**Abstract**

New scientific evidence raises awareness concerning the human-specific interplay among primary environmental conditions, such as the light–dark cycle, activity–rest alternation, nutritional patterns, and their reflection on the physiological and pathological characteristics that are displayed uniquely by every individual. One of the critical aspects in the clinic is to understand the role of circadian rhythms as remarkable modulators of the biological effects of drugs and to aim for an optimal overlapping of the time of administration of medicines with the physiologic release of certain hormones, the time-dependent expression of genes, or the key-regulatory protein synthesis, which are all circadian-driven processes. The pharmacokinetics and pharmacodynamics profiles, as well as the possible drug interactions of neurotropic and cardiovascular agents, are intensely subjected to endogenous circadian rhythms, being essential to identify as much as possible the patients' multiple risk factors, from age and gender to lifestyle elements imprinted by dietary features, sleep patterns, psychological stress, all the way to various other associated pathological conditions and their own genetic and epigenetic background. This review chapter will highlight the involvement of biological rhythms in physiologic processes and their impact on various pathological mechanisms, and will focus on the nutritional impact on the circadian homeostasis of the organism and neurologic and cardiovascular chronotherapy.

**Keywords:** biological rhythms, chronopharmacology, chronotherapy, chrononutrition, cardiovascular drugs, neurologic diseases, sleep disorders

### **1. Introduction**

Chronopharmacology, in its broadest sense, is the science that studies drug effects according to the time of their administration. As the human organism portrays a set of biological rhythms, its response to drug administration depends on its particular conditions at the moment when the drug enters the system. Indeed, the existence of rhythmic variations in the body circumstances reflects in the response to drugs: chronopharmacology studies these phenomena by assessing the variations in the activity, toxicity, and kinetics of medicines. Chronotherapy is the application of chronopharmacology outcomes, whose aim is to improve the benefit/risk ratio of the drug by optimizing the time of administration [1–3].

Many physiological processes in the array of metabolic balance, hormones synthesis, and release and nevertheless the sleep–wake behavior, are regulated by the circadian clock system, being closely related to everyday environmental inputs, such as the light–dark cycle, food consumption, and drug administration [4].

### **2. Chronobiology's importance from the perspective of human health**

Chronopharmacology is a punctual aspect of chronobiology, reflecting the variations in the activity or toxicity of a therapeutic agent according to the time of administration, but it also studies the modifications of biological rhythms as the length of their cycle and time of their greatest and weakest intensity due to drugs. Its goal is to improve therapeutic efficacy and reduce unsolicited effects [1].

Relevant to metabolic activity, chronopharmacology allows to preserve or improve the health state, while associating circadian modifications in the digestive, hepatic, and endocrine systems with the exact time of the patient's meals. Studies show that sleep disorders or jet lag can be treated with drugs due to their beneficial impact on the adjustment of the circadian system. The connection between food and the circadian clock system has recently been encompassed in the term chrononutrition (**Figure 1**) [5, 6].

## **3. Human circadian rhythms, entrainment mechanisms, and major regulatory pathways**

For humans, the most prevalent circadian rhythm is represented by the sleep– wake cycle, being at its turn in close relationship with the light–dark pattern, imprinted by environmental circumstances.

The central pivotal role in generating and maintaining basal circadian rhythms is played by the suprachiasmatic nucleus (SCN) located at the level of the anterior hypothalamus, which is the most important circadian pacemaker responsible for establishing the physiological cycles and nevertheless behavioral and endocrine circadian patterns displayed by human beings. The SCN function is highly important for daily rhythms that, when it is surgically removed, as has been experimentally performed in rodent studies, the animals lose their ability to temporally synchronize with the environment [3].

*Chronotherapy Advances in the Management of Chronic Neurological and Cardiovascular… DOI: http://dx.doi.org/10.5772/intechopen.106950*

### **Figure 1.**

*Illustration of chronopharmacological and chrononutritional interactions with human organism and behavior.*

The accumulated forfeits of different harmful events resident at the level of SCN essentially encountered in end-stage neurodegenerative diseases, translate into losing the sense of time: patients are going to sleep during the day or are remaining in a wakeful state in the dark period, they are feeling permanently hungry or going to the toilet at random intervals during the day or night [7, 8].

At this level, a link is established between the outer world and the interior one, considering the mechanisms of entrainment of the organism by sensing the light signals and transposing them into temporal information, and regulatory patterns disseminated to all downstream effector organs, tissues, and cells. The circadian regulatory pathway has remarkable profound echoes, implementing changes even in time-dependent genes, which modulate the expression of protein synthesis, resetting all other biological clocks present in the pineal gland, the pituitary gland, or the adrenal gland. Besides light, there are different important zeitgebers that coordinate the hepatic or gastrointestinal tract clocks, mainly by the time of meals or by drug administration. The flexibility of these internal clocks is mandatory, in terms of connecting the SCN signals to the hunger and satiety center located also in the hypothalamus, instructing the relevant organs to act at the solicited time. After a desynchronizing event, the downstream reverberations are perceived slowly, but firmly, and the system resets itself within a few days, for example, midnight nutrients ingestion resets the gut and liver clocks in less than a week, aligning the metabolic machinery to the new consumption pattern [9–12].

## **4. Phase shift modulation in the context of disruptive versus resynchronizing events**

The human circadian structures are conceptualized in three distinctive components: a circadian oscillator with a rhythm of about 24 hours, pathways for the perception of light and other stimuli that synchronize the pacemaker with the environment,

through zeitgebers, and effector systems and proper activities determined by SCN refinement. In humans, light is the dominant synchronizing agent for the internal clock, the photic information being conducted by direct and indirect pathways to the circadian system. In addition to the photic signal, the suppression of melatonin synthesis at the level of the pineal gland is a complementary mechanism implicated in conducting phase shifts in human circadian rhythms [12, 13].

The circadian shifts have an impact on activities including drug or nutrient absorption, distribution, metabolism, and excretion. Acknowledging these parameters when prescribing a drug and establishing the posology, dose and individual chemical characteristics, or the interactions with food intake can help improve human health and disease by increasing the potency of pharmacological and functional food effects. Secondly, just like light stimulation, drugs and food may be used to alter the phase of circadian clocks [14–16]. Internal clock disruptive events can occur simply by changing the timing of meals. Accordingly, the term chrononutrition also includes the following two elements: the involvement of food components and meal timing in the preservation of the health state and the role of food components in rapidly changing or reorganizing the endogenous clocks [10].

The importance of well-established nutritional routines, considering mainly the time of meals and the dietary habits, is highly acknowledged by all research studies in the field of nutrition. The reveal of the biochemical mechanism by which biological clocks are operating, namely the negative feedback regulation for the transcriptional process by means of binding Clock/Bmal1 to the E-box, was solid proof for pleading for stable eating habits. Circadian rhythms involve a clock regulated by negative transcriptional feedback. Clock/Bmal1, transcription factors, bind to E-box hexanucleotides to activate transcription of Per and Cry clock genes. The complex formed by Per and Cry inhibits its transcriptional activation by Clock/Bmal1. Subsequently, decreased activation of Per and Cry in turn causes transcriptional activation. This cycle takes approximately 24 hours. Although small gaps appear between cells, these gaps are adjusted by synchronizers [3, 17, 18].

This stability assures a certain equilibrium in the regulation of lipid metabolism, but more importantly, regulates the expression of the liver clock genes and the CYP7A1 isoform [4, 14, 16].

As such, chrononutrition will become a standard technique for maintaining our health via circadian rhythm system modulation. Knowing all the mechanistic details of food entrainment of the circadian clock will support the development of chrononutritional approaches for assuring nutritional optimal functionality.

## **5. The involvement of nutritional inputs and patterns in maintaining the circadian homeostasis of the organism**

It is now understood that all cells have their own autonomous 24-hour clocks that work together as organ clocks, collectively forming a factor-integrated clock that synchronizes all organs. The rhythm of the digestive system is reversed when meal times are reversed, indicating that the digestive system clock synchronizer is sometimes stronger than the primary stimulus, namely light. It has been concluded by certain researchers that meals are among the strongest synchronizers for all organs and systems [19, 20].

The clocks of the organs cooperate to control the functions of the whole body, which can be defined as healthy. Experiments using mice with the clock gene

*Chronotherapy Advances in the Management of Chronic Neurological and Cardiovascular… DOI: http://dx.doi.org/10.5772/intechopen.106950*

removed show that its loss causes not only behavioral but also metabolic disorders. Experimental studies on circadian clock mutant mice exhibiting obesity or metabolic syndrome received much attention. In addition to arrhythmia, which was originally predicted, metabolic disorders in mice revealed that the circadian clock is strongly linked to peripheral metabolism [7, 21, 22]. On the other hand, there is a report of familial advanced sleep phase syndrome due to Per2 mutations in humans.

Gastric and intestinal digestion and absorption follow a circadian rhythm, being affected by clock genes rhythmically produced in the intestine and by the daily food intake (**Figure 2**). Extensive research has been conducted on the circadian expression of clock genes in the gastrointestinal tract. The obtained results revealed an advanced phase characteristic for the upper gut, being entrained faster than the lower gut, which is translated into a modification of the nutritional delivery rate at this level [17, 23].

The gastrointestinal system is subjected to a series of influence factors that are under tight circadian control, performed through genes exhibiting circadian patterns, which in their turn represent a signaling pathway. The most pronounced influence is driven by the nutritional schedule, being able to advance the idea of nutritional signaling. The colonic motility displays a clear rhythm, being active during the light period of the day and extremely silent during the night, the nitric oxide synthase activity and the clock genes regulating this cyclic process. The intestinal enzymes that perform the digestion of nutrients at this level have a circadian modulated activity timetable, which intimately follows the meal ingestion patterns, predicting the ideal time for synthesizing or activating these molecules. Consequent to this, the intestinal absorption of nutrients and xenobiotics registers a circadian fluctuation in close relationship with specific transporters' expression [16, 17, 24].

### **Figure 2.**

*Circadian rhythmicity of nutrition-related processes regulators. AMPK, 5*′ *adenosine monophosphate-activated protein kinase; SIRT1, sirtuin 1 or silent mating type information regulation 2 homologue; PPAR, peroxisome proliferator-activated receptor; PGC1a, peroxisome proliferator-activated receptor gamma coactivator-1 alpha; Sglt1, sodium-dependent glucose cotransporter 1; Glut2, glucose transporter 2; Pept1, human peptide transporter 1.*

The circadian system has an impact on food digestion, absorption, and metabolism. Furthermore, epithelial cell motility and proliferation in digestive compartments, particularly the colon, show diurnal rhythms. The absorption of glucose and water by the isolated small intestine is higher at night than during the day. The expression of sodium/glucose cotransporter 1 (Sglt1), glucose transporter 2 (Glut2), and glucose transporter 5 (Glut5) has clear circadian oscillations and is regulated by clock genes through E-box activity. Furthermore, PER1 activity regulates Sglt1 independently of the E-box. Following a scheduled feeding experiment, it has been concluded that feeding circumstances directly impact these transporters [9].

Food-derived phenolic compounds can interact with clock genes, which regulate the biological rhythms. In addition, nutrient signaling can affect gut circadian systems. Many important transporters are under circadian regulation, and circadian disruption also leads to abnormal drug absorption [22].

### **6. Circadian molecular mechanisms modulating the lipid metabolism**

It is well known that changing the phase shift by night feeding leads to obesity, the main hypothesis states that the extra energy flow during the rest time is easily converted into lipids accumulation in the adipose tissue. In laboratory practice, it is common to use a high-fat diet to create an animal model of obesity [21, 22]. Although these phenomena are easy to understand, the molecular mechanisms are not fully elucidated.

Abnormalities in the body clock functioning, driven by a high-fat diet, are initiating the weight gain process in mice. This dietary habit also changes the liver clock and the hepatic rhythmicity of lipid metabolism. The influence of meal timing on lipid metabolism is not considered highly significant, while the importance of well-regulated eating habits is recognized [9]. Therefore, the influence of meal timing was examined using genetically unmodified animals. A feeding protocol was developed in which animals ate continuously regardless of time; although restricted feeding (e.g., feeding only during the day) causes day/night reversal in nocturnal rats, they become accustomed to it. It was reported that irregular meals cause abnormalities in the liver circadian clock and increase blood cholesterol levels. It was indicated that differences in meal timing cause abnormalities in cholesterol metabolism, even if the same quantity of food is provided [25]. Hypercholesterolemia was caused by advanced changes in the circadian rhythm and gene expression of CYP7A1, an isoenzyme that limits the rate of bile acid synthesis. Thus, cholesterol metabolism was profoundly altered and bile acid levels excreted decreased. These results indicate that well-regulated dietary habits normalize the liver clock gene and regulate the CYP7A1 rhythm and that blood cholesterol levels are better controlled due to a lower secretion of VLDL (very low-density lipoprotein), namely lowering LDL-cholesterol and raising HDL-cholesterol levels [19].

## **7. Expanding the perspective of the interplay between chrononutrition and chronotherapy**

Time-restricted feeding, a nutritional approach in which food consumption is limited to certain times of the day, allows a daily fasting period of 12 hours or more, thus conferring metabolic resting-frames used by the cellular machinery to initiate

### *Chronotherapy Advances in the Management of Chronic Neurological and Cardiovascular… DOI: http://dx.doi.org/10.5772/intechopen.106950*

and develop complex processes of repair, decreasing the level of accumulated errors due to oxidative stress injuries or aberrant mutations. Understanding the link between time, nutrients, and the benefits of fasting leads to the identification of chrononutritional strategies that mimic fasting and achieve similar changes to those triggered by fasting [3].

Acknowledging the pervasive and constant benefits of time-restricted feeding and fast-mimicking diets, basic science and translational research are willing to transform time-managed fasting-related interventions into complex clinical approaches with a remarkable potential to improve human health.

In the clinical scenery, an accurate identification must be performed for all interactions among drugs, drugs and food supplements, drugs and food and, nevertheless, drugs and genetic and epigenetic factors, all being able to impact the therapeutic outcome considerably. The absorption, distribution, metabolism, and elimination of drugs can be highly influenced by slight variations of the environmental factors and endogenous elements, mainly affecting their bioavailability, efficacy, and metabolism to toxic compounds [26].

The most exposed to this phenomenon are neurologic and cardiovascular patients due to the complexity of their pathology and the particularities of these anatomic and physiologic systems. Restricted scheduled food intake in experimental models determines the occurrence of food anticipatory activity in animals, which is observed approximately 2 hours before the feeding time. The learning process of specific times of feeding is acquired by the internal food-entrainable oscillator mechanism and this food-dependent entraining also encompasses clock gene expression rhythms in major cerebral and peripheral tissues, except the SCN. Several experimental studies demonstrated that by scheduled feeding, the animals depicted Per1, Per2, D-site-binding protein, and cholesterol 7 alpha-hydroxylase mRNA expression rhythms that underwent rapid phase shifting and entrainment at the hepatic level, and a slower rate in kidneys, heart, and pancreas and did not undergo at all scheduled feedings-phase shifting in the SCN [3, 5].

Regarding antihypertensive and neurotropic drugs, when evaluating their therapeutic efficacy, we have to equally consider the time of administration, their precise dose, and eventual matrix effects that can completely change their bioavailability profile. This is mainly due to their direct interdependence with biological rhythms, blood pressure physiologic oscillation during 24 hours, and nevertheless the circadian rate of metabolism at the hepatic level. The nutritional impact can also be displayed by food constituents that have additive or antagonist effects such as phenolic compounds and peptides, in conjunction with blood pressure levels [27].

Chronotherapeutic-chrononutritional studies conducted by Matsunaga et al. are of unique relevance in this field assessing the circadian pattern of hepatotoxicity and mortality rates after acetaminophen administration in mice subjected to ad libitum versus time-restricted feeding patterns, and food-entrained circadian rhythms modulated toxic effects through CYP2E1 and hepatic glutathione activities [28]. Analogous employments of food timing patterns on the chrono-pharmacokinetics were described in the activity of sodium valproate and the nephrotoxicity of gentamicin [29, 30].

Insulin signaling is one of the most important factors for food entrainment, as it directly induces Per2 expression in hepatic tissue and cultured hepatocytes [31]. AMPK, a fundamental cellular energy sensor, is another possible factor for food entrainment, being activated by fasting or low glucose levels. It undergoes phosphorylation and destabilizes CRY1 protein. Nutritional ingredients such as caffeine, an

antagonist of the adenosine receptors and an inhibitor of phosphodiesterase, increasing cAMP concentrations, can lead to considerable changes in the circadian system as it was reported to lengthen the circadian clock period in the SCN and peripheral tissues and modulates the behavioral rhythms [32]. Functional nutrition may soon become an increasing topic of relevance in future chronotherapeutic strategies.

In most animal species as in humans, the feeding frames alternate with fasting frames. This specific metabolic picture is predominantly dependent on ketone bodies after a prolonged fasting time, glucose, and glycogen being consumed in the first fragment of the fast. Based on this restricted availability of glucose at the cellular level, many hypotheses were formulated to understand the great impact of fasting in preventing a series of metabolic imbalances and also in accompanying the treatment of chronic diseases, mainly cardiovascular, inflammatory, and oncological ones [16, 25, 33, 34].

## **8. Chronotherapeutic approaches: recognizing the importance of timing factors in the treatment of neurological diseases and sleep disorders**

The suprachiasmatic nucleus (SCN) acquires valuable information from the environment, through input signals, such as the light–dark cycle, and nevertheless from other brain areas. There are several important chemical structures that were studied for their influence on the circadian entrainment mechanism of SCN, namely exogenous melatonin and ramelteon, a powerful selective melatonin MT1/MT2 receptor agonist. When administered during the active phase, they act as non-photic trainers that advance SCN circadian rhythms [35–37].

The field of neurology is an extremely complex one, reuniting a series of chronic neurological disabilities from insomnia, epilepsy, and neuromuscular disorders to degenerative diseases, dementia and brain tumors. As a highly prevalent and neurologic imbalance promoting affection, insomnia is affecting more than 30% of the general population, the sleep disturbances being a consequence of stressful life conditions, shift working, physiological aging, but nevertheless being the first clinical sign of a neurologic impairment stage. Its intimate connection with circadian misalignment is undoubtedly approved, addressing an interesting scientific intersection point in chronopharmacology [38–40].

The barbiturates, namely phenobarbital, were among the first-generation drugs used for insomnia, but due to their high abuse potential and associated risks of overdosing, were replaced by benzodiazepines (lorazepam and triazolam).

This second generation of hypnotics displayed different side effects in the area of cognitive and psychomotor impairment, displaying also phenomena of addiction and tolerance, urging the need for a different therapeutic approach. Benzodiazepine receptor agonists (zolpidem and zopiclone) represented the following generation of hypnotics having non-benzodiazepine chemical structures and exhibiting reduced side effects. After extensive clinical studies, it was concluded that the major drawback of this class was that the sleep induced by these pharmacologic agents is electrophysiologically different from the naturally prompted physiological sleep, as they are severely reducing the rapid eye movement (REM) phases of sleep [7, 41].

Melatonin, the pineal hormone discovered in 1958, is the major endogenous regulator of sleep–wake cycles, its synthesis being initiated by the diminishing photic signal, at sunset, and being stopped upon sensing the first light signal. The pineal synthesis pathway includes the essential amino acid tryptophan and most importantly

### *Chronotherapy Advances in the Management of Chronic Neurological and Cardiovascular… DOI: http://dx.doi.org/10.5772/intechopen.106950*

the neurotransmitter serotonin. It has exceptional characteristics, being highly soluble in lipid medium, simply diffusing through almost every cellular membrane, including the blood–brain barrier, the ultimate frontier for most molecules, even the endogenous ones [13, 36, 42].

The half-life of melatonin is extremely short, around 30 minutes, being immediately enzymatically transformed in a series of metabolites, with particular functions in the oxidative stress array, in order to be finally converted by the liver and then urinary excreted. No other endogenous molecule shares the same unique strong circadian pattern of synthesis in healthy human organisms: the plasma level is detectable immediately after sunset, registering a peak around 3 a.m. and becomes untraceable in the early morning, a period superposable with the light signal initiation [43].

The intimate connection between melatonin and the utmost central nervous system structures is achieved through the specific receptors which are found in high densities in circadian regulatory entities, and in fact, to a certain extent, in most human organs. It is by this mechanism that it is understood the role of melatonin as a master hormone, endogenous synchronizer, and circadian modulator of all biological internal systems. Melatonin mediates the information regarding the dark signals throughout the entire body, conducting chronobiotic and phase shift effects, hypnotic by imprinting sleep–wake robust cycles, but at the same time, having a versatile modulatory ability to adjust the circadian pattern in disruptive circumstances [35].

Considered the initiator and maintainer of sleep in humans, the darkness hormone has proved its sleep-inducing effects only concerning the endogenous molecule, as the exogenous supplementation has resulted in controversial conclusions, mainly due to its short half-life, increased first-pass metabolism, and weak receptors binding. As the major non-photic entrainer of the circadian rhythm, exogenous melatonin is a powerful pharmacologic tool in correcting circadian misalignments in patients [44].

Melatonin was subjected lately to modern pharmaceutical formulations that assure better bioavailability characteristics that were efficient for inducing sleep and increasing the quality and length of sleeping time in elderly patients suffering from chronic insomnia, as it is acknowledged that the endogenous melatonin synthesis declines physiologically by aging, due to pineal gland calcification, decreased sensing of the light signal, or a decline in the SCN function [21].

Chronopharmacological approaches are of remarkable importance for a chronobiotic agent such as melatonin. A series of experimental and clinical studies have assessed the relationship between the administered melatonin dose, the time of administration, and the occurrence of biological effects and their intensity, in a plethora of circadian rhythm-derived sleep disorders, from a jet lag sleep disorder, shift work sleep disorder, delayed sleep phase syndrome, primary insomnia occurring in various psychiatric illness. The conclusions are unanimous stating that the time of the day used for administering exogenous melatonin is indisputably determining the precise effect on the circadian rhythms: delaying them after the morning administration, and on the contrary, advancing the circadian phase and subsequent evening sleep induction, following a late afternoon or night drug administration [40, 45].

Based on the clinical data, but mostly on the evidence suggesting the tremendous therapeutic effect displayed upon selectively binding the melatoninergic receptors, the MT1/MT2 agonist ramelteon was assessed for its role in circadian re-entrainment and for inducing sleep in refractory insomnia. The time of administration is also an important issue, taken into consideration by Watanabe et al. study, which concluded on the efficiency of small doses of 1–2 mg taken at more than 5 hours before bedtime, assumed as an early administration pattern [46]. In the vast majority of the

performed trials, ramelteon proved good effects, especially on refractory insomnia cases, often combined with serious disturbances in circadian rhythms of sleep–wake cycles. All scientific data indicate that ramelteon acts not only as a hypnotic agent but also at a molecular level it is mimicking all central effects of melatonin as a circadian entrainer [37, 47, 48].

Numerous other central nervous system-acting drugs are of utmost chronotherapeutic importance due to their particular pharmacologic patterns in connection with their time of administration. For instance, the night-time administration of benzodiazepines down-regulates the expression of Per1 and Per2 genes, having a direct impact on the entrainment process at the level of SCN. Lithium, a classic mood stabilizer prescribed in manic episodes associated with bipolar disorder, inhibits glycogen synthase kinase-3 (GSK-3) in the suprachiasmatic nucleus, increasing the locomotor activity cycle [44, 49]. Anesthetic agents significantly influence circadian rhythms, causing either phase shifts, or diminishing the rhythmic amplitude of clock gene expression. Many central nervous system drugs, when administered together, can affect circadian rhythm via their target receptors and metabolism enzymes [2].
