Chronotherapeutic strategy: Rhythm monitoring, manipulation and disruption

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Abstract

Mammalians circadian pacemaker resides in the paired suprachiasmatic nuclei (SCN) and influences a multitude of biological processes, including the sleep–wake rhythm. Clock genes are the genes that control the circadian rhythms in physiology and behavior. 24 h rhythm is demonstrated for the function of physiology and the pathophysiology of diseases. The effectiveness and toxicity of many drugs vary depending on dosing time. Such chronopharmacological phenomena are influenced by not only the pharmacodynamics but also pharmacokinetics of medications. The underlying mechanisms are associated with 24 h rhythms of biochemical, physiological and behavioral processes under the control of circadian clock. Thus, the knowledge of 24 h rhythm in the risk of disease plus evidence of 24 h rhythm dependencies of drug pharmacokinetics, effects, and safety constitutes the rationale for pharmacotherapy. Chronotherapy is especially relevant, when the risk and/or intensity of the symptoms of disease vary predictably over time as exemplified by allergic rhinitis, arthritis, asthma, myocardial infarction, congestive heart failure, stroke, and peptic ulcer disease. Morning once-daily administration of corticosteroid tablet medications results in little adrenocortical suppression, while the same daily dose split into four equal administrations to coincide with daily meals and bedtime results in significant hypothalamus–pituitary–adrenal (HPA) axis suppression. However, the drugs for several diseases are still given without regard to the time of day. Identification of a rhythmic marker for selecting dosing time will lead to improved progress and diffusion of chronopharmacotherapy. To monitor the rhythmic marker such as clock genes it may be useful to choose the most appropriate time of day for administration of drugs that may increase their therapeutic effects and/or reduce their side effects. Furthermore, to produce new rhythmicity by manipulating the conditions of living organs by using rhythmic administration of altered feeding schedules or several drugs appears to lead to the new concept of chronopharmacotherapy. Several drugs cause alterations in the 24 h rhythms of biochemical, physiological and behavioral processes. The alteration of rhythmicity is sometimes associated with therapeutic effects, or may lead to illness and altered homeostatic regulation. Attention should be paid to the alteration of biological clock and consider it an adverse effect, when it leads to altered regulation of the circadian system which is a serious problem affecting basic functioning of living organisms. One approach to increasing the efficiency of pharmacotherapy is administering drugs at times during which they are best tolerated. From viewpoints of pharmaceutics, the application of biological rhythm to pharmacotherapy may be accomplished by the appropriate timing of conventionally formulated tablets and capsules, and the special drug delivery system to synchronize drug concentrations to rhythms in disease activity. New technology for delivering medications precisely in a time-modulated fashion by bedside or ambulatory pumps is developing to manage human diseases. Therefore, we introduce an overview of the dosing time-dependent alterations in therapeutic outcome and safety of drug. The underlying mechanisms and usefulness are introduced from viewpoint of chronopharmacology and chronotherapy.

Introduction

Mammalians circadian pacemaker resides in SCN and influences a multitude of biological processes, including the sleep–wake rhythm [1]. The circadian clock acts like a multifunction timer to regulate homeostatic systems such as sleep and activity, hormone levels, appetite, and other bodily functions with 24 h cycles. Clock genes are identified as the genes that ultimately control a vast array of circadian rhythms in physiology and behavior [2], [3].

The study on the individualization of pharmacotherapy (personalized pharmacotherapy) has been carried out aiming at further improvement of pharmacotherapy [4]. The individualization of pharmacotherapy has been performed mainly by monitoring drug concentrations. However, intraindividual variability as well as interindividual variability should be considered to aim at further improvement of rational pharmacotherapy. Because many drugs vary in potency and/or toxicity associated with the rhythmicity of biochemical, physiological and behavioral processes [5], [6], [7], [8], [9], [10]. Theoretically, it has been argued that drug administration at certain times of the day should improve the outcome of pharmacotherapy.

Biological rhythms not only impact the function of physiology, but the pathophysiology of diseases [5], [6], [7], [8], [9], [10]. Chronopharmacology is the investigative science that elucidates the biological rhythm dependencies of medications. The effectiveness and toxicity of many drugs vary depending on dosing time associated with 24 h rhythms of biochemical, physiological and behavioral processes under the control of circadian clock. Such chronopharmacological phenomena are influenced by not only the pharmacodynamics but also pharmacokinetics of medications. The knowledge of 24 h rhythm in the risk of disease plus evidence of 24 h rhythm dependencies of drug pharmacokinetics, effects, and safety constitutes the rationale for pharmacotherapy (chronotherapy). Chronotherapy is especially relevant in the following cases [5], [6], [7], [8], [9], [10]. The risk and/or intensity of the symptoms of disease vary predictably over time as exemplified by allergic rhinitis, arthritis, asthma, myocardial infarction, congestive heart failure, stroke, and peptic ulcer disease. From viewpoints of pharmaceutics, the application of biological rhythm to pharmacotherapy may be accomplished by the appropriate timing of conventionally formulated tablets and capsules, and the special drug delivery system to synchronize drug concentrations to rhythms in disease activity [7], [11]. Pharmaceutical companies have focused on investigation of underlying mechanisms as well as the conduct of multicenter clinical investigations involving numerous patients with the purpose of devising chronotherapeutic interventions with a variety of medications. New technology for delivering medications precisely in a time-modulated fashion by bedside or ambulatory pumps is developing to manage human diseases. Chronopharmacologists have the responsibility to carefully evaluate and use this new technology to ensure the devices and clinical findings are well accepted by colleagues currently involved in more classical research.

On the other hand, the drugs for several diseases are still given without regard to the time of day. The chronopharmacological findings should be systematically summarized in an applicable format for clinical practice. A reference rhythm for circadian timing of medications plays a key role to achieve the purpose. Therefore identification of a rhythmic marker for selecting dosing time will lead to improved progress and diffusion of chronopharmacotherapy. Several drugs are not only influenced by biological rhythms, but also act on the biological rhythms [12], [13]. On the horizon are drugs to fix broken biological clocks, perhaps a factor in all illness, in the opinion of some physicians. In contrast, several drugs cause alterations in the 24 h rhythms of biochemical, physiological and behavioral processes. The alteration of rhythmicity is sometimes associated with therapeutic effects (i.e. antidepressant drugs), or may lead to illness and altered homeostatic regulation. The knowledge of interactions between biological clock and drug should be very useful for the clinical practice.

The aim of this review is to provide an overview of the dosing time-dependent alterations in therapeutic outcome and safety of drug. The underlying mechanisms and usefulness are introduced from viewpoint of chronopharmacology and chronotherapy.

Section snippets

Biological time structure

Biological time structure describes the sum of non-random and thus predictable time-dependent biologic changes, including, with growth, development and aging, a spectrum of rhythm with different frequencies [5], [6]. Basically, the concept of biology is based on the construct of homeostasis, which is maintained in relative constancy over time by specific feedback mechanisms. However, important findings from the new science of biological rhythms clearly reveal that biological functions are not

Circadian time structure

The SCN of the anterior hypothalamus are the site of the circadian pacemaker in mammals [1], [2], [3] (Fig. 1). Like any timing system, the circadian clock is made up of three components [1], [2], [3]: an input pathway adjusting the time, a central oscillator generating the circadian signal, and an output pathway manifesting itself in circadian physiology and behavior. The daily changes in light intensities are thought to be the major environmental cue involved in circadian entrainment.

Definition of chronopharmacology

Chronopharmacology describes the results of a chronobiological approach to pharmacological phenomena [5], [6]. Chronobiological methodology involves less risk of error and/or false information than the conventional homeostatic approach. Chronopharmacology includes the chronotoxicology describing undesired or harmful effects from chemical, physical or other agents including poisons, pollutants and overdoses of drugs upon biologic temporal characteristics and as a function of biologic timing and

24 h rhythm in disease occurrence or severity

Chronotherapeutic approach is based on the presence of 24 h rhythms in physiological functions and diseases. The examples are described below. Fig. 3 shows the approximate peak time of 24 h rhythms relative to the diurnally active human beings [5], [6], [7]. The peak in serum cortisol, aldosterone, testosterone, platelet adhesiveness, blood viscosity and NK-cell activity is observed during the initial hours of daytime. Hematocrit is greatest and airway caliber (FEV1) best around the middle and

Chronotherapy in clinical practice

The knowledge of 24 h rhythm in the risk of disease plus evidence of 24 h rhythm dependencies of drug pharmacokinetics, effects, and safety constitutes the rationale for pharmacotherapy (chronotherapy) [7]. One approach to increasing the efficiency of pharmacotherapy is the administration of drugs at times at which they are most effective and/or best tolerated. The chronotherapy of a medication may be accomplished by the appropriate timing of conventionally formulated tablets and capsules, and

Relevance of chronobiology and chronopharmacologic concepts to drug effectiveness and side effect

The chronopharmacological concepts to drug efficacy and safety have been exemplified in terms of drug testing and post-approval drug surveillance. The findings of human circadian rhythms in chronopharmacology have been identified by the conventional endpoints of response as shown in classical manifestation during asthma and cancer therapy. The term chronopharmacology refers specifically to predictable-in-time variation in patient sensitivity to the effects of medications due to biological

Influence of biological rhythms on pharmacodynamics and pharmacokinetics

Biological rhythms not only impact the pathophysiology of diseases, but the pharmacokinetics and pharmacodynamics of medications. Chronopharmacology is the investigative science that elucidates the biological rhythm dependencies of medications.

Influence of drugs on biological rhythms: disruption of rhythms

The alteration of circadian rhythm can be a side effect of several drugs. It is very important to evaluate the alteration of the circadian time structure, such as evidenced by delayed, advanced or disrupted sleep–wake circadian rhythm, as a new side effect of medications that might show manifestation only as a result of particular administration-time schedule. The alteration of rhythmicity is sometimes associated with therapeutic effects, or may lead to illness and altered homeostatic

Influence of drugs and environmental factors on biological rhythms: adjustment and manipulation of rhythms

The 24 h rhythms of physiology and behavior are influenced by various environmental factors such as feeding schedules, genetic factors and social interactions as well as lighting condition and several drugs [12], [13], [18], [30], [101], [102], [103], [104]. Since the period of the central circadian pacemaker in humans is slightly longer than 24 h described above, synchronization of the circadian system with the light–dark cycle occurs by daily phase advances of the circadian clock. In humans,

Conclusions

The effectiveness and toxicity of many drugs vary depending on dosing time associated with 24 h rhythms of biochemical, physiological and behavioral processes under the control of circadian clock. The knowledge of 24 h rhythm in the risk of disease plus evidence of 24 h rhythm dependencies of drug pharmacokinetics, effects, and safety constitutes the rationale for pharmacotherapy. The drugs for several diseases are still given without regard to the time of day. The chronopharmacological findings

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    This review is part of the Advanced Drug Delivery Reviews theme issue on “Chrono-Drug-Delivery Focused on Biological Clock: Intra- and Inter-Individual Variability of Molecular Clock”.

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