Clinical chronopharmacology in the elderly

The behavior and effects of medications may be modified in the elderly. Factors contributing to such alterations may involve differences in drug pharmacokinetics and response and/or social and economic factors that affect nutrition and compliance to medications. Many studies have been devoted to such factors, but most of them have not taken into account chronopharmacologic data. Indeed, drug-administration time constitutes an additional factor of variability in drug response in the elderly. Biological rhythm-dependent differences in the kinetics and dynamics of medications seem to be diminished or altered with aging. Chronopathological (rhythmic aspects of disease) data in the elderly are of particular importance, taking into account frequently associated diseases, such as chronic obstructive pulmonary disease, cancer, diabetes, glaucoma, hypertension, and inflammatory conditions, among others. Although some chronobiological data are available, chronopharmacologic phenomena have yet to be extensively investigated in the elderly. Most of the sparse studies concern drug chronokinetics, but the data found in the literature do not reveal a clear trend in the age-related changes. Chronokinetic variations in the elderly, compared to young adults, suggest an amplification of the administration-time effects, as demonstrated for digoxin; dampening, as demonstrated for indomethacin; or detection of administration-time effects only in aged but not in young subjects, as found for others medications. Additional studies are needed to better understand the influence of age on the chronokinetics of medications. Moreover, the literature on possible administration-time differences in drug dynamics in the elderly is also very sparse. Altered receptor and/or post-receptor properties and impaired sensitivity of homeostatic mechanisms have yet to be studied from a chronopharmacological point of view. Thus, additional studies are needed to properly understand how drug responses in the elderly may vary in relation to the circadian timing of medications.     

Food interactions with once-a-day theophylline preparations: a review

At present, theophylline is used predominantly as sustained-release dosage forms. Since the mid-seventies many such products have been introduced and have found huge application for use with a dosage interval of 12 hr ('twice-a-day' preparations). Since 1983 theophylline has also been available as preparations that can be given with an interval of 24 hr ('once-a-day' preparations). The release of theophylline from sustained-release dosage forms can be influenced (either increased or decreased) by concomitant intake of food. Obviously, ultra-slow-releasing products are most vulnerable to food effects. With some preparations the composition of the meal, especially its fat content, determines the degree of the food effect. The effect of meal timing and content on once-a-day theophylline preparations must be known since rather large doses are ingested all at a single time. If food can alter the release of theophylline in an unexpected manner from ultra-slow preparations, drug effectiveness may be impaired if release is inhibited or toxicity might result if sudden release of drug occurs. Herein, information about food interaction with once-a-day theophylline preparations is reviewed as this topic is important both for clinicians as well as those concerned with chronopharmacologic investigations of such medications.     

Aspects of chronopharmacology and chronotherapy in children

Pediatric studies involving chronopharmacology until now have been limited mainly to investigation of circadian patterns in children of 6 to 15 years. This means that: a. data on newborns and even on infants of one year or younger are not available, and b. other bioperiodicities, such as those of one year (infradian rhythms), have not yet been explored in older children. Biological time-related changes have been documented for phenytoin and theophylline with regard to their pharmacokinetics and for orciprenaline, ipratropium bromide, corticosteroids and anticancerous agents with regard to their effectiveness. Despite the small number of investigations performed to date, results indicate that: a. more comprehensive and precise characterization of pharmacokinetic and pharmacodynamic phenomena can be achieved by a chronopharmacological approach than the conventional one and, b. better therapeutics can be achieved using chronopharmacological facts since an appropriate timing of medicines with regard to biological rhythms is likely to enhance desired and/or reduce undesired effects.     

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.     

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.     

动物内源褪黑素调控生物节律的研究进展

内源褪黑素对人类和其他哺乳动物的节律行为具有调控功能。生物节律是自然进化赋予生命的基本特征之一,生物体的生命活动受到生物节律的控制与影响。在哺乳动物中,节律调控中心是松果体,其主要功能是合成和分泌褪黑素。褪黑素广泛参与生物体节律行为的调节,本文从褪黑素的产生和作用机制,分别阐述褪黑素对昼夜节律行为和多种年节律行为的调控作用,同时明确褪黑素与生物钟及神经内分泌系统的直接作用和反馈互动的复杂集合,进一步揭示褪黑素调控生物节律的重要作用,以期为褪黑素的基础研究以及未来探究生物体的生物钟内源性发生机制提供参考。     

Constant Pharmacologic Effect and Chronopharmacology: Theoretical Aspects

The theoretical drug infusion rates requisite to obtain a constant pharmacologic effect are determined taking into account chronopharmacologic phenomena. The introduction of chronopharmacology into pharmacokinetic theory leads to a clocktime-dependent infusion rate. The infusion modulation depends both on type of chronophenomenon, chronopharmacokinetics or chronestesy, and plasma clearance rate of the drug. In the presence of chronestesy of a biosystem the pharmacologic effect can be maintained constant only when plasma drug clearance is fast enough to allow an adequate modulation of the plasma drug concentration. Although the established equations proceed from theoretical concept they could be useful for programming drug delivery systems.     

Constant Pharmacologic Effect and Chronopharmacology: Theoretical Aspects

The theoretical drug infusion rates requisite to obtain a constant pharmacologic effect are determined taking into account chronopharmacologic phenomena. The introduction of chronopharmacology into pharmacokinetic theory leads to a clocktime-dependent infusion rate. The infusion modulation depends both on type of chronophenomenon, chronopharmacokinetics or chronestesy, and plasma clearance rate of the drug. In the presence of chronestesy of a biosystem the pharmacologic effect can be maintained constant only when plasma drug clearance is fast enough to allow an adequate modulation of the plasma drug concentration. Although the established equations proceed from theoretical concept they could be useful for programming drug delivery systems.     

Biological and psychological rhythms: An integrative approach to rhythm disturbances in autistic disorder

Biological rhythms are crucial phenomena that are perfect examples of the adaptation of organisms to their environment. A considerable amount of work has described different types of biological rhythms (from circadian to ultradian), individual differences in their patterns and the complexity of their regulation. In particular, the regulation and maturation of the sleep–wake cycle have been thoroughly studied. Its desynchronization, both endogenous and exogenous, is now well understood, as are its consequences for cognitive impairments and health problems. From a completely different perspective, psychoanalysts have shown a growing interest in the rhythms of psychic life. This interest extends beyond the original focus of psychoanalysis on dreams and the sleep–wake cycle, incorporating central theoretical and practical psychoanalytic issues related to the core functioning of the psychic life: the rhythmic structures of drive dynamics, intersubjective developmental processes and psychic containment functions. Psychopathological and biological approaches to the study of infantile autism reveal the importance of specific biological and psychological rhythmic disturbances in this disorder. Considering data and hypotheses from both perspectives, this paper proposes an integrative approach to the study of these rhythmic disturbances and offers an etiopathogenic hypothesis based on this integrative approach.     

Interindividual Differences in Chronopharmacologic Effects of Drugs: A Background for Individualization of Chronotherapy

In order to optimize chronotherapeutic schedules (designs), we examined the interindividual differences in chronopharmacologic effects of drugs with consideration of the following three factors: (a) inherited factors of direct relevance to chronopharmacology (genetic variability, gender-related differences) as well as age-related differences; (b) interindividual difference in chronoeffective-ness related to disease (e.g., various types and stages of cancer, affective disorders, etc.) as well as to drug-dependent alteration (phase shifts, distortion) of biological rhythms; and (c) means to solve problems resulting from the need of individualization in chronotherapy. These involve the use of circadian marker rhythms (MR) whose characteristics (peak or trough time, amplitude, etc.) can be precisely quantified and thus are applicable as a reference system for physiologic, pathologic, pharmacologic, and therapeutic uses. The MR has to be specific and pertinent and must be easily monitored and documented. This approach can be further advanced by the use of a battery of MRs rather than a single MR. Other suggested means relate to the fact that chronobiotics (agents capable of influencing parameters of a set of biological rhythms) should be considered (e.g., corticoids and adrenocorticotropic hormone) and/or to the subject's synchronization should be enforced by “conventional” zeitgebers (e.g., bright light, physical activity).     

Interindividual Differences in Chronopharmacologic Effects of Drugs: A Background for Individualization of Chronotherapy

In order to optimize chronotherapeutic schedules (designs), we examined the interindividual differences in chronopharmacologic effects of drugs with consideration of the following three factors: (a) inherited factors of direct relevance to chronopharmacology (genetic variability, gender-related differences) as well as age-related differences; (b) interindividual difference in chronoeffective-ness related to disease (e.g., various types and stages of cancer, affective disorders, etc.) as well as to drug-dependent alteration (phase shifts, distortion) of biological rhythms; and (c) means to solve problems resulting from the need of individualization in chronotherapy. These involve the use of circadian marker rhythms (MR) whose characteristics (peak or trough time, amplitude, etc.) can be precisely quantified and thus are applicable as a reference system for physiologic, pathologic, pharmacologic, and therapeutic uses. The MR has to be specific and pertinent and must be easily monitored and documented. This approach can be further advanced by the use of a battery of MRs rather than a single MR. Other suggested means relate to the fact that chronobiotics (agents capable of influencing parameters of a set of biological rhythms) should be considered (e.g., corticoids and adrenocorticotropic hormone) and/or to the subject's synchronization should be enforced by “conventional” zeitgebers (e.g., bright light, physical activity).     

Aging and biological rhythms in primates

All living organisms exhibit rhythmic activities in a wide variety of endocrine and behavioural parameters. These biological rhythms are endogenously generated by a circadian clock, and they are entrained by cyclic variations of environmental factors called synchronizers. Aging is associated with changes in amplitude and temporal organization of many daily and seasonal rhythms. In humans, daily rhythms of sleep, thermoregulation and hormonal secretion are severely altered with aging. Except in humans, studies on primates are scarce. However, age-related effects on biological rhythms are relatively consistent among primate species studied to date, including humans. Therefore, non human primates are of valuable use for such investigations. Most studies have been performed on the Rhesus macaque (longevity 35-40 years) and on the gray mouse lemur (longevity 10-12 years). Like in humans, the rest-activity rhythm becomes fragmented in aged primates, and shows an increased activity during the resting period. Aging induces a decrease in amplitude of the body temperature rhythm and an increase in energy consumption. Various hormonal secretions exhibit a decrease with aging, but the rhythmic components of these declines have not always been depicted. Moreover, changes (amplitude or phase) in daily variations depended of the hormonal secretion tested. Taken together, these results suggest that the biological clock in the brain would be a primary target of aging. The main central clock is located in the suprachiasmatic nucleus of the hypothalamus whose endogenous oscillations are entrained by light. In this brain structure, cellular function and sensitivity to light show drastic changes with age in the mouse lemur. The precise knowledge of age-related alterations of biological rhythms in primates can have important consequences on the development of new treatments to maintain or restore biological rhythmicity in the elderly.     

Mechanists Must be Holists Too! Perspectives from Circadian Biology

The pursuit of mechanistic explanations in biology has produced a great deal of knowledge about the parts, operations, and organization of mechanisms taken to be responsible for biological phenomena. Holist critics have often raised important criticisms of proposed mechanistic explanations, but until recently holists have not had alternative research strategies through which to advance explanations. This paper argues both that the results of mechanistic strategies has forced mechanists to confront ways in which whole systems affect their components and that new representational and modeling strategies are providing tools for understanding these effects of whole systems upon components. Drawing from research on the mechanism responsible for circadian rhythms in mammals, I develop two examples in which mechanistic analysis is being integrated into a more holist perspective: research revealing intercellular integration of circadian mechanisms with those involved in cell metabolism and research revealing that stable?rhythms are dependent on how individual cells in the suprachiasmatic nucleus synchronize with each other to generate regular rhythms. Tools such as network diagramming and computational modeling are providing means to integrate mechanistic models into accounts of whole systems.     

In-vitro circadian rhythm of murine bone marrow progenitor production

Hematopoietic processes display 24h rhythms both in rodents and in human beings. We hypothesized these rhythms to be in part generated by a circadian oscillator within the bone marrow. The ability of murine bone marrow granulo-monocytic (GM) precursors to form colonies following colony-stimulating factor (rm GM-CSF) exposure was investigated in liquid culture samples obtained every 3 h for a span of up to 198 h. The CFU-GM count varied rhythmically over the first 4 d of culture, with a reproducible maximum in the early morning hours, similar to that observed in vivo. These experiments provide the first evidence that bone marrow progenitors sustain in vitro circadian rhythmicity, and they demonstrate the presence of a circadian time-keeping system within these cells. The results support the potential usefulness of bone marrow cultures for investigating chronopharmacologic effects of anticancer drugs and cytokines on this target system.     

In-vitro circadian rhythm of murine bone marrow progenitor production

Hematopoietic processes display 24h rhythms both in rodents and in human beings. We hypothesized these rhythms to be in part generated by a circadian oscillator within the bone marrow. The ability of murine bone marrow granulo-monocytic (GM) precursors to form colonies following colony-stimulating factor (rm GM-CSF) exposure was investigated in liquid culture samples obtained every 3 h for a span of up to 198 h. The CFU-GM count varied rhythmically over the first 4 d of culture, with a reproducible maximum in the early morning hours, similar to that observed in vivo. These experiments provide the first evidence that bone marrow progenitors sustain in vitro circadian rhythmicity, and they demonstrate the presence of a circadian time-keeping system within these cells. The results support the potential usefulness of bone marrow cultures for investigating chronopharmacologic effects of anticancer drugs and cytokines on this target system.     

Regulation of output from the plant circadian clock

Plants, like many other organisms, have endogenous biological clocks that enable them to organize their physiological, metabolic and developmental processes so that they occur at optimal times. The best studied of these biological clocks are the circadian systems that regulate daily (approximately 24 h) rhythms. At the core of the circadian system in every organism are oscillators responsible for generating circadian rhythms. These oscillators can be entrained (set) by cues from the environment, such as daily changes in light and temperature. Completing the circadian clock model are the output pathways that provide a link between the oscillator and the various biological processes whose rhythms it controls. Over the past few years there has been a tremendous increase in our understanding of the mechanisms of the oscillator and entrainment pathways in plants and many useful reviews on the subject. In this review we focus on the output pathways by which the oscillator regulates rhythmic plant processes. In the first part of the review we describe the role of the circadian system in regulation at all stages of a plant's development, from germination and growth to reproductive development as well as in multiple cellular processes. Indeed, the importance of a circadian clock for plants can be gauged by the fact that so many facets of plant development are under its control. In the second part of the review we describe what is known about the mechanisms by which the circadian system regulates these output processes.     

Resolving the kinetics of lipid, protein and peptide diffusion in membranes

Recent developments in the understanding of molecular diffusion phenomena in membranes are reviewed. Both model bilayers and biological membranes are considered in respect of lateral diffusion, rotational diffusion and transverse diffusion (flip-flop). For model systems, particular attention is paid to recent data obtained using surface-specific techniques such as sum frequency generation vibrational spectroscopy on supported lipid bilayers, and fluorescence correlation spectroscopy on giant unilamellar vesicles, both of which have yielded new insights into the intrinsic rates of diffusion and the energetic barriers to processes such as lipid flip-flop. Advances in single-molecule and many-molecule fluorescence methodologies have enabled the observation of processes such as anomalous diffusion for some membrane species in biological membranes. These are discussed in terms of new models for the role of membrane interactions with the cytoskeleton, the effects of molecular crowding in membranes, and the formation of lipid rafts. The diffusion of peptides, proteins and lipids is considered, particularly in relation to the means by which antimicrobial peptide activity may be rationalized in terms of membrane poration and lipid flip-flop.     

Evidence for the adaptive significance of circadian rhythms

Circadian (∼24 h) clock regulated biological rhythms have been identified in a wide range of organisms from prokaryotic unicellular cyanobacteria to higher mammals. These rhythms regulate an enormous variety of processes including gene expression, metabolic processes, activity and reproduction. Given the widespread occurrence of circadian systems it is not surprising that extensive efforts have been directed at understanding the adaptive significance of circadian rhythms. In this review we discuss the approaches and findings that have resulted. In studies on organisms in their natural environments, some species show adaptations in their circadian systems that correlate with living at different latitudes, such as clines in circadian clock properties. Additionally, some species show plasticity in their circadian systems suggested to match the demands of their physical and social environment. A number of experiments, both in the field and in the laboratory, have examined the effects of having a circadian system that does not resonate with the organism's environment. We conclude that the results of these studies suggest that having a circadian system that matches the oscillating environment is adaptive.     

Time-patterned drug administration: insights from a modeling approach

The physiological effects of a drug depend not only on its molecular structure but also on the time-pattern of its administration. One of the main reasons for the importance of temporal patterns in drug action is biological rhythms—particularly those of circadian period. These rhythms affect most physiological functions as well as drug metabolism, clearance, and dynamic processes that may alter drug availability and target cell responsiveness with reference to biological time. We present an overview of the importance of time-patterned signals in physiology focused on the insights provided by a modeling approach. We first discuss examples of pulsatile intercellular communication by hormones such as gonadotropin-releasing hormone, and by cyclic adenosine monophosphate (cAMP) signals in Dictyostelium amoebae. Models based on reversible receptor desensitization account in both cases for the existence of optimal patterns of pulsatile signaling. Turning to circadian rhythms, we examine how models can be used to account for the response of 24h patterns to external stimuli such as light pulses or gene expression, and to predict how to restore the physiological characteristics of altered rhythms. Time-patterned treatments of cancer involve two distinct lines of research. The first, currently evaluated in clinical trials, relies on circadian chronomodulation of anticancer drugs, while the second, mostly based on theoretical studies, involves a resonance phenomenon with the cell-cycle length. We discuss the implications of modeling studies to improve the temporal patterning of drug administration.