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Hiroshi Tsuneki, Tsutomu Wada, Toshiyasu Sasaoka
Sleep, a mysterious behavior, has recently been recognized as a crucial factor for health and longevity. The daily sleep/wake cycle provides the basis of biorhythms controlling whole-body homeostasis and homeodynamics; therefore, disruption of sleep causes several physical and psychological disorders, including cardiovascular disease, obesity, diabetes, cancer, anxiety, depression, and cognitive dysfunction. However, the mechanism linking sleep disturbances and sleep-related disorders remains unknown. Orexin (also known as hypocretin) is a neuropeptide produced in the hypothalamus...
December 28, 2017: Pharmacology & Therapeutics
Chanel A Griggs, Scott W Malm, Rosa Jaime-Frias, Catharine L Smith
Valproic acid (VPA) is a well-established therapeutic used in treatment of seizure and mood disorders as well as migraines and a known hepatotoxicant. About 50% of VPA users experience metabolic disruptions, including weight gain, hyperlipidemia, and hyperinsulinemia, among others. Several of these metabolic abnormalities are similar to the effects of circadian rhythm disruption. In the current study, we examine the effect of VPA exposure on the expression of core circadian transcription factors that drive the circadian clock via a transcription-translation feedback loop...
December 8, 2017: Toxicology and Applied Pharmacology
Björn Lemmer
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...
October 2017: Heart Failure Clinics
Yuki Fujiwara, Hitoshi Ando, Kentaro Ushijima, Michiko Horiguchi, Chikamasa Yamashita, Akio Fujimura
The anticoagulant effect of rivaroxaban, a direct inhibitor of activated factor X (FX), might be influenced by its dosing time because the activity of the coagulofibrinolytic system exhibits daily rhythmicity. In rats, FX activity follows a 24-h rhythm with a peak in the middle of the light phase and a trough at the beginning of the dark phase. Consistent with these findings, a single dose of rivaroxaban had a stronger inhibitory effect on FX activity after dosing at the beginning of the light phase than after dosing at the beginning of the dark phase...
August 2017: Journal of Pharmacological Sciences
Paola Tognini, Christoph A Thaiss, Eran Elinav, Paolo Sassone-Corsi
Microbial infection poses a threat to organismal homeostasis and therefore must be efficiently counteracted by host defense mechanisms. It has been recently demonstrated that the immune system may anticipate an emerging pathogenic exposure through a heightened inflammatory state. Such anticipatory responses to fluctuating environmental conditions are typically orchestrated by the circadian clock, an intrinsic time-keeping system that adapts tissue physiology to diurnal variations in external influences. Here, we review current knowledge about the interplay between the circadian clock and antimicrobial responses...
August 9, 2017: Cell Host & Microbe
Rong-Kun Chang, Neil Mathias, Munir A Hussain
This article discusses the range of outcomes from biopharmaceutical studies of specific modified release (MR) product examples in preclinical models and humans. It touches upon five major biopharmaceutical areas for MR drug products: (1) evidence for regional permeability throughout the GI tract, (2) susceptibility to food-effect, (3) susceptibility to pH-effect, (4) impact of chronopharmacology in designing MR products, and (5) implications to narrow therapeutic index products. Robust bioperformance requires that product quality is met through a thorough understanding of the appropriate critical quality attributes that ensure reliable and robust manufacture of a MR dosage form...
July 5, 2017: AAPS Journal
Peter Potucek, Michal Radik, Gabriel Doka, Eva Kralova, Peter Krenek, Jan Klimas
Chronopharmacological effects of antihypertensives play a role in the outcome of hypertension therapy. However, studies produce contradictory findings when combination of valsartan plus amlodipine (VA) is applied. Here, we hypothesized different efficacy of morning versus evening dosing of VA in spontaneously hypertensive rats (SHR) and the involvement of circadian clock genes Bmal1 and Per2. We tested the therapy outcome in short-term and also long-term settings. SHRs aged between 8 and 10 weeks were treated with 10 mg/kg of valsartan and 4 mg/kg of amlodipine, either in the morning or in the evening with treatment duration 1 or 6 weeks and compared with parallel placebo groups...
June 30, 2017: Clinical and Experimental Hypertension: CHE
Samira Khodadoustan, Iran Nasri Ashrafi, K Vanaja Satheesh, Chethan Kumar, Shekar Hs, Chikkalingaiah S
In clinical practice, circadian rhythms play a prominent role in pharmacokinetics and cell responses to therapy, hence necessitating in designing a defined protocol for drug administration. Clinical evidence for chronopharmacological behavior of cardiovascular active drugs in human subjects has been limited for amlodipine. Hence, the present study was undertaken to study the chronopharmacokinetic and chronopharmacodynamic phenomena of amlodipine and evaluate the effect of time of dosage in hypertensive subjects...
June 9, 2017: Clinical and Experimental Hypertension: CHE
E V Kostenko
AIM: To study the efficacy of melaxen on the dynamics of sleep disturbance, cognitive and emotional disorders, BDNF and the level of secretion of melatonin (6-SOMT) in patients with stroke in the early and late recovery phase. MATERIAL AND METHODS: One hundred and ten patients in the rehabilitation period of stroke (mean age of 58.4±6.4 years), including 60 patients in the early recovery phase (group 1) and 50 patients in the late phase (group 2), were studied...
2017: Zhurnal Nevrologii i Psikhiatrii Imeni S.S. Korsakova
Ricardo Orozco-Solis, Emilie Montellier, Lorena Aguilar-Arnal, Shogo Sato, Marquis P Vawter, Blynn G Bunney, William E Bunney, Paolo Sassone-Corsi
BACKGROUND: Conventional antidepressants usually require several weeks to achieve a full clinical response in patients with major depressive disorder, an illness associated with dysregulated circadian rhythms and a high incidence of suicidality. Two rapid-acting antidepressant strategies, low-dose ketamine (KT) and sleep deprivation (SD) therapies, dramatically reduce depressive symptoms within 24 hours in a subset of major depressive disorder patients. However, it is unknown whether they exert their actions through shared regulatory mechanisms...
September 1, 2017: Biological Psychiatry
Annabelle Ballesta, Pasquale F Innominato, Robert Dallmann, David A Rand, Francis A Lévi
Chronotherapeutics aim at treating illnesses according to the endogenous biologic rhythms, which moderate xenobiotic metabolism and cellular drug response. The molecular clocks present in individual cells involve approximately fifteen clock genes interconnected in regulatory feedback loops. They are coordinated by the suprachiasmatic nuclei, a hypothalamic pacemaker, which also adjusts the circadian rhythms to environmental cycles. As a result, many mechanisms of diseases and drug effects are controlled by the circadian timing system...
April 2017: Pharmacological Reviews
Carlos K B Ferrari, Eduardo L França, Luciane A Monteiro, Bruno L Santos, Alfredo Pereira-Junior, Adenilda C Honorio-França
OBJECTIVES: To investigate the chronopharmacological effects of growth hormone on executive function and the oxidative stress response in rats. MATERIALS AND METHODS: Fifty male Wistar rats (36-40 weeks old) had ad libitum access to water and food and were separated into four groups: diurnal control, nocturnal control, diurnal GH-treated, and nocturnal GH-treated animals. Levels of Cu, Zn superoxide dismutase (Cu, Zn-SOD), and superoxide release by spleen macrophages were evaluated...
January 2017: Iranian Journal of Basic Medical Sciences
Robert Dallmann, Alper Okyar, Francis Lévi
Daily rhythms in physiology significantly modulate drug pharmacokinetics and pharmacodynamics according to the time-of-day, a finding that has led to the concept of chronopharmacology. The importance of biological clocks for xenobiotic metabolism has gained increased attention with the discovery of the molecular circadian clockwork. Mechanistic understanding of the cell-autonomous molecular circadian oscillator and the circadian timing system as a whole has opened new conceptual and methodological lines of investigation to understand first, the clock's impact on a specific drug's daily variations or the effects/side effects of environmental substances, and second, how clock-controlled pathways are coordinated within a given tissue or organism...
May 2016: Trends in Molecular Medicine
Wilhelmus H I M Drinkenburg, Abdallah Ahnaou, Gé S F Ruigt
Current research on the effects of pharmacological agents on human neurophysiology finds its roots in animal research, which is also reflected in contemporary animal pharmaco-electroencephalography (p-EEG) applications. The contributions, present value and translational appreciation of animal p-EEG-based applications are strongly interlinked with progress in recording and neuroscience analysis methodology. After the pioneering years in the late 19th and early 20th century, animal p-EEG research flourished in the pharmaceutical industry in the early 1980s...
2015: Neuropsychobiology
Akio Fujimura
Blunted blood pressure (BP) decline during night-time leads to the higher risk of cardiovascular events in hypertensive patients. Therefore, to improve the prognosis of the patients, it is essential for properly controlling BP during night-time sleep as well as day-time activity. In addition, the dosing-time dependent changes are observed in the pharmacokinetics and pharmacodynamics of some antihypertensive drugs. Thus, the efficacy and toxicity of drugs might be affected by their dosing-time. Chronotherapy is the therapeutic application of chronopharmacology and chronotoxicology to enhance the effectiveness and tolerance of drugs by determining optical dosing-time of drugs from a circadian perspective...
November 2015: Nihon Rinsho. Japanese Journal of Clinical Medicine
Isaac K Sundar, Hongwei Yao, Michael T Sellix, Irfan Rahman
Disrupted daily or circadian rhythms of lung function and inflammatory responses are common features of chronic airway diseases. At the molecular level these circadian rhythms depend on the activity of an autoregulatory feedback loop oscillator of clock gene transcription factors, including the BMAL1:CLOCK activator complex and the repressors PERIOD and CRYPTOCHROME. The key nuclear receptors and transcription factors REV-ERBα and RORα regulate Bmal1 expression and provide stability to the oscillator. Circadian clock dysfunction is implicated in both immune and inflammatory responses to environmental, inflammatory, and infectious agents...
November 15, 2015: American Journal of Physiology. Lung Cellular and Molecular Physiology
K L Ode, H R Ueda
Recent advances in methods for making mammalian organs translucent have made possible whole-body fluorescent imaging with single-cell resolution. Because organ-clearing methods can be used to image the heterogeneous nature of cell populations, they are powerful tools to investigate the hierarchical organization of the cellular circadian clock, and how the clock synchronizes a variety of physiological activities. In particular, methods compatible with genetically encoded fluorescent reporters have the potential to detect circadian activity in different brain regions and the circadian-phase distribution across the whole body...
September 2015: Diabetes, Obesity & Metabolism
Sandrine Dulong, Annabelle Ballesta, Alper Okyar, Francis Lévi
Cancer chronotherapy aims at enhancing tolerability and efficacy of anticancer drugs through their delivery according to circadian clocks. However, mouse and patient data show that lifestyle, sex, genetics, drugs, and cancer can modify both host circadian clocks and metabolism pathways dynamics, and thus the optimal timing of drug administration. The mathematical modeling of chronopharmacology could indeed help moderate optimal timing according to patient-specific determinants. Here, we combine in vitro and in silico methods, in order to characterize the critical molecular pathways that drive the chronopharmacology of irinotecan, a topoisomerase I inhibitor with complex metabolism and known activity against colorectal cancer...
September 2015: Molecular Cancer Therapeutics
Diego A Golombek, Seithikurippu R Pandi-Perumal, Gregory M Brown, Daniel P Cardinali
The last decade has witnessed the emergence of new chronopharmacological perspectives. In the case of sleep disorders, the accumulating evidence suggests that even a minor dysfunction in the biological clock can impact broadly upon body physiology causing increases in sleep onset latency, phase delays or advances in sleep initiation, frequent nocturnal awakenings, reduced sleep efficiency, delayed and shortened rapid eye movement sleep and increased periodic leg movements, among others. Thus, restoration of the adequate circadian pattern of proper sleep hygiene, targeted exposure to light and the use of chronobiotic drugs, such as melatonin, which affect the output phase of clock-controlled circadian rhythms, can help to recover the sleep-wake cycle...
September 5, 2015: European Journal of Pharmacology
Isaac K Sundar, Hongwei Yao, Michael T Sellix, Irfan Rahman
Airway diseases are associated with abnormal circadian rhythms of lung function, reflected in daily changes of airway caliber, airway resistance, respiratory symptoms, and abnormal immune-inflammatory responses. Circadian rhythms are generated at the cellular level by an autoregulatory feedback loop of interlocked transcription factors collectively referred to as clock genes. The molecular clock is altered by cigarette smoke, LPS, and bacterial and viral infections in mouse and human lungs and in patients with chronic airway diseases...
September 2015: American Journal of Respiratory Cell and Molecular Biology
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