of chronopharmacology in neurological diseases, the field is still in its infancy. Studies including a sufficiently large number of patients and measuring gold standard markers of the circadian rhythmicity are still needed to evaluate the beneficial effect of administration times over the 24‐hour day but also of clock modulating drugs. [ABSTRACT FROM AUTHOR]

Pharmacokinetics of hypertension medications is significantly affected by circadian rhythms that influence absorption, distribution, metabolism and elimination. Furthermore, their pharmacodynamics is affected by ingestion-time differences in kinetics and circadian rhythms comprising the biological mechanism of the 24 h blood pressure (BP) pattern. However, hypertension guidelines do not recommend the time to treat patients with medications. We conducted a systematic review of published evidence regarding ingestion-time differences of hypertension medications and their combinations on ambulatory BP-lowering, safety, and markers of target organ pathology. Some 153 trials published between 1976 and 2020, totaling 23,869 hypertensive individuals, evaluated 37 different single and 14 dual-fixed combination therapies. The vast (83.7%) majority of the trials report clinically and statistically significant benefits – including enhanced reduction of asleep BP without inducing sleep-time hypotension, reduced prevalence of the higher cardiovascular disease risk BP non-dipping 24 h profile, decreased incidence of adverse effects, improved renal function, and reduced cardiac pathology – when hypertension medications are ingested at-bedtime/evening rather than upon-waking/morning. Non-substantiated treatment-time difference in effects by the small proportion (16.3%) of published trials is likely explained by deficiencies of study design and conduct. Systematic and comprehensive review of the literature published the past 45 years reveals no single study reported significantly better benefit of the still conventional, yet unjustified by medical evidence, upon-waking/morning hypertension treatment schedule. [Display omitted] [ABSTRACT FROM AUTHOR]

Introduction: The 24-hour variations in drug absorption, distribution, metabolism, and elimination, collectively known as pharmacokinetics, are fundamentally influenced by rhythmic physiological processes regulated by the molecular clock. Recent advances have elucidated the intricacies of the circadian timing system and the molecular interplay between biological clocks, enzymes and transporters in preclinical level., Area Covered: Circadian rhythm of the drug metabolizing enzymes and carrier efflux functions possess a major role for drug metabolism and detoxification. The efflux and metabolism function of intestines and liver seems important. The investigations revealed that the ABC and SLC transporter families, along with cytochrome p -450 systems in the intestine, liver, and kidney, play a dominant role in the circadian detoxification of drugs. Additionally, the circadian control of efflux by the blood-brain barrier is also discussed., Expert Opinion: The influence of the circadian timing system on drug pharmacokinetics significantly impacts the efficacy, adverse effects, and toxicity profiles of various drugs. Moreover, the emergence of sex-related circadian changes in the metabolism and detoxification processes has underscored the importance of considering gender-specific differences in drug tolerability and pharmacology. A better understanding of coupling between central clock and circadian metabolism/transport contributes to the development of more rational drug utilization and the implementation of chronotherapy applications.

The circulating of leukocytes in the vasculature to reach various organs is a crucial step that allows them to perform their function. With a sequence of interaction with the endothelial cells, the leukocytes emigrate from the circulation either by firm attachment to vascular beds or by trafficking into the tissues. Recent findings reveal that the leukocyte recruitment shows time as well as tissue specificity depending on the cell type and homing location. This spatiotemporal distribution of leukocyte subsets is driven by the circadian expression of pro-migratory molecules expressed on the leukocytes and the endothelium. Both the systemic circadian signals and the cell's intrinsic molecule clock contribute to the oscillatory expression of pro-migratory molecules. The rhythmic recruitment of leukocytes plays an important role in the time-dependency of immune responses. It also helps to update blood components and maintain the tissue circadian microenvironment. In this review, we discuss the current knowledge about the mechanisms of the circadian system regulating the leukocyte rhythmic migration, the recruitment pattern of leukocyte subsets into different tissue/organs, and the time-dependent effects behind this process.

Abstract The 2017 Nobel Prize for Physiology or Medicine, awarded for the discoveries made in the past 15 years on the genetic and molecular mechanisms regulating many physiological functions, has renewed the attention to the importance of circadian rhythms. These originate from a central pacemaker in the suprachiasmatic nucleus in the brain, photoentrained via direct connection with melanopsin containing, intrinsically light-sensitive retinal ganglion cells, and it projects to periphery, thus creating an inner circadian rhythm. This regulates several activities, including sleep, feeding times, energy metabolism, endocrine and immune functions. Disturbances of these rhythms, mainly of wake/sleep, hormonal secretion and feeding, cause decrease in quality of life, as well as being involved in development of obesity, metabolic syndrome and neuropsychiatric disorders. Most immunological functions, from leukocyte numbers, activity and cytokine secretion undergo circadian variations, which might affect susceptibility to infections. The intensity of symptoms and disease severity show a 24 h pattern in many immunological and allergic diseases, including rheumatoid arthritis, bronchial asthma, atopic eczema and chronic urticaria. This is accompanied by altered sleep duration and quality, a major determinant of quality of life. Shift work and travel through time zones as well as artificial light pose new health threats by disrupting the circadian rhythms. Finally, the field of chronopharmacology uses these concepts for delivering drugs in synchrony with biological rhythms.

Sibutramine is a non‐selective serotonin‐norepinephrine reuptake inhibitor orally administered for weight loss. In a previous study, we showed pharmacological mechanisms involved in the reduction of sperm quality and fertility of rats exposed for 30 days to this anorexigen in the light phase of the light‐dark (l/d) cycle. It is already known that rodents are nightlife animals, with higher metabolic activity during the dark phase than in the light phase of the light‐dark (l/d) cycle. Thus, the present study aimed to investigate whether the deleterious effects on reproductive parameters after sibutramine administration would be enhanced after a shorter period of exposure during the dark phase of the l/d cycle. For this, adult male Wistar rats were treated with sibutramine (10 mg/kg/d) or vehicle for 15 days during the dark phase of the l/d cycle. Sibutramine treatment decreased final body and reproductive organ weights, as well as serum testosterone levels. Sperm transit time through the epididymis was accelerated, and sperm concentration and motility were diminished in the sibutramine‐exposed rats. The decrease in sperm concentration was also verified in the epididymal histological sections. In conclusion, the deleterious effects of sibutramine on reproductive parameters of male rats were enhanced when the exposure occurred in the dark phase of the l/d cycle, even after a short exposure duration. Our results reinforce the impact of timing on drug therapeutic action. [ABSTRACT FROM AUTHOR]

The chronopharmacology refers to the utilization of physiological circadian rhythms to optimize the administration time of drugs, thus increasing their efficacy and safety, or reducing adverse effects. Simvastatin is one of the most widely prescribed drugs for the treatment of hypercholesterolaemia, hyperlipidemia and coronary artery disease. There are conflicting statements regarding the timing of simvastatin administration, and convincing experimental evidence remains unavailable. Thus, we aimed to examine whether different administration times would influence the efficacy of simvastatin. High‐fat diet‐fed mice were treated with simvastatin at zeitgeber time 1 (ZT1) or ZT13, respectively, for nine weeks. Simvastatin showed robust anti‐hypercholesterolaemia and anti‐hyperlipidemia effects on these obese mice, regardless of administration time. However, simvastatin administrated at ZT13, compared to ZT1, was more functional for decreasing serum levels of total cholesterol, triglycerides, non‐esterified free fatty acids and LDL cholesterol, as well as improving liver pathological characteristics. In terms of possible mechanisms, we found that simvastatin did not alter the expression of hepatic circadian clock gene in vivo, although it failed to change the period, phase and amplitude of oscillation patterns in Per2::Luc U2OS and Bmal1::Luc U2OS cells in vitro. In contrast, simvastatin regulated the expression of Hmgcr, Mdr1 and Slco2b1 in a circadian manner, which potentially contributed to the chronopharmacological function of the drug. Taken together, we provide solid evidence to suggest that different administration times affect the lipid‐lowering effects of simvastatin. [ABSTRACT FROM AUTHOR]

The main purpose of this commentary is to update, based on our extensive review of the published literature of the past 45 yrs, the differential therapeutic effects of hypertension medications of various classes and their combinations when ingested in the evening/at-bedtime versus in the morning/upon-awakening. Interestingly, revision of the currently available evidence on the differential circadian-time-dependent effects of hypertension medications of six different classes and their combinations indicates among the 137 published hypertension medication trials that evaluated blood pressure (BP)-lowering efficacy according to treatment-time, 112 (81.75%) documented significant better benefits by evening/bedtime compared to morning/awakening-scheduled therapy. The remaining 25 published trials found no treatment-time difference in effects; indeed, no single study has reported better benefits of the still conventional, but scientifically unjustified, morning than evening/at-bedtime treatment scheme. [ABSTRACT FROM AUTHOR]

Des rythmes biologiques sous-tendent le fonctionnement de notre organisme. La chronopharmacologie et la chronothérapie prennent en compte la chronophysiologie pour optimiser les horaires de prise médicamenteuse. L'équipe officinale doit savoir expliquer l'importance de les respecter afin d'augmenter l'efficacité et la tolérance des médicaments. Biological rhythms underpin the functioning of our organism. Chronopharmacology and chronotherapy take chronophysiology into account to identify the optimal times for taking medication. The pharmacy team must be able to explain the importance of respecting these times in order to increase the efficacy and tolerance of the medicines. [ABSTRACT FROM AUTHOR]

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. Conducting therapy while monitoring the concentration of certain drugs in blood (Therapeutic Drug Monitoring; TDM procedure) is also one of the factors enabling treatment individualization. Furthermore, another material, and yet still a marginalized pharmacotherapeutic factor, is chronopharmacology, which indirectly determines the values of drug concentrations evaluated in the TDM procedure. This paper is a brief overview of chronopharmacology, especially chronopharmacokinetics, and its connection with the clinical interpretation of the meaning of the drug concentrations determined in the TDM procedure.

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.