Mind the time : 24-hour rhythms in drug exposure and effect

Many physiological processes, including those involved in the absorption, distribution, metabolism, elimination, pharmacodynamics and toxicity of therapeutic drugs, show profound fluctuations over the course of the day and night. This may lead to time-of-day dependent changes in the exposure and effect of therapeutic drugs. The aim of this thesis is to provide a structured framework for chronopharmacological studies, while concurrently touching upon several critical issues encountered during the development and optimization of new and existing drug treatments. Firstly, we studied 24-hour variation in the pharmacokinetics of both midazolam and levofloxacin in healthy male subjects and found that for both drugs, absorptive processes show time-of-day dependency. Moreover, the magnitude of QT prolongation induced by levofloxacin, a common side-effect induced by many types of drugs, varied considerably and systematically over the course of the day. Furthermore, we investigated daily variation of drug distribution to the brain and found that time of day can be a considerable source of variation that could influence the effectiveness of drugs targeted to the brain. Taken together, these studies show that chronopharmacological aspects should not be overlooked in order to benefit from the systematic fluctuations in physiological processes during the development and optimization of drug treatments.  LUMC / Geneeskund

Beginning to see the light: lessons learned from the development of the circadian system for optimizing light conditions in the neonatal intensive care unit

The circadian timing system optimizes health by temporally coordinating behavior and physiology. During mammalian gestation, fetal circadian rhythms are synchronized by the daily fluctuations in maternal body temperature, hormones and nutrients. Circadian disruption during pregnancy is associated with negative effects on developmental outcomes in the offspring, highlighting the importance of regular and robust 24-h rhythms over gestation. In the case of preterm birth (before 37 weeks of gestation), maternal cues no longer synchronize the neonate's circadian system, which may adversely affect the neonate. There is increasing evidence that introducing robust light-dark cycles in the Neonatal Intensive Care Unit has beneficial effects on clinical outcomes in preterm infants, such as weight gain and hospitalization time, compared to infants exposed to constant light or constant near-darkness. However, the biological basis for these effects and the relationship with the functional and anatomical development of the circadian system is not fully understood. In this review, we provide a concise overview of the effects of light-dark cycles on clinical outcomes of preterm neonates in the NICU and its alignment with the development of the circadian system.Circadian clocks in health and diseas

Effects of shift work on the eating behavior of police officers on patrol

Recent studies indicate that the timing of food intake can significantly affect metabolism and weight management. Workers operating at atypical times of the 24-h day are at risk of disturbed feeding patterns. Given the increased risk of weight gain, obesity and metabolic syndrome in shift working populations, further research is required to understand whether their eating behavior could contribute to these increased metabolic risks. The objective of this study was to characterize the dietary patterns of police officers across different types of shifts in their natural environments. Thirty-one police officers (six women; aged 32.1 +/- 5.4 years, mean +/- SD) from the province of Quebec, Canada, participated in a 28- to 35-day study, comprising 9- to 12-h morning, evening, and night shifts alternating with rest days. Sleep and work patterns were recorded with actigraphy and diaries. For at least 24 h during each type of work day and rest day, participants logged nutrient intake by timestamped photographs on smartphones. Macronutrient composition and caloric content were estimated by registered dieticians using the Nutrition Data System for Research database. Data were analyzed with linear mixed effects models and circular ANOVA. More calories were consumed relative to individual metabolic requirements on rest days than both evening- and night-shift days (p = 0.001), largely sourced from increased fat (p = 0.004) and carbohydrate (trend, p = 0.064) intake. Regardless, the proportions of calories from carbohydrates, fat, and protein did not differ significantly between days. More calories were consumed during the night, between 2300 h and 0600 h, on night-shift days than any other days (p < 0.001). Caloric intake occurred significantly later for night-shift days (2308 h 0114 h, circular mean +/- SD) than for rest days (1525 h +/- 0029 h; p < 0.01) and was dispersed across a longer eating window (13.9 h 3.1 h vs. 11.3 h +/- 1.8 h, mean +/- SD). As macronutrient proportions were similar and caloric intake was lower, the finding of later meals times on night-shift days versus rest days is consistent with emerging hypotheses that implicate the biological timing of food intake-rather than its quantity or composition-as the differentiating dietary factor in shift worker health.Circadian clocks in health and diseas

Effects of the neonatal intensive care environment on circadian health and development of preterm infants

The circadian system in mammals ensures adaptation to the light-dark cycle on Earth and imposes 24-h rhythmicity on metabolic, physiological and behavioral processes. The central circadian pacemaker is located in the brain and is entrained by environmental signals called Zeitgebers. From here, neural, humoral and systemic signals drive rhythms in peripheral clocks in nearly every mammalian tissue. During pregnancy, disruption of the complex interplay between the mother’s rhythmic signals and the fetal developing circadian system can lead to long-term health consequences in the offspring. When an infant is born very preterm, it loses the temporal signals received from the mother prematurely and becomes totally dependent on 24/7 care in the Neonatal Intensive Care Unit (NICU), where day/night rhythmicity is usually blurred. In this literature review, we provide an overview of the fetal and neonatal development of the circadian system, and short-term consequences of disruption of this process as occurs in the NICU environment. Moreover, we provide a theoretical and molecular framework of how this disruption could lead to later-life disease. Finally, we discuss studies that aim to improve health outcomes after preterm birth by studying the effects of enhancing rhythmicity in light and noise exposure.</p

Diurnal variation in P-glycoprotein-mediated transport and cerebrospinal fluid turnover in the brain.

Nearly all bodily processes exhibit circadian rhythmicity. As a consequence, the pharmacokinetic and pharmacodynamic properties of a drug may also vary with time of day. The objective of this study was to investigate diurnal variation in processes that regulate drug concentrations in the brain, focusing on P-glycoprotein (P-gp). This efflux transporter limits the distribution of many drugs in the brain. To this end, the exposure to the P-gp substrate quinidine was determined in the plasma and brain tissue after intravenous administration in rats at six different time points over the 24-h period. Our results indicate that time of administration significantly affects the exposure to quinidine in the brain. Upon inhibition of P-gp, exposure to quinidine in brain tissue is constant over the 24-h period. To gain more insight into processes regulating brain concentrations, we used intracerebral microdialysis to determine the concentration of quinidine in brain extracellular fluid (ECF) and cerebrospinal fluid (CSF) after intravenous administration at two different time points. The data were analyzed by physiologically based pharmacokinetic modeling using NONMEM. The model shows that the variation is due to higher activity of P-gp-mediated transport from the deep brain compartment to the plasma compartment during the active period. Furthermore, the analysis reveals that CSF flux is higher in the resting period compared to the active period. In conclusion, we show that the exposure to a P-gp substrate in the brain depends on time of administration, thereby providing a new strategy for drug targeting to the brain.Pharmacolog

The relationship between preterm birth and sleep in children at school age: a systematic review

Premature birth (before 37 weeks of gestation) has been linked to a variety of adverse neurological outcomes. Sleep problems are associated with decreased neurocognitive functioning, which is especially common in children born preterm. The exact relationship between prematurity and sleep at school age is unknown. A systematic review is performed with the aim to assess the relationship between prematurity and sleep at school age (5th to 18th year of life), in comparison to sleep of their peers born full-term. Of 347 possibly eligible studies, nine were included. The overall conclusion is that prematurity is associated with earlier bedtimes and a lower sleep quality, in particular more nocturnal awakenings and more non-rapid eye movement stage 2 sleep. Interpretations and limitations of the review are discussed. Moreover, suggestions for future research are brought forward, including the need for a systematic approach with consistent outcome measures in this field of research. A better understanding of the mechanisms that influence sleep in the vulnerable group of children born preterm could help optimize these children's behavioral and intellectual development. (C) 2021 The Author(s). Published by Elsevier Ltd.Circadian clocks in health and diseas

Impact of Shift Work on the Circadian Timing System and Health in Women

Circadian clocks in health and diseas

Individual metabolomic signatures of circadian misalignment during simulated night shifts in humans

Circadian clocks in health and diseas

Metabolic and cardiovascular consequences of shift work: The role of circadian disruption and sleep disturbances

Shift work, defined as work occurring outside typical daytime working hours, is associated with an increased risk of various non-communicable diseases, including diabetes and cardiovascular disease. Disruption of the internal circadian timing system and concomitant sleep disturbances is thought to play a critical role in the development of these health problems. Indeed, controlled laboratory studies have shown that short-term circadian misalignment and sleep restriction independently impair physiological processes, including insulin sensitivity, energy expenditure, immune function, blood pressure and cardiac modulation by the autonomous nervous system. If allowed to persist, these acute effects may lead to the development of cardiometabolic diseases in the long term. Here, we discuss the evidence for the contributions of circadian disruption and associated sleep disturbances to the risk of metabolic and cardiovascular health problems in shift workers. Improving the understanding of the physiological mechanisms affected by circadian misalignment and sleep disturbance will contribute to the development and implementation of strategies that prevent or mitigate the cardiometabolic impact of shift work.Circadian clocks in health and diseas