Clinical Chronobiology and Chronotherapeutics with Applications to Asthma

The concept of homeostasis (i.e., constancy of the milieu interne) has long dominated the teaching and practice of medicine. Concepts and findings from chronobiology, the scientific study of biological rhythms, challenge this construct. Biological processes and functions are not at all constant; rather, they are organized in time as rhythms with period lengths that range in duration from as short as a second or less to as long as a year. It is the body's circadian (24h) rhythms that have been researched most intensely. The peak and trough of these rhythms are ordered rather precisely in time to support the biological requirements of activity during the day and sleep at night. The timing of the peak and trough plus the magnitude of variation (amplitude) of physiological and biochemical functions during the 24h give rise to predictable-in-time, day-night patterns in the manifestation and exacerbation of many common medical conditions. Circadian rhythms also can influence the response of patients to diagnostic tests and therapeutic interventions according to their timing with reference to body rhythms. Rhythms in the pathophysiology of medical conditions and patient tolerance to medications constitute the basis for chronotherapeutics, the timing of treatment in relation to biological rhythm determinants as a means of optimizing beneficial effects and safety. The article discusses recent advances in medical chronobiology and chronotherapeutics and their relevance to clinical medicine in general and the management of asthma in particular. Indeed, since asthma is a disease that exhibits rather profound circadian rhythmicity, investigation of its pathophysiology and therapy necessitates a chronobiologic approach.     

Knowledge and Attitudes of American Physicians and Public About Medical Chronobiology and Chronotherapeutics. Findings of Two 1996 Gallup Surveys

Two Gallup telephone interview surveys were conducted during 1996 of 320 American primary care physicians and 1011 adults to assess their knowledge and attitudes about medical chronobiology and chronotherapeu-tics. Of the doctors, 88% claimed to possess at least some familiarity with the concept of chronobiology and circadian rhythms; however, many were not often able to identify correctly the time of day or night when common medical conditions and events most likely occur or worsen. Furthermore, a significant number of doctors believed that chronotherapies, special dosage forms that proportion medications during the day and night in synchrony to need with reference to 24h patterns in the intensity of symptoms and risk of severe medical events, were already being marketed in the United States for angina pectoris, hypertension, respiratory allergies, and other medical conditions even though this was not the case at the time of the survey. On the other hand, the doctors were relatively unaware of those chronotherapies that actually did exist to treat asthma and peptic ulcer disease. American adults also lacked knowledge of temporal patterns in disease and were seldom able to identify the clock time when asthma and myocardial infarction are of greatest risk or when blood pressure is highest. Although neither the American physicians nor adults possessed knowledge of these facts, both had a strong positive attitude toward the concept of chronotherapeutics. Overall, the findings of these Gallup surveys indicate that a massive educational effort is necessary immediately to ensure new developments in medical chronobiology and chronotherapeutics are correctly comprehended and properly incorporated by physicians into clinical medicine and wisely utilized by patients.     

时间生物学—2017年诺贝尔生理或医学奖解读

时间生物学主要研究生物节律的产生及生物钟的运行机制,2017年诺贝尔生理或医学奖的颁布再次引发人们对该领域诸多科学问题的高度关注。生物钟与日月运行引起的环境信号周期性保持同步,有利于生物节律的相位和组织稳态的精确维持。本文介绍了生物节律现象的早期研究及随后生物钟理论体系建立的发展简史,并结合2017年诺贝尔生理或医学奖的解读阐述了果蝇生物钟基因的发现与分子调控机理,进而简单归纳当前时间生物学领域的前沿科学问题,阐明生物钟研究的意义。     

Chronopharmacology and Therapeutic Drug Regulations: Commentary

A quiet, little-publicized development has taken place in the biomedical sciences in recent years. The new terms chronobiology, chronopharmacology, chronopharma-codynamics, chronopharmacokineties, and even chronotoxicology very gently have entered our language and our science. Chronobiologic considerations have been proved to increase or decrease therapeutic drug effectiveness or modify their toxicology. Many authors have pointed out that cues to these advantages or disadvantages may be obtained from animal studies that show that normal changes of cellular rhythms take place at prescribed intervals for many biologic parameters. We are observing replacement of the traditional unidimensional reference intervals by timing drug administration most effectively according to the rhythms having phase, frequency, and amplitude. Oncologists have utilized these concepts most successfully to increase the therapeutic effectiveness and decrease toxicity of antineoplastic agents. In addition, asthma has received great attention as a circadian rhythm-related disorder; angina and myocardial infarction, hypertension, peptic ulcer, and epilepsy are other disease conditions that have been treated successfully by understanding how biological rhythms influence diagnosis and therapy.     

Chronopharmacology and Therapeutic Drug Regulations: Commentary

A quiet, little-publicized development has taken place in the biomedical sciences in recent years. The new terms chronobiology, chronopharmacology, chronopharma-codynamics, chronopharmacokineties, and even chronotoxicology very gently have entered our language and our science. Chronobiologic considerations have been proved to increase or decrease therapeutic drug effectiveness or modify their toxicology. Many authors have pointed out that cues to these advantages or disadvantages may be obtained from animal studies that show that normal changes of cellular rhythms take place at prescribed intervals for many biologic parameters. We are observing replacement of the traditional unidimensional reference intervals by timing drug administration most effectively according to the rhythms having phase, frequency, and amplitude. Oncologists have utilized these concepts most successfully to increase the therapeutic effectiveness and decrease toxicity of antineoplastic agents. In addition, asthma has received great attention as a circadian rhythm-related disorder; angina and myocardial infarction, hypertension, peptic ulcer, and epilepsy are other disease conditions that have been treated successfully by understanding how biological rhythms influence diagnosis and therapy.     

Chronobiology in mental retardation research: progress and prospects.

The premise of this review is that chronobiology, the science of biologic time structure and rhythms, is important in investigations concerning the etiology, mechanisms and effects of deficient mental adaptive development. Chronobiology is also shown to have potential importance in therapeutics and rehabilitation. Most of the information available now and supporting this wide-spread relevance of chronobiology relates to circadian rhythms, but physiological and behavioral rhythms having other cycle lengths also contribute. Recent findings in seven topic areas of chronobiology are reviewed with emphasis on facts and relationships actually or potentially important for consideration in mental retardation research. These are: 1) development of sleep and EEG patterns; 2) rhythmic susceptibility to seizures; 3) adrenocortical and dependent rhythms; 4) circadian rhythms in amino acids and biogenic amines; 5) rhythmic behaviors; 6) circadian rhythms in susceptibility and responses to drugs; and 7) circadian rhythms in human perception and performance.     

Circadian patterns of basic emotional reactivity and stress related events revisited in mice treated with lithium: behavioral rhythmometric analyses

This research dealt with rhythmometric methods for estimating and comparing the main temporal parameters characterizing the circadian structure of behavioral events in mice with and without lithium treatment. Such comparative chronobiologic studies would tend to demonstrate in psychophysiology that this drug does not displace the circadian patterns of basic emotionality, but does displace some behavioral circadian rhythms associated with more corticalized integrations. The present behavioral observations would tend to support the hypothesis that lithium salts modify the circadian structure of emotionality by cortical modulation rather than only by physiological subcortical integrations. Such circadian studies show also that behavioral chronobiology raises some working hypotheses in comparative ethology and permits the development of new heuristic concepts in the field of biological psychiatry.     

CIRCADIAN RHYTHM IN PEAK EXPIRATORY FLOW: ALTERATION WITH NOCTURNAL ASTHMA AND THEOPHYLLINE CHRONOTHERAPY*

We investigated changes in the circadian rhythm of peak expiratory flow (PEF) in seven persons with nocturnal asthma for a 24h span when (1) they were symptom free and their disease was stable, (2) their asthma deteriorated and nocturnal symptoms were frequent, and (3) they were treated with theophylline chronotherapy. Subjects recorded their PEF every 4h between 07:00 and 23:00 one day each period. Circadian rhythms in PEF were assessed using the group-mean cosinor method. The circadian rhythm in PEF varied according to asthma severity. Significant circadian rhythms in PEF were detected during the period when asthma was stable and when it was unstable and nocturnal symptoms were frequent. When nocturnal symptoms were present, the bathyphase (trough time) of the PEF rhythm narrowed to around 04:00; during this time of unstable asthma, the amplitude of the PEF pattern increased 3.9-fold compared to the symptom-free period. No significant group circadian rhythm was detected during theophylline chronotherapy. Evening theophylline chronotherapy proved to be prophylactic for persons whose symptoms before treatment had occurred between midnight and early morning. Changes in the characteristics of the circadian rhythm of PEF, particularly amplitude and time of bathyphase, proved useful in determining when to institute theophylline chronotherapy to avert nocturnal asthma symptoms. (Chronobiology International, 17(4), 513–519, 2000)     

Chronobiologic perspectives of black time—Accident risk is greatest at night: An opinion paper

Simon Folkard in 1997 introduced the phrase black time to draw attention to the fact that the risk of driving accidents (DA) is greater during the night than day in usually diurnally active persons. The 24 h temporal pattern in DA entails circadian rhythms of fatigue and sleep propensity, cognitive and physical performance, and behavior that are controlled, at least in part, by endogenous clocks. This opinion paper extends the concept of black time to reports of excess nighttime accidents and injuries of workers and nocturnal occurrence of certain man-caused catastrophes. We explore the chronobiology of work-related black time accidents and injuries taking into account laboratory and field investigations describing, respectively, circadian rhythms in cognitive performance and errors and mistakes by employees in the conduct of routine occupational tasks. Additionally, we present results of studies pertaining to 24 h patterns of both the number and relative risk (number of events per h/number of workers exposed per h) of work-related accidents (WRA) and injuries (WRI) as well as indices of performance and alertness of a self-selected homogenous survivor cohort of French firefighters (FFs) to explore two possible explanations of black time, namely, 24 h variation in sleep propensity/drossiness characterized by a nocturnal peak and circadian rhythms in cognitive performance characterized by a nocturnal trough. We propose the 24 h pattern of WRA and WRI, particularly of FFs and other highly skilled self-selected cohorts, is more strongly linked to circadian rhythms of fatigue and sleepiness than cognitive performance. Other possible explanations –suppressed expression of circadian rhythms and/or unmasking of ultradian periodicities in cognitive performance in specific circumstances, e.g., highly stressful work, competitive, or life-threatening settings, are also discussed.     

The Rhythmic GABAergic System

GABA is the major inhibitory neurotransmitter in the mammalian brain, and has been implicated in the regulation of a variety of behavioral functions, including biological rhythms. The focus of this minireview is the rhythmic variation of the central GABAergic system, comprising fluctuations of GABA levels and turnover, GABA receptor affinity and postsynaptic activity on the chloride ionophore in rodent's brain. Neurochemical rhythms correlated with diurnal and circadian changes in several behaviors associated with the GABA_A receptor, e.g., anxiolysis-related behavior. GABA is considered to be the principal neurotransmitter of the mammalian circadian system, being present in the suprachiasmatic nuclei and the intergeniculate leaflet. Pharmacological manipulations of GABA_A receptors phase shift circadian rhythms and alter circadian responses to light. Administration of putative modulators of GABA function, like melatonin or neuroactive steroids, affects the timing of biological rhythms. Therefore, not only does the GABAergic system exhibit strong diurnal and circadian variations, but it also serves as one of the key modulators of the circadian apparatus.     

Circadian rhythm in peak expiratory flow: alteration with nocturnal asthma and theophylline chronotherapy

We investigated changes in the circadian rhythm of peak expiratory flow (PEF) in seven persons with nocturnal asthma for a 24h span when (1) they were symptom free and their disease was stable, (2) their asthma deteriorated and nocturnal symptoms were frequent, and (3) they were treated with theophylline chronotherapy. Subjects recorded their PEF every 4h between 07:00 and 23:00 one day each period. Circadian rhythms in PEF were assessed using the group-mean cosinor method. The circadian rhythm in PEF varied according to asthma severity. Significant circadian rhythms in PEF were detected during the period when asthma was stable and when it was unstable and nocturnal symptoms were frequent. When nocturnal symptoms were present, the bathyphase (trough time) of the PEF rhythm narrowed to around 04:00; during this time of unstable asthma, the amplitude of the PEF pattern increased 3.9-fold compared to the symptom-free period. No significant group circadian rhythm was detected during theophylline chronotherapy. Evening theophylline chronotherapy proved to be prophylactic for persons whose symptoms before treatment had occurred between midnight and early morning. Changes in the characteristics of the circadian rhythm of PEF, particularly amplitude and time of bathyphase, proved useful in determining when to institute theophylline chronotherapy to avert nocturnal asthma symptoms. (Chronobiology International, 17(4), 513-519, 2000)     

Circadian disruption: New clinical perspective of disease pathology and basis for chronotherapeutic intervention

Biological processes are organized in time as innate rhythms defined by the period (τ), phase (peak [Φ] and trough time), amplitude (A, peak-trough difference) and mean level. The human time structure in its entirety is comprised of ultradian (τ < 20 h), circadian (20 h > τ < 28 h) and infradian (τ > 28 h) bioperiodicities. The circadian time structure (CTS) of human beings, which is more complicated than in lower animals, is orchestrated and staged by a brain central multioscillator system that includes a prominent pacemaker – the suprachiasmatic nuclei of the hypothalamus. Additional pacemaker activities are provided by the pineal hormone melatonin, which circulates during the nighttime, and the left and right cerebral cortices. Under ordinary circumstances this system coordinates the τ and Φ of rhythms driven by subservient peripheral cell, tissue and organ clock networks. Cyclic environmental, feeding and social time cues synchronize the endogenous 24 h clocks and rhythms. Accordingly, processes and functions of the internal environment are integrated in time for maximum biological efficiency, and they are also organized and synchronized in time to the external environment to ensure optimal performance and response to challenge. Artificial light at night (ALAN) exposure can alter the CTS as can night work, which, like rapid transmeridian displacement by air travel, necessitates realignment of the Φ of the multitude of 24 h rhythms. In 2001, Stevens and Rea coined the phrase “circadian disruption” (CD) to label the CTS misalignment induced by ALAN and shift work (SW) as a potential pathologic mechanism of the increased risk for cancer and other medical conditions. Current concerns relating to the effects of ALAN exposure on the CTS motivated us to renew our long-standing interest in the possible role of CD in the etiopathology of common human diseases and patient care. A surprisingly large number of medical conditions involve CD: adrenal insufficiency; nocturia; sleep-time non-dipping and rising blood pressure 24 h patterns (nocturnal hypertension); delayed sleep phase syndrome, non-24 h sleep/wake disorder; recurrent hypersomnia; SW intolerance; delirium; peptic ulcer disease; kidney failure; depression; mania; bipolar disorder; Parkinson’s disease; Smith–Magenis syndrome; fatal familial insomnia syndrome; autism spectrum disorder; asthma; byssinosis; cancers; hand, foot and mouth disease; post-operative state; and ICU outcome. Poorly conceived medical interventions, for example nighttime dosing of synthetic corticosteroids and certain β-antagonists and cyclic nocturnal enteral or parenteral nutrition, plus lifestyle habits, including atypical eating times and chronic alcohol consumption, also can be causal of CD. Just as surprisingly are the many proven chronotherapeutic strategies available today to manage the CD of several of these medical conditions. In clinical medicine, CD seems to be a common, yet mostly unrecognized, pathologic mechanism of human disease as are the many effective chronotherapeutic interventions to remedy it.     

How shall we proceed?

As we all know, the 2017 Nobel Prize in Physiology or Medicine was awarded in the field of Chronobiology. This was received with great excitement by all those who study different aspects of Biological Rhythms. In this brief essay, I would like to address the question, how shall we proceed after such great accomplishment from our esteemed colleagues? The short answer is, of course, keep up with the good work! There are plenty of unsolved questions beyond unravelling the molecular circadian clock. My choice of imperative topic is to teach circadian physiology at medical schools. Here, I suggest the term Chronostasis, to refer to the concept of timing physiological processes. The use of such concept will help medical students to understand physiology and medicine in circadian perspective to foster translational chronobiology in the short term.     

Overexpression of lalA, a paralog of labA, is capable of affecting both circadian gene expression and cell growth in the cyanobacterium Synechococcus elongatus PCC 7942

In the cyanobacterium Synechococcus elongatus, LabA negatively regulates circadian gene expression under the control of Kai-protein-based clock. Here we conducted a molecular genetic analysis of lalA, a paralog of labA. Although a lalA loss of function mutant did not exhibit any apparent phenotype under our experimental conditions, lalA overexpression inhibited cell growth and decreased cell viability. Moderate lalA overexpression brought about abnormalities in circadian gene expression: reduced amplitude of kaiBC expression rhythm, and altered peak and trough timing of psbAI and kaiA expression rhythms. These results imply that lalA is capable of affecting circadian gene expression and cell growth.     

International Society of Chronobiology: Membership Information

The International Society for Chronobiology has as its aims, furthering the study of temporal changes in living matter, including biological rhythms in development and ageing in individuals and populations; studying and defining the mechanisms of temporal changes; fostering practical applications for chronobiological findings to mankind in basic and applied biology, physiology, work hygiene and the medical sciences; promoting education in and wide understanding of chronobiology; and furthering contact between scientists in the field and providing a forum for practitioners of chronobiology.     

Sharing time on the fly

The investigation of circadian clock function in Drosophila has progressed from the identification of clock genes to the analysis of timing mechanisms in the cells and tissues where these genes are expressed. As the biological context for investigating circadian clock systems is expanded, new features of molecular timing mechanisms are becoming apparent. Examples come first from studies on peripheral clocks, which perform local, tissue-specific functions as well as global functions that relate to the control of individual behavior, and second from the evaluation of social influences on circadian rhythms. The identification of inter-organismal components of the circadian system in Drosophila suggests new perspectives as the progression continues from the systems level to the social level and onwards to the level of ecosystems.     

Chronobiology of the mammalian response to ionizing radiation. Potential applications in oncology

Ionizing radiation from all sources under appropriate conditions leads to cell death and tissue damage. It is used in cancer treatment under the assumption of a higher radiosensitivity of the fast dividing tumor cells as compared with adjacent host tissues. The radiosensitivities of proliferating host tissues like bone marrow and gastrointestinal lining epithelium are dose limiting. Since these host tissues and many tumors show circadian and other periodicities in their cell proliferation, the timing of radiation treatment according to host and/or tumor rhythms is expected to improve the toxic/therapeutic ratio of the treatment. The experimental data on the chronobiology of radiation exposure show circadian rhythmicity in radiation response after whole body irradiation in mice and rats with highest toxicity in light-dark 12h:12h synchronized animals during their daily activity span. Bone marrow toxicity as well as gastrointestinal epithelial damage show circadian rhythms in part due to radiation damage to the stem cells involved and especially in the intestine also due to damage to the microvasculature. Chronoradiotherapy of malignant tumors seems promising, alone or in combination with response modifiers, provided the host and potential tumor rhythms can be monitored.     

International Society of Chronobiology: Membership Information

The International Society for Chronobiology has as its aims, furthering the study of temporal changes in living matter, including biological rhythms in development and ageing in individuals and populations; studying and defining the mechanisms of temporal changes; fostering practical applications for chronobiological findings to mankind in basic and applied biology, physiology, work hygiene and the medical sciences; promoting education in and wide understanding of chronobiology; and furthering contact between scientists in the field and providing a forum for practitioners of chronobiology.