Circadian Influences on Myocardial Ischemia-Reperfusion Injury and Heart Failure.

The impact of circadian rhythms on cardiovascular function and disease development is well established, with numerous studies in genetically modified animals emphasizing the circadian molecular clock's significance in the pathogenesis and pathophysiology of myocardial ischemia and heart failure progression. However, translational preclinical studies targeting the heart's circadian biology are just now emerging and are leading to the development of a novel field of medicine termed circadian medicine. In this review, we explore circadian molecular mechanisms and novel therapies, including (1) intense light, (2) small molecules modulating the circadian mechanism, and (3) chronotherapies such as cardiovascular drugs and meal timings. These promise significant clinical translation in circadian medicine for cardiovascular disease. (4) Additionally, we address the differential functioning of the circadian mechanism in males versus females, emphasizing the consideration of biological sex, gender, and aging in circadian therapies for cardiovascular disease.

Chronotherapy for patients with a depressive episode treated in a public outpatient mental healthcare clinic in Norway: protocol for a randomised controlled trial.

INTRODUCTION: Depression is highly prevalent in outpatients receiving treatment for mental disorders. Treatment as usual (TAU) usually consists of either psychotherapy and/or antidepressant medication and often takes several weeks before clinical effect. Chronotherapy, consisting of sleep deprivation, sleep-wake phase advancement and stabilisation, and light therapy, is a possible addition to TAU that may decrease the time to treatment response. This randomised controlled trial will examine the benefits of adding chronotherapy to TAU compared with TAU alone. METHODS AND ANALYSIS: The trial will include 76 participants with a depressive episode who initiate outpatient treatment at a secondary mental healthcare outpatient clinic at St. Olavs University Hospital. Participants will be randomly allocated 1:1 to either chronotherapy in addition to TAU or TAU alone. Assessments will be performed at baseline, day 3, day 4, day 7, day 14 and weeks 4, 8, 24 and 52, in addition to longer-term follow ups. The main outcome is difference in levels of depressive symptoms after week 1 using the Inventory of Depressive Symptomatology Self-Report. Secondary outcomes include levels of depressive symptoms at other time points, as well as anxiety, health-related quality of life and sleep assessed through subjective and objective measures. ETHICS AND DISSEMINATION: The study protocol has been approved by the Regional Committee for Medical Research Ethics Central Norway (ref: 480812) and preregistered at ClinicalTrials.gov (ref: NCT05691647). Results will be published via peer-reviewed publications, presentations at research conferences and presentations for clinicians and other relevant groups. The main outcomes will be provided separately from exploratory analysis. TRIAL REGISTRATION NUMBER: NCT05691647.

Circadian Regulation of Drug Responses: Toward Sex-Specific and Personalized Chronotherapy.

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.

Circadian rhythm-based cancer therapy in randomised clinical trials.

INTRODUCTION: Since the 2017 Nobel Prize awarded to J. Hall, M. Rosbash and M.W. Young for their discoveries of molecular mechanisms behind the biological clock, circadian rhythm-based therapy, also known as chronotherapy, is receiving more attention in oncology and the number of anatomical sites of interest in this field is increasing. This observation is in line with the clinical evidence provided by trials on head and neck, lung, colorectal and cervical cancers, as well as the presently ongoing chronotherapy trials for breast and brain cancers. AREAS COVERED: The aim of this review was to collate all randomized trials conducted on chronotherapy for various tumor sites and to appraise the evidence for chrono-oncology to advance personalized therapy. Relevant literature was collected from Pubmed/Medline databases and from clinicatrials.gov. EXPERT OPINION: Current randomized clinical trials offer a certain level of evidence for the potential of chronotherapy to personalize oncologic treatment. However, comparison of trial results is hindered by the differences in timing of radiation/chemotherapy, the absence of harmonized recommendations for treatment outcome evaluation and not ultimately, the general lack of considering gender as a matched variable in trials, which was found to be a powerful factor influencing response to treatment.

Implications of biological clocks in pharmacology and pharmacokinetics of antitumor drugs.

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.

An in silico investigation: Can melatonin serve as an adjuvant in NR1D1-linked chronotherapy for amyotrophic lateral sclerosis?

Chronobiology, which studies biological rhythms and their impacts on health, presents a potential avenue for treating amyotrophic lateral sclerosis. Clock gene-related therapies, focusing on genes responsible for regulating biological rhythms, may hold promise in the treatment. Among these clock genes, nuclear receptor subfamily 1 Group D member 1 (NR1D1) plays a vital role in neurodegenerative diseases. In this particular study, it was aimed to investigate the potential of FDA-approved drugs commonly used in amyotrophic lateral sclerosis treatment and melatonin, a hormone known for its role in regulating sleep-wake cycles, as ligands for clock gene-related therapy. The ligands were subjected to molecular docking and molecular dynamics simulation methods against the NR1D1 clock gene. These results suggested that combining melatonin with FDA-approved medications commonly used in the treatment might yield positive outcomes. This study provides preliminary data and lays the groundwork for future investigations involving in vitro (laboratory-based) and in vivo (animal or human-based) research on chronotherapy. In summary, this research highlights the potential of clock gene-related therapy utilizing melatonin in conjunction with FDA-approved drugs for amyotrophic lateral sclerosis treatment, offering insights into novel treatment strategies. The findings underscore the need for further studies to explore the effectiveness of this hypothetical approach in experimental and clinical settings.

Critical appraisal of recent translational chronopharmacology and chronotherapeutic reviews, meta-analyses, and pragmatic patient trials discloses significant deficiencies of design and conduct and suspect findings.

The conduct of molecular and laboratory animal circadian rhythm research has increased exponentially in the past few decades, such that today investigations are being performed by scientists of many diverse disciplines. Knowledge gained from past works is now being explored for translational applications to clinical medicine, often termed "circadian medicine," through the implementation of patient trials. However, these trials are being led, more often than not, by investigators who have little or no formal training and in-depth expertise in the methods of human circadian rhythm research, causing them to be deficient in design and produce dubious findings that have already led to unnecessary medical controversy at the expense of advances in patient care. Evidence of the very significant shortcomings of today's translational circadian medicine research is exemplified in two recent publications in well-read reputable medical journals concerning the chronotherapy of blood pressure (BP) medications: one a review and meta-analysis by Maqsood et al. published in the journal Hypertension in 2023 that pertains to ingestion-time differences in the extent of BP reduction exerted by hypertensive medications and the other a report by Mackenzie et al. in the journal Lancet in 2022 that details the results of the pragmatic TIME study that assessed ingestion-time differences in cardiovascular disease outcomes. Herein, we appraise the inaccurate trial selection, lack of quality assessment, and the numerous other shortcomings that culminated in suspect findings and faulty conclusions of the former, as well as the deficiencies in design and conduct of the latter using as reference the eight items identified in 2021 by a working committee of the International Society for Chronobiology and American Association for Medical Chronobiology and Chronotherapeutics as being necessary for high-quality research of circadian rhythm-dependencies of the therapeutic effects of BP-lowering medications. The TIME study when rated for its quality according to the extent to which its investigational methods satisfy all of the eight recommended items attains a very low overall score of + 1 out of a possible range of -1 to + 7. Moreover, our review of the methods of the currently ongoing pragmatic BedMed trial discloses major deficiencies of the same sort rending a poor quality score of + 0.5. Although the focus of this article is the appraisal of the quality of contemporary circadian medicine hypertension chronotherapy research, it additionally exposes the inadequacies and dubious quality of the critique of such manuscripts submitted for publication to influential journals, in that some peer reviewers might also be deficient in the knowledge required to properly rate their merit.

The circadian rhythm: an influential soundtrack in the diabetes story.

Type 2 Diabetes Mellitus (T2DM) has been the main category of metabolic diseases in recent years due to changes in lifestyle and environmental conditions such as diet and physical activity. On the other hand, the circadian rhythm is one of the most significant biological pathways in humans and other mammals, which is affected by light, sleep, and human activity. However, this cycle is controlled via complicated cellular pathways with feedback loops. It is widely known that changes in the circadian rhythm can alter some metabolic pathways of body cells and could affect the treatment process, particularly for metabolic diseases like T2DM. The aim of this study is to explore the importance of the circadian rhythm in the occurrence of T2DM via reviewing the metabolic pathways involved, their relationship with the circadian rhythm from two perspectives, lifestyle and molecular pathways, and their effect on T2DM pathophysiology. These impacts have been demonstrated in a variety of studies and led to the development of approaches such as time-restricted feeding, chronotherapy (time-specific therapies), and circadian molecule stabilizers.

Understanding the role of chronopharmacology for drug optimization: what do we know?

INTRODUCTION: 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. AREAS COVERED: 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. EXPERT OPINION: 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.

Gulf war illness inflammation reduction trial: A phase 2 randomized controlled trial of low-dose prednisone chronotherapy, effects on health-related quality of life.

BACKGROUND: Gulf War illness (GWI) is a deployment-related chronic multisymptom illness impacting the health-related quality of life (HRQOL) of many U.S. Military Veterans of the 1990-91 Gulf War. A proinflammatory blood biomarker fingerprint was discovered in our initial study of GWI. This led to the hypothesis that chronic inflammation is a component of GWI pathophysiology. OBJECTIVES: The GWI inflammation hypothesis was tested in this Phase 2 randomized controlled trial (RCT) by measuring the effects of an anti-inflammatory drug and placebo on the HRQOL of Veterans with GWI. The trial is registered at ClinicalTrials.gov, Identifier: NCT02506192. RCT DESIGN AND METHODS: Gulf War Veterans meeting the Kansas case definition for GWI were randomized to receive either 10 mg modified-release prednisone or matching placebo. The Veterans RAND 36-Item Health Survey was used to assess HRQOL. The primary outcome was a change from baseline in the physical component summary (PCS) score, a measure of physical functioning and symptoms. A PCS increase indicates improved physical HRQOL. RESULTS: For subjects with a baseline PCS <40, there was a 15.2% increase in the mean PCS score from 32.9±6.0 at baseline to 37.9±9.0 after 8 weeks on modified-release prednisone. Paired t-test analysis determined the change was statistically significant (p = 0.004). Eight weeks after cessation of the treatment, the mean PCS score declined to 32.7±5.8. CONCLUSIONS: The prednisone-associated improvement in physical HRQOL supports the GWI inflammation hypothesis. Determining the efficacy of prednisone as a treatment for GWI will require a Phase 3 RCT.

Controlled Release Technologies for Chronotherapy: Current Status and Future Perspectives.

The expression "as sure as night follows a day" emulates those certain cycles in the environment that are always stable. Circadian rhythms are a group of processes that occur within the body in synchronisation with the external factors in a 24 h cycle. Changes in lifestyle and work shifts have disrupted these stable rhythms, which is a leading cause of lifestyle diseases. Associations between these biological clocks and diseases are abundant. However, it is also known that certain drugs work more efficiently and have minimum toxicity when given during a particular phase of the circadian cycle. Chronotherapeutics focuses on treating diseases according to the endogenous processes which mediate xenobiotic metabolism and drug response at a cellular level. Therefore, treatment of those diseases that show aggravation of symptoms according to the circadian rhythms at a particular time is highly beneficial by chronotherapy. In this article, we have emphasised how the changes in rhythms caused diseases and how chronotherapeutic approaches such as controlled drug release technologies can be a better option for these circadian manipulations that seem to influence all types of disease conditions.

Circadian control of white and brown adipose tissues.

White and brown adipose tissues are highly dynamic organs anticipating and responding to changes in the environment. The circadian timing system facilitates anticipation, and it is therefore not surprising that circadian disturbances, a prominent feature of modern 24/7 society, increase the risk for (cardio)metabolic diseases. In this mini-review, we will address mechanisms and strategies to mitigate disease risk associated with circadian disturbances. In addition, we discuss the opportunities arising from the knowledge we gained about circadian rhythms in these adipose tissues, including the application of chronotherapy, optimizing endogenous circadian rhythms to allow for more effective intervention, and the identification of novel therapeutic targets.

Chronotherapy in dentistry: A scoping review.

The circadian clock modulates almost all vital aspects of our physiology and metabolism, including processes relevant to dentistry, such as healing, inflammation and nociception. Chronotherapy is an emerging field aiming to improve therapeutic efficacy and decrease adverse effects on health outcomes. This scoping review aimed to systematically map the evidence underpinning chronotherapy in dentistry and to identify gaps in knowledge. We conducted a systematic scoping search using four databases (Medline, Scopus, CINAHL and Embase). We identified 3908 target articles screened by two blinded reviewers, and only original animal and human studies investigating the chronotherapeutic use of drugs or interventions in dentistry were included. Of the 24 studies included, 19 were human studies and five were animal studies. Chrono-radiotherapy and chrono-chemotherapy reduced treatment side effects and improved therapeutic response, leading to higher survival rates in cancer patients. Animal studies reported that tooth movement and periodontal tissue response to orthodontic forces follow a diurnal rhythm that might influence bone metabolism. Profound and prolonged local anesthesia could be achieved when injected in the evening. Although the overall quality of the included studies was low, chronotherapy applications in dentistry seem to have favourable outcomes, especially in head and neck cancer treatments.

A new time dimension in the fight against metastasis.

Despite advances in uncovering vulnerabilities, identifying biomarkers, and developing more efficient treatments, cancer remains a threat because of its ability to progress while acquiring resistance to therapy. The circadian rhythm governs most of the cellular functions implicated in cancer progression, and its exploitation therefore opens new promising directions in the fight against metastasis. In this review we summarize the role of the circadian rhythm in tumor development and progression, with emphasis on the circadian rhythm-regulated elements that control the generation of circulating tumor cells (CTCs) and metastasis. We then present data on chronotherapy and discuss how circadian rhythm investigations may open new paths to more effective anticancer treatments.

Chronotherapy in Glioblastoma: state of the art and future perspectives.

Circadian rhythms regulate various processes in the human body, including drug metabolism. Chronotherapy optimizes treatment timing based on the circadian rhythm of the individual patient, such that the treatment efficacy is maximized, and adverse effects are minimized. It has been explored in different cancers with varying conclusions. Glioblastoma multiforme (GBM) is the most aggressive type of brain tumour with a very dismal prognosis. In recent years, there has been very little success in designing successful therapies to fight this disease. Chronotherapy offers the opportunity to leverage existing treatments to extend patient survival and to increase their quality of life. Here, we discuss recent advances in using chronotherapy regimens in the treatment of GMB, such as radiotherapy, temozolomide (TMZ) and bortezomib, as well as discuss novel treatments with drugs of short half-life or circadian phase specific activity, and examine the therapeutic potential of new approaches that target elements of the core circadian clock.

Impact of Chronotherapy on 6-Mercaptopurine Metabolites in Inflammatory Bowel Disease: A Pilot Crossover Trial.

INTRODUCTION: Chronotherapy is the timing of medication according to biological rhythms of the host to optimize drug efficacy and minimize toxicity. Efficacy and myelosuppression of azathioprine/6-mercaptopurine (AZA/6-MP) are correlated with the metabolite 6-thioguanine, while the metabolite 6-methylmercaptopurine correlates with hepatotoxicity. METHODS: This was a single-center, 10-week prospective crossover trial involving 26 participants with inactive inflammatory bowel disease (IBD) on a stable dose and time of AZA or 6-MP therapy. Participants were switched to the opposite delivery time (morning or evening) for 10 weeks, and metabolite measurements were at both time points. RESULTS: In the morning vs evening dosing, 6-thioguanine levels were 225.7 ± 155.1 vs 175.0 ± 106.9 ( P < 0.01), and 6-methylmercaptopurine levels were 825.1 ± 1,023.3 vs 2,395.3 ± 2,880.3 ( P < 0.01), with 69% (18 out of 26) of participants had better metabolite profiles in the morning. Participants with optimal dosing in the morning had an earlier chronotype by corrected midpoint of sleep. DISCUSSION: In the first study on a potential role of chronotherapy in IBD, we found (i) morning dosing of AZA or 6-MP resulted in more optimal metabolite profiles and (ii) host chronotype could help identify one-third of patients who would benefit from evening dosing. Circadian regulation of metabolic enzymes of AZA/6-MP activity in the liver is the likely cause of these differences. This pilot study confirms the need to incorporate chronotherapy in future multicenter clinical trials on IBD disease.

Temozolomide Chronotherapy in Glioma: A Systematic Review.

Outcomes for patients with high-grade glioma remain poor. Temozolomide (TMZ) is the only drug approved for first-line treatment of glioblastoma multiforme, the most aggressive form of glioma. Chronotherapy highlights the potential benefit of timed TMZ administration. This is based on pre-clinical studies of enhanced TMZ-induced glioma cytotoxicity dependent on circadian, oscillating expression of key genes involved in apoptosis, DNA damage repair, and cell-cycle mediated cell death. The current systematic review's primary aim was to evaluate the efficacy and toxicity of TMZ chronotherapy. A systemic review of literature following PRISMA guidelines looking at clinical outcomes on TMZ chronotherapy on gliomas was performed. The search in the English language included three databases (PubMed, EMBASE, and Cochrane) and five conferences from 1946 to April 2022. Two independent reviewers undertook screening, data extraction, and risk-of-bias assessment. A descriptive analysis was conducted due to limited data. Of the 269 articles screened, two unique studies were eligible and underwent abstraction for survival and toxicity findings. Both studies-one a retrospective cohort study (n = 166) and the other a prospective randomized feasibility study (n = 35)-were conducted by the same academic group and suggested a trend for improved overall survival, but possibly increased toxicity when TMZ was administered in the morning (vs. evening). There was limited evidence suggesting possible therapeutic value from administering TMZ in the morning, which may be consistent with the pre-clinical observations of the importance of the timing of TMZ administration in vitro. Larger, pragmatic, prospective randomized controlled trials are needed to ascertain the value of TMZ chronotherapy to provide optimized and equitable care for this population.

Hair Follicles as a Critical Model for Monitoring the Circadian Clock.

Clock (circadian) genes are heterogeneously expressed in hair follicles (HFs). The genes can be modulated by both the central circadian system and some extrinsic factors, such as light and thyroid hormones. These circadian genes participate in the regulation of several physiological processes of HFs, including hair growth and pigmentation. On the other hand, because peripheral circadian genes are synchronized with the central clock, HFs could provide a noninvasive and practical method for monitoring and evaluating multiple circadian-rhythm-related conditions and disorders among humans, including day and night shifts, sleep-wake disorders, physical activities, energy metabolism, and aging. However, due to the complexity of circadian biology, understanding how intrinsic oscillation operates using peripheral tissues only may be insufficient. Combining HF sampling with multidimensional assays such as detection of body temperature, blood samples, or certain validated questionnaires may be helpful in improving HF applications. Thus, HFs can serve as a critical model for monitoring the circadian clock and can help provide an understanding of the potential mechanisms of circadian-rhythm-related conditions; furthermore, chronotherapy could support personalized treatment scheduling based on the gene expression profile expressed in HFs.