Insufficient reply by Hermida et al. to the critical comments to the MAPEC and HYGIA studies.

The reply of Hermida et al. (2020) to our critical comments on the MAPEC and HYGIA Lemmer and Middeke (2020) studies in this Journal is insufficient and incomplete. Hermida does not address our first and main point on the baseline blood pressure values of 131/77 mmHg over 48 hours comprising 57.4% of the treated hypertensives (according to Table 1 in HYGIA) and consequently 42.6% of the untretated hypertensives! We criticized that in the HYGIA study; both normal and treated patients were included in one group not separated by statistics and without information on the baseline blood pressure values in each subgroup. This basic failure is our key issue of criticism and the basis of unreliability concerning the whole publication. This issue was not picked up in the recent comment of Hermida et al. (2020). They just concentrated on minor points in order to reject our severe criticism.

A commentary on the Spanish hypertension studies MAPEC and HYGIA.

The recently published chronotherapeutic Spanish papers MAPEC and HYGIA proposing that antihypertensive drug treatment should be given at bedtime suffers from obvious deficiencies in study design and are not a valid basis for drug treatment of hypertension.

Caelius Aurelianus' textbook on medicine of the fifth century: rhythm in asthma, pain, and drug effects.

Caelius Aurelianus was a Greek-Roman physician in the fifth century. He translated the work of Soranus from Ephesus into Latin and extended the medical knowledge of his time in several textbooks. His book "De Morbis acutis et chronicis" was reprinted many times up to the 19th century and served as the handbook for physicians. Aurelianus aready described in detail the rhythmic pattern - daily and seasonally - of asthma. Tooth pain was also first described by Caelius Aurelianus to peak at night and that drugs were not able to fully suppress the pain, a first indication of chronopharmacology.

No correlation between lunar and menstrual cycle - an early report by the french physician J. A. Murat in 1806.

Jean Arnaud Murat was a physician at the Medical School of Montpellier in France. In 1806 he published his outstanding book "De L'Influence de la Nuit sur les Maladies ou Traité des Maladies Nocturne". In his book he concentrated on the following questions: - Does the night has an influence on a disease? - Are there diseases in which this is more or less obvious? - What is the physical background of this influence? Murat described in detail certain diseases which dominate at night and he concluded that the most evident motivation for his observations is the constant and periodic movement of the earth around its axis, resulting in a period of about 24 h, and the elliptic rotation around the sun. Most important Murat presented for the first time data that the menstrual cycle is not governed by the lunar cycle.

The physiologist Johann Autenrieth (1772-1835) at Tübingen University: early reports on biological rhythms and their use for medical lectures.

Johann, Heinrich, Ferdinand von Autenrieth [1772-1835], was a teacher of anatomy, physiology and pharmacology at the University of Tübingen, Germany. He was the author of a famous textbook on Physiology and one of the earliest pharmacologists [Öffentlicher Lehrer der Arzneykunst]. In his textbooks, he presented a lot of information that and how biological rhythms influenced physiological functions in the human body, the book was used for his medical lectures for students. He can be regarded as on of the earliest chronophysiologists. Most important, he assumed a chemical stimulation responsible for generating the periodicities in the human body.

The Role of Circadian Rhythms in the Hypertension of Diabetes Mellitus and the Metabolic Syndrome.

PURPOSE OF THE REVIEW: Cellular circadian clocks regulate physiological functions during day and night. It has been convincingly demonstrated that hypertension in patients suffering from diabetes mellitus or metabolic syndrome is characterized in most cases by a disturbed 24-h profile resulting in a nondipper pattern. We consider possible correlation between biological clocks and symptoms of the metabolic syndrome. RECENT FINDINGS: Changes in circadian clock function have been linked to metabolic disorders in genome-wide association studies. Epidemiological studies have shown that a loss of nocturnal decline in blood pressure increases the risk of cardiovascular morbidity and mortality and end-organ damage. Looking at clock genes, however, there is no obvious association between symptoms of diabetes or metabolic syndrome and clock gene expression. Emerging data suggest that circadian rhythm disruption is a risk factor for metabolic and cardiovascular disorders, while disease feedback on clock function is limited.

Signal Transduction and Chronopharmacology of Regulation of Circadian Cardiovascular Rhythms in Animal Models of Human Hypertension.

Inbred strains of rats can be used as models of human hypertension to evaluate mechanisms of regulation of the circadian rhythms underlying hypertension. Blood pressure and heart rate rhythms in rodents are endogenous (circadian). Studies have been performed in rats on the turnover of norepinephrine, on processes of signal transduction in the beta-adrenoceptor-adenylate cyclase-cyclic AMP-phosphodiesterase system and in the renin-angiotensin-aldosterone system, and on circadian rhythms in blood pressure and heart rate using radiotelemetry. The findings allowed a better understanding of the circadian phase-dependent kinetics and effects of cardiovascular active drugs (chronopharmacology) used in humans.

[Light and Medicine]. / Licht und Medizin.

There would be no life without light. The rotation of the earth around its axis has introduced the development of biological clocks in all living subjects regulating all functions of the body. The rhythms best described are the 24-hour/circadian and the seasonal rhythms. The rhythmic composition around the body clock has great impact on health and disease, both in diagnostics and treatment. Nowadays, bright light, e.g. in seasonal affective disorder, can be regarded as a drug, being even more effective than selective serotonin reuptake inhibitors.

Circadian rhythms in blood pressure, heart rate, hormones, and on polysomnographic parameters in severe obstructive sleep apnea syndrome patients: effect of continuous positive airway pressure.

INTRODUCTION: Seventeen male patients with severe obstructive sleep apnea syndrome (OSAS; apnea-hypopnea index>30/h) were monitored by polysomnography in the sleep lab before and after about 8 weeks of continuous positive airway pressure (CPAP). Twelve of the patients were hypertensive, but treated by antihypertensive drugs. The circadian rhythms in blood pressure (BP) and heart rate were determined by ambulatory BP monitoring and motor activity was monitored by a motion logger. As the sympathetic tone is reported to be increased in sleep apnea, the circadian rhythm in plasma norepinephrine was studied in parallel and as a marker rhythm of the biological clock plasma melatonin was determined around the clock by radioimmunoassay. RESULTS: Level and rhythm in BP and heart rate were not significantly affected by CPAP in this group of patients, but the number of dippers increased after CPAP intervention. The high 24 h plasma values of norepinephrine were lowered by CPAP therapy. In contrast, melatonin values were disturbed in OSAS patients with a loss in nocturnal increase; this pattern was not corrected by CPAP. Sleep functions (deep sleep, slow wave sleep, rapid eye movement sleep, arousal index, apnea-hypopnea index, desaturation index) were disturbed in OSAS patients as monitored by polysomnography and were significantly improved by CPAP therapy. CONCLUSION: The study indicates that BP-controlled hypertensive patients with OSAS can additionally benefit from CPAP therapy by increasing the number of dippers. This treatment significantly improved sleep functions and OSAS symptoms. In addition, arousal movements at night were also reduced and the high sympathetic tone during early morning hours was also decreased. However, there is still an indication of a disturbed function of the biological clock as the loss in the rhythm in plasma melatonin was not corrected by CPAP.

RFID Technology for Continuous Monitoring of Physiological Signals in Small Animals.

Telemetry systems enable researchers to continuously monitor physiological signals in unrestrained, freely moving small rodents. Drawbacks of common systems are limited operation time, the need to house the animals separately, and the necessity of a stable communication link. Furthermore, the costs of the typically proprietary telemetry systems reduce the acceptance. The aim of this paper is to introduce a low-cost telemetry system based on common radio frequency identification technology optimized for battery-independent operational time, good reusability, and flexibility. The presented implant is equipped with sensors to measure electrocardiogram, arterial blood pressure, and body temperature. The biological signals are transmitted as digital data streams. The device is able of monitoring several freely moving animals housed in groups with a single reader station. The modular concept of the system significantly reduces the costs to monitor multiple physiological functions and refining procedures in preclinical research.

Influence of acoustic stimulation on the circadian and ultradian rhythm of premature infants.

UNLABELLED: The aim of the present study was to evaluate the development of the circadian rhythm of the salivary cortisol in premature infants and its correlation with the onset of the sleep-activity behavior pattern during the first 3 weeks of life under controlled light:dark conditions. Furthermore, we investigated the influence of acoustic stimulation by audiotaped lullabies or the maternal voice on the cortisol values and long-term sleep-activity patterns. The study was a block-randomized, prospective clinical trial with a study population of 62 preterm neonates (30<37 gestational age). We compared two study groups who listened either to music or to the maternal voice (music: N=20; maternal voice: N=20) with a matched control group (N=22). The acoustic stimulation took place every evening between 20:00 and 21:00 h for 30 min over a period of 2 weeks. The cortisol values and activity-rest behavior of the neonates were determined during the first 3 weeks of life on the 1st, 7th and 14th day. Actigraphic monitoring was used to record the activity pattern continuously over 24 h and a validated algorithm for neonates was used to estimate sleep and wakefulness. The saliva samples were obtained 10 min before and 10 min after the acoustic interventions for the study groups. Additionally, saliva samples were obtained from the control group seven times over a 24-h period (20:00, 21:00, 01:00, 05:00, 08:00, 13:00 and 17:00 h). The cortisol data were analyzed by fast Fourier transformation to assess periodic characteristics and frequencies. Hierarchical linear modeling was further performed for the statistical analysis. RESULTS: The cortisol rhythm analysis indicated a circadian rhythm pattern for only one premature infant, all others of the neonates showed no circadian or ultradian rhythm in cortisol. Cortisol level of the premature neonates was significantly higher during the first day of the study period at night-time (median: 17.1 nmol/L, IQR=9.7-24.4 nmol/L) than on days 7 (median: 9.6 nmol/L, IQR=4.7-14.6 nmol/L; Tukey-HSD, z=4.12, p<0.001) and 14 (IQR=5.8-13.7 nmol/L; Tukey-HSD, z=2.89, p<0.05). No significant effect of acoustic stimulation was observed on the cortisol concentration and sleep-wake behavior. The activity-sleep rhythm of preterm neonates was dominated by ultradian rhythm patterns with a prominent period length of 4 h (30.5%). Activity frequencies of neonates were also significantly higher overnight on the first study day (mean: 329±185.1 U) than of night seven (mean: 260.2±132.4 U; Tukey-HSD, z=2.50, p<0.05). Quiet-activity patterns increased, whereas high-activity patterns decreased during the observation period. Average sleep time increased significantly during the study time from day 1 to day 7 (Tukey-HSD, z=2.51, p<0.05). In conclusion, premature infants showed higher cortisol levels - without a circadian rhythmicity - and higher activity frequencies in the first days after birth which may reflect an adaptation process of neonates after birth. Cortisol concentrations and the activity patterns were not influenced by music interventions.

Safety pharmacology--current and emerging concepts.

Safety pharmacology (SP) is an essential part of the drug development process that aims to identify and predict adverse effects prior to clinical trials. SP studies are described in the International Conference on Harmonisation (ICH) S7A and S7B guidelines. The core battery and supplemental SP studies evaluate effects of a new chemical entity (NCE) at both anticipated therapeutic and supra-therapeutic exposures on major organ systems, including cardiovascular, central nervous, respiratory, renal and gastrointestinal. This review outlines the current practices and emerging concepts in SP studies including frontloading, parallel assessment of core battery studies, use of non-standard species, biomarkers, and combining toxicology and SP assessments. Integration of the newer approaches to routine SP studies may significantly enhance the scope of SP by refining and providing mechanistic insight to potential adverse effects associated with test compounds.

Circadian variations in exsorptive transport: in situ intestinal perfusion data and in vivo relevance.

The circadian timing system (CTS) governs the 24-h rhythm of the organism and, hence, also main pathways responsible for drug pharmacokinetics. P-glycoprotein (P-gp) is a drug transporter that plays a pivotal role in drug absorption, distribution, and elimination, and temporal changes in its activity may affect input, output, activity, and toxicity profile of drugs. In the current study, the influence of different circadian stages on the overall intestinal permeability (P(eff)) of the P-gp substrates talinolol and losartan was evaluated in in situ intestinal perfusion studies in rats. Additionally, in vivo studies in rats were performed by employing the P-gp probe talinolol during the day (nonactive) and night (active) period in rats. Effective intestinal permeabilities of talinolol and losartan were smaller in studies performed during the night (p < .05), indicating that P-gp-dependent intestinal secretion is greater during the nighttime activity span than daytime rest span of the animals. P-gp modulators vinblastine and PSC833 led to a significant decrease of talinolol and losartan exsorption in the intestinal segments as compared with control groups. Strikingly, the permeability-enhancing effect of vinblastine and PSC833 was higher with night perfusions, for both talinolol and losartan. In vivo studies performed with talinolol revealed-consistent with the in situ studies (P(eff) day > night)-a day vs. night difference in the oral availability of talinolol in the group of male rats in terms of the area under the curve (AUC) data (AUC(day) > AUC(night)). The P-gp modulator vinblastine significantly increased talinolol AUC(day) (p < .05), whereas only a weak vinblastine effect was seen in night. According to the in situ data, the functional activity of P-gp was regulated by the CTS in jejunum and ileum, which are major intestinal segments for energy-dependent efflux. In conclusion, circadian rhythms may affect carrier-mediated active efflux and play a role in the absorption process. In addition to daily rhythms in P-gp activity in rat intestine, the in vivo studies indicate that absorption-, distribution-, metabolism-, and elimination-relevant rhythms may be involved in the circadian kinetics of the drug, besides transporter-dependent efflux, such well-known aspects as metabolic or renal clearance or motility. Since this also holds true for a potentially interacting second compound (modulator), modulator effects should be evaluated carefully in transporter related drug-drug interactions.

Chronopharmacology of roflumilast: a comparative pharmacokinetic study of morning versus evening administration in healthy adults.

The human circadian system is known to affect the pharmacokinetics and pharmacodynamics of several classes of respiratory disease medications. The current study involving 16 healthy adults investigated if the time-of-day of dosing of roflumilast, a novel phosphodiesterase-4 inhibitor, affects its pharmacokinetics. The rate of drug absorption (t(max): 1.50 versus 2.00 h) and peak concentration at t(max) (C(max): 3.79 versus 3.06 µg/L) was slightly greater with morning than evening administration, but without clinical significance. The extent of drug absorption (AUC) and drug elimination (t(1/2)) did not differ between the two dosing times. The pharmacokinetics of the active main metabolite, roflumilast N-oxide, also was not affected by the time of drug administration. Finally, the safety and tolerability of roflumilast did not differ between the two different times of administration.

[Chronopharmacology--importance of the biological clock in drug treatment]. / Chronopharmakologie. Bedeutung der inneren Uhr für die Arzneitherapie.

Nearly all functions of living creatures including man exhibit significant daily variations. Today, internal biological clocks are traced down to the molecular level. In man pathophysiological events such as coronary infarction, angina pectoris, asthma attacks and gastro-intestinal ulcers do not occur at random but exhibit a clear-cut daily rhythmic pattern. It is, therefore, not surprising that the pharmacokinetics as well the effects and side-effects of drugs can vary significantly with the time of day as has been documented in many clinical studies. Thus, "time-of-day" has to be regarded as an important factor to evaluate drug efficacy and its therapeutic window.

Discoveries of rhythms in human biological functions: a historical review.

Though there are very early and ancient observations on the daily variation in physiological and pathophysiological functions (e.g., bronchial asthma), more detailed and scientific reports were not published until the beginning of the 17th century. The aim of this review is to bring those reports to the attention of researchers of chronobiology and chronopharmacology. The ancient books and their contents, which constitute the basis for this review, are part of the personal library collection of the author; numerous observations and reports on biologic rhythms in man are presented here for the first time. The intent of this review is to demonstrate that the fields of chronobiology and chronopharmacology are not only a new and modern branch of science, but that it stands on the shoulders of wonderful and insightful observations and explanations made by our scientific forefathers. It is the hope that the reader will enjoy the richness of the ancient reports that contribute to our present knowledge achieved through astute early biologic rhythm research.