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Aims/hypothesis The objective was to investigate if metformin pharmacokinetics is modulated by time-of-day in humans using empirical and mechanistic pharmacokinetic modelling techniques on a large clinical dataset. This study also aimed to generate and test hypotheses on the underlying mechanisms, including evidence for chronotype-dependent interindividual differences in metformin plasma and efficacy-related tissue concentrations. Methods A large clinical dataset consisting of individual metformin plasma and urine measurements was analysed using a newly developed empirical pharmacokinetic model. Causes of daily variation of metformin pharmacokinetics and interindividual variability were further investigated by a literature-informed mechanistic modelling analysis. Results A significant effect of time-of-day on metformin pharmacokinetics was found. Daily rhythms of gastrointestinal, hepatic and renal processes are described in the literature, possibly affecting drug pharmacokinetics. Observed metformin plasma levels were best described by a combination of a rhythm in GFR, renal plasma flow (RPF) and organic cation transporter (OCT) 2 activity. Furthermore, the large interindividual differences in measured metformin concentrations were best explained by individual chronotypes affecting metformin clearance, with impact on plasma and tissue concentrations that may have implications for metformin efficacy. Conclusions/interpretation Metformin’s pharmacology significantly depends on time-of-day in humans, determined with the help of empirical and mechanistic pharmacokinetic modelling, and rhythmic GFR, RPF and OCT2 were found to govern intraday variation. Interindividual variation was found to be partly dependent on individual chronotype, suggesting diurnal preference as an interesting, but so-far underappreciated, topic with regard to future personalised chronomodulated therapy in people with type 2 diabetes. Graphical abstract

Earth rotation around its axis imposes a 24-hour rhythmicity to all life on the planet. Rather than passively responding to these periodic changes, nature has given us an internal timekeeper, the circadian clock, to anticipate to our advantage the fluctuations in the environment. The circadian clock is a cell-autonomous pervasive molecular oscillator with a period of about a day. The core of the clock is a transcriptional-transaltional negative feedback loop involving a few dozen genes. This set of genes induces 24-hour rhythms in many downstream processes which are responsible for the daily oscillations in behaviour and physiology. A functioning timekeeper has been associated with well-being while disruptions of the clock have been linked with a variety of diseases, including cancer. To study the properties and behaviour of the circadian clock in mammals the field has relied heavily on animal models and timed animal omics experiments, due to the difficulty of performing relevant human experiments. However, there is a vast set of human data coming from the clinic without a time stamp, so not directly exploitable to study circadian oscillations. Many methods have been proposed to assign time stamps to a set of omics snapshots; we take inspiration from their strengths and flaws to develop a new probabilistic method of circadian phase inference, CHIRAL. The physiological impact of the circadian clock in humans is not fully characterised. We exploited the Genotype-Tissue Expression project (GTEx), assigning time stamps to the samples using CHIRAL. We used existing relationships among samples to both robustly infer one time stamp per donor, and transfer time information from robust clocks to weaker ones. This procedure allowed us to study human mRNA rhythms in 46 tissues and compare circadian behaviour across sexes and ages. Clock transcripts showed highly conserved phase and amplitude relationships across tissues, and were tightly synchronised across the body. Tissue rhythmic gene expression programs differed in breadth, covering global and tissue-specific functions, including metabolic pathways and systemic responses. The circadian clock structure and amplitude was conserved across sexes and age groups. However, overall gene expression rhythms were highly sex-dimorphic and more sustained in females. Moreover, rhythmic programs dampened with age across the body. Together, our stratified analysis unveiled a rich organization of sex- and age-specific circadian gene expression rhythms in humans. To study the clock we took advantage of its low dimensional structure. In fact, projecting high dimensional biological data onto low dimensional manifolds is a widespread technique in biology. In particular, it has proved very useful to exploit single cell transcriptome data. In the single cell framework the RNA velocity technique arose. RNA velocity tackles the idea that cells move in the low dimensional manifolds; it infers the future state of a cell combining current spliced and unspliced RNA counts. However, it is still a very new technique, so not all of the possible adjustments have been made. We develop an analytical framework to add constrains to RNA velocity dynamical systems and differential geometry, allowing for trajectory reconstruction and calculation of time distances on the low dimensional manifold. We apply our method to the cell cycle and infer its period across different brain regions in mouse.

We previously reported that brotizolam, but not suvorexant, delayed recovery from isoflurane anesthesia in mice. However, the effects of hypnotics may be altered by the circadian rhythm. Locomotor activity was measured using sighted (ICR and C57BL/6J) and blind (FVB/N and C3H/HeN) mice, and the effects of hypnotics on isoflurane anesthesia were compared during the light and dark periods. In sighted mice, recovery induced by brotizolam was delayed in the light period, while that by suvorexant was delayed in the dark period. In C57BL/6J mice, delayed recovery induced by brotizolam was marked, and that by suvorexant was observed in the light and dark periods. Locomotor activity was low in the last 6 h of the dark period in blind mice, and was similar to that in the light period. In blind mice, delayed recovery induced by brotizolam was identical in both periods, while suvorexant did not influence recovery from isoflurane anesthesia. These results suggest that the effects of hypnotics on isoflurane anesthesia are altered by the circadian rhythm and that daily light–dark stimuli may be required for the chronopharmacological effects of hypnotics.

Aims. The present study aimed to investigate the knowledge of Libyan pharmacists about the concept of chronopharmacology of antihypertensive medications. Methods. Questioners were studied at the East region (Cities) of Libya (Albyda, Benghazi and Almarj). All the samples were analysed by Excel Software. The pharmacists were asked to fill the questioner whether the antihypertensive medications are given in the morning, evening, bed time, anytime or not sure. Results. Although they did not know about the concept of chronopharmacology, findings shows that 50% of the of the pharmacists in the current study described the tested medications to be taken on the right time dependent on the type of each one. Conclusion. The current study indicated that the practice of pharmacists regarding to the awareness of chronopharmacology concept needs further improvement. The improvement can be done by contribution of healthcare professional and providers to feedback about the importance of chronopharmacology.

The objective of the optimization of pharmacotherapy compliant with the basic rules of clinical pharmacology is its maximum individualization, ensuring paramount effectiveness and security of the patient’s therapy. Thus, multiple factors that are decisive in terms of uniqueness of treatment of the given patient must be taken into consideration, including, but not limited to, the patient’s age, sex, concomitant diseases, special physiological conditions (e.g., pregnancy, lactation, extreme age groups), polypharmacotherapy and polypragmasia (particularly related to increased risk of drug interactions), and patient’s phenotypic response to the administered drug with possible genotyping. Conducting therapy while monitoring the concentration of certain drugs in blood (Therapeutic Drug Monitoring; TDM procedure) is also one of the factors enabling treatment individualization. Furthermore, another material, and yet still a marginalized pharmacotherapeutic factor, is chronopharmacology, which indirectly determines the values of drug concentrations evaluated in the TDM procedure. This paper is a brief overview of chronopharmacology, especially chronopharmacokinetics, and its connection with the clinical interpretation of the meaning of the drug concentrations determined in the TDM procedure.

Physiological functions of cardiovascular system (CVS) are exhibiting circadian patterns regulated by complex system of endogenous factors. Preserving this rhythmicity is important for its normal function, whereas disturbing the synchronization with natural day–night cycle can increase the risk of cardiovascular damage. Cardiovascular pathophysiology also follows cyclic variation; time susceptibility and period with maximum risk associated with elevated blood pressure (BP) can be predicted. Given this rhythmic nature, significant changes in efficacy between morning and evening administration of the drug may occur; appropriate timing of pharmacological intervention in therapy of hypertension may affect the efficacy of the treatment.

In the United States, hypertension affects over 90% of all patients with cardiovascular disease (CVD), and it is a major risk factor for end-organ injury, CVD, and death. The study of chronobiology, chronopharmacology, and chronotherapy in the treatment of hypertension started a few decades ago. Blood pressure (BP) and cardiovascular disease (CVD) are affected by our behaviour, such as what we eat, and also by the time of day, according to research published in the last decade.In addition, as compared to office BP calculated only once, the capacity of the night: day ratio of systolic BP to predict the risk of cardiovascular events is more accurate. The evidence clearly shows that nocturnal BP is the BP that is most consistently associated with cardiovascular risk prediction and offers more frequent safety monitoring. The circadian rhythm plays an important role in blood pressure control. As a result, a circadian condition like hypertension necessitates the use of chronopharmacotherapy. However, different medications have been studied for their chronopharmacology and potential chronotherapy. The chronobiology of hypertension, as well as the chronopharmacology and chronotherapy of the different drugs used to treat it, are discussed in this article. Knowing the risk factors associated with this disease disorder, researchers are expected to develop more innovative chronopharmaceutical formulations for the control or treatment of hypertension.

Made available in DSpace on 2020-12-12T02:46:16Z (GMT). No. of bitstreams: 0 Previous issue date: 2020-01-01 Sibutramine is a non-selective serotonin-norepinephrine reuptake inhibitor orally administered for weight loss. In a previous study, we showed pharmacological mechanisms involved in the reduction of sperm quality and fertility of rats exposed for 30 days to this anorexigen in the light phase of the light-dark (l/d) cycle. It is already known that rodents are nightlife animals, with higher metabolic activity during the dark phase than in the light phase of the light-dark (l/d) cycle. Thus, the present study aimed to investigate whether the deleterious effects on reproductive parameters after sibutramine administration would be enhanced after a shorter period of exposure during the dark phase of the l/d cycle. For this, adult male Wistar rats were treated with sibutramine (10 mg/kg/d) or vehicle for 15 days during the dark phase of the l/d cycle. Sibutramine treatment decreased final body and reproductive organ weights, as well as serum testosterone levels. Sperm transit time through the epididymis was accelerated, and sperm concentration and motility were diminished in the sibutramine-exposed rats. The decrease in sperm concentration was also verified in the epididymal histological sections. In conclusion, the deleterious effects of sibutramine on reproductive parameters of male rats were enhanced when the exposure occurred in the dark phase of the l/d cycle, even after a short exposure duration. Our results reinforce the impact of timing on drug therapeutic action. Department of Structural and Functional Biology Institute of Biosciences UNESP - São Paulo State University Department of Morphology Stomatology and Physiology USP – University of São Paulo Department of Structural and Functional Biology Institute of Biosciences UNESP - São Paulo State University

The circulating of leukocytes in the vasculature to reach various organs is a crucial step that allows them to perform their function. With a sequence of interaction with the endothelial cells, the leukocytes emigrate from the circulation either by firm attachment to vascular beds or by trafficking into the tissues. Recent findings reveal that the leukocyte recruitment shows time as well as tissue specificity depending on the cell type and homing location. This spatiotemporal distribution of leukocyte subsets is driven by the circadian expression of pro-migratory molecules expressed on the leukocytes and the endothelium. Both the systemic circadian signals and the cell's intrinsic molecule clock contribute to the oscillatory expression of pro-migratory molecules. The rhythmic recruitment of leukocytes plays an important role in the time-dependency of immune responses. It also helps to update blood components and maintain the tissue circadian microenvironment. In this review, we discuss the current knowledge about the mechanisms of the circadian system regulating the leukocyte rhythmic migration, the recruitment pattern of leukocyte subsets into different tissue/organs, and the time-dependent effects behind this process.

Objective(s): 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. For memory testing, adaptation and walking in an open field platform was used. GH-treated animals demonstrated better performance in exploratory and spatial open-field tests. Results: The latency time in both GH-treated groups was significantly lower compared with the latency time of the control groups. The diurnal GH treatment did not stimulate superoxide release but increased the CuZn-SOD enzyme levels. The nocturnal GH treatment did not influence the superoxide release and CuZn-SOD concentration. GH treatment also resulted in heart atrophy and lung hypertrophy. Conclusion: Growth hormone treatment improved the performance of executive functions at the cost of oxidative stress triggering, and this effect was dependent on the circadian period of hormone administration. However, GH treatment caused damaging effects such as lung hypertrophy and heart atrophy.

Предоставление в распоряжении лечащего врача современной аналитической методики, дает возможность проверить применяемые до сих пор дозировки лекарственных препаратов и по-новому освещает некоторые вопросы фармакотерапии. Для достижения максимального терапевтического эффекта при минимальных токсических эффектах, контроль концентрации лекарственных веществ необходимо осуществлять в месте действия препарата. Эта задача решается с помощью контролируемой фармакотерапии. При использовании препаратов с узким терапевтическим коридором, таких как дигоксин -это особенно важно. Значительная часть препаратов не требует контролируемой терапии с определенными концентрации препарата в сыворотке крови. Такими препаратами являются соединения с большим интервалом между токсической и терапевтической дозами, а также лекарственные средства, действие которых можно легко определить клинически (мочегонные, гипотензивные средства). При отсутствии высокой корреляции между концентрацией препарата в крови и фармакологическим эффектом (соединения бета-адреноблокаторов, амиодарон), контролируемая терапия также не проводится. Лечение при контролируемой концентрации препарата способствует рациональной и более безопасной терапии, при условии умелой интерпретации измеренной концентрации. Ошибки, как правило, являются следствием неправильного забора крови или неправильной оценки клинической ситуации., Providing the attending physician with a modern analytical technique makes it possible to check the dosages of medicines used so far and in a new light covers some issues of pharmacotherapy. To achieve the maximum therapeutic effect with minimal toxic effects, the concentration of drugs must be controlled at the site of action of the drug. This problem is solved with the help of controlled pharmacotherapy. When using drugs with a narrow therapeutic corridor, such as anticonvulsants, antiarrhythmic drugs, antibiotics, immunosuppressants, antiepileptic drugs, this is especially important. A significant part of the drugs does not require controlled therapy with certain concentrations of the drug in the blood serum. Such drugs are compounds with a large interval between toxic and therapeutic doses, as well as drugs whose effect can be easily determined clinically (diuretics, antihypertensives). In the absence of a high correlation between the concentration of the drug in the blood and the pharmacological effect (beta-adrenoblocker compounds, amiodarone), controlled therapy is also not carried out. Treatment with a controlled concentration of the drug contributes to a rational and safer therapy, provided that the measured concentration is skillfully interpreted. Errors are usually the result of improper blood sampling or an incorrect assessment of the clinical situation., №15(183) (2020)

В хронофармакологическом эксперименте рассмотрено действие трех препаратов в комбинациях на поведение экспериментальных животных, подвергнутых хронической алкогольной интоксикации. Выявлено снижение порога чувствительности к электрическому раздражению и длительности агрессивной реакции на фоне применения депримирующих средств и повышение данных показателей при комбинации данных препаратов с антиоксилантом. Показано десинхронизирующее дейтвие антиоксиданта на поведенческие реакции лабораторных животных в течение двух суток, что свидетельствует о выраженном адаптационном влиянии.

Background: Empagliflozin is an SGLT2 inhibitor approved for use in patients with diabetes mellitus type 2 (DMT2) with or without other cardiovascular disease. Empagliflozin is taken once daily without rationale on the optimal timing for administration. This study aimed to determine the chronopharmacological effects of morning vs evening administration of empagliflozin (10 mg) in healthy Egyptian adults, by investigating the pharmacokinetics and pharmacodynamics parameters of empagliflozin depending on the intake time. Methods: An open label, sequential, two‐way crossover trial comprised of two periods with a washout period of 7 days. All participants received a single oral dose of empagliflozin (JARDIANCE ®; 10 mg film coated tablet) in the evening, and after a seven-day washout period, the morning. Pharmacokinetics parameters (primary endpoints: tmax (h), Cmax (ng/ml), AUC 0-t (ng.h/ml); secondary endpoints: AUC 0 to ∞(ng.h/ml)) were assessed. Method validation was done prior to injection in LC/MS/MS and samples were processed by Liquid-Liquid extraction. The pharmacodynamic profile (UGE 0-24) was determined after method validation (glucose hexokinase method). Results: Tmax increased by 35% in the evening phase compared to the morning phase, while Cmax decreased by -6.5% in the evening dose compared to the morning dose. Additionally, AUC0 to ∞ increased in the evening phase by 8.25% compared to the morning phase. The mean cumulative amount of glucose excreted (UGE (0-24)) increased by 43% in the evening dose compared to the morning dose Conclusion: Despite the difference in pharmacokinetics parameters between evening and morning doses, Cmax, AUC0-t, AUC 0-∞, didn’t differ on the bioequivalence level. In addition, as UGE (0-24) didn’t statistically differ, thus, we can conclude that there is no statistical significance between the morning and evening doses. Trial registration: Clinal Trials.gov, ID: NCT03895229 (registered on 29th March 2019).

The pathogenesis and therapeutics of depression are linked to the operation of the circadian system. Here, we studied the chronopharmacological action of a tricyclic antidepressant, imipramine. Male adult Wistar–Hannover rats were administered imipramine acutely or chronically in the morning or in the evening. The antidepressant action of imipramine was analyzed using the forced swim test (FST). A single dose of imipramine (30 mg/kg) in the morning, but not in the evening, reduced immobility and increased climbing in the FST. The plasma concentrations of imipramine and its metabolite, desipramine, were slightly higher in the morning than in the evening, which might explain the dosing time-dependent action of imipramine. Next, we analyzed the effect of chronic imipramine treatment. Rats received imipramine in the morning or in the evening for 2 weeks. The morning treatment resulted in larger effects in the FST than the evening treatment, and was effective at a dose that was ineffective when administered acutely. The levels of brain α-adrenergic receptors tended to decrease after chronic imipramine treatment. Imipramine might interact with noradrenergic neurons, and this interaction might chronically alter receptor expression. This alteration seemed greater in the morning than in the evening, which might explain the dosing time-dependent action of imipramine., Article 5

The 2017 Nobel Prize for Physiology or Medicine, awarded for the discoveries made in the past 15 years on the genetic and molecular mechanisms regulating many physiological functions, has renewed the attention to the importance of circadian rhythms. These originate from a central pacemaker in the suprachiasmatic nucleus in the brain, photoentrained via direct connection with melanopsin containing, intrinsically light-sensitive retinal ganglion cells, and it projects to periphery, thus creating an inner circadian rhythm. This regulates several activities, including sleep, feeding times, energy metabolism, endocrine and immune functions. Disturbances of these rhythms, mainly of wake/sleep, hormonal secretion and feeding, cause decrease in quality of life, as well as being involved in development of obesity, metabolic syndrome and neuropsychiatric disorders. Most immunological functions, from leukocyte numbers, activity and cytokine secretion undergo circadian variations, which might affect susceptibility to infections. The intensity of symptoms and disease severity show a 24 h pattern in many immunological and allergic diseases, including rheumatoid arthritis, bronchial asthma, atopic eczema and chronic urticaria. This is accompanied by altered sleep duration and quality, a major determinant of quality of life. Shift work and travel through time zones as well as artificial light pose new health threats by disrupting the circadian rhythms. Finally, the field of chronopharmacology uses these concepts for delivering drugs in synchrony with biological rhythms.

The pharmacokinetics and pharmacodynamics of drugs are influenced by daily fluctuations in physiological processes. The aim of this study was to determine the effect of dosing time on the pharmacokinetics and brain distribution of morphine. To this end, 4 mg/kg morphine was administered intravenously to Wistar rats that were either pre-treated with vehicle or tariquidar and probenecid to inhibit processes involved in the active transport of morphine. Non-linear mixed effects modelling was used to describe the concentration-time profiles of morphine and its metabolite M3G in plasma and brain tissue. We found that the concentrations of morphine in the brain and of M3G in plasma depended on the time of day, which could be quantified by a 24-hour rhythm in the efflux of morphine from brain tissue back into the circulation, with the lowest efflux during the two light-dark phase transitions with a difference between peak and trough of 20%. The active processes involved in the clearance of morphine and its metabolite M3G from plasma also showed 24-hour variation with the highest value in the middle of the dark phase being 54% higher than the lowest value at the start of the light phase. Hence, time of day presents a considerable source of variation in the pharmacokinetics of morphine, which could be used to optimize the dosing strategy of morphine.

Objective(s): 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. For memory testing, adaptation and walking in an open field platform was used. GH-treated animals demonstrated better performance in exploratory and spatial open-field tests. Results: The latency time in both GH-treated groups was significantly lower compared with the latency time of the control groups. The diurnal GH treatment did not stimulate superoxide release but increased the CuZn-SOD enzyme levels. The nocturnal GH treatment did not influence the superoxide release and CuZn-SOD concentration. GH treatment also resulted in heart atrophy and lung hypertrophy. Conclusion: Growth hormone treatment improved the performance of executive functions at the cost of oxidative stress triggering, and this effect was dependent on the circadian period of hormone administration. However, GH treatment caused damaging effects such as lung hypertrophy and heart atrophy.

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.

Circadian rhythms are generated by an endogenously organized timing system that drives daily rhythms in behavior, physiology and metabolism. In mammals, the suprachiasmatic nucleus (SCN) of the hypothalamus is the locus of a master circadian clock. The SCN is synchronized to environmental changes in the light:dark cycle by direct, monosynaptic innervation via the retino-hypothalamic tract. In turn, the SCN coordinates the rhythmic activities of innumerable subordinate clocks in virtually all bodily tissues and organs. The core molecular clockwork is composed of a transcriptional/post-translational feedback loop in which clock genes and their protein products periodically suppress their own transcription. This primary loop connects to downstream output genes by additional, interlocked transcriptional feedback loops to create tissue-specific ‘circadian transcriptomes’. Signals from peripheral tissues inform the SCN of the internal state of the organism and the brain’s master clock is modified accordingly. A consequence of this hierarchical, multilevel feedback system is that there are ubiquitous effects of circadian timing on genetic and metabolic responses throughout the body. This overview examines landmark studies in the history of the study of circadian timing system, and highlights our current understanding of the operation of circadian clocks with a focus on topics of interest to the neuroscience community.

Background Curcuminoids of the spice turmeric and their enhanced derivatives have much potential as cancer treatments. They act on a wide variety of biological pathways, including those regulating cell division and circadian rhythms. It is known that circadian clocks can modify cancer therapy effectiveness, according to studies aimed at optimizing treatments based on the circadian cycle. It is therefore important to determine whether treatments with curcumin or similar chemotherapeutic agents are regulated by circadian timing. Similarly, it is important to characterize any effects of curcumin on timing abilities of the circadian clocks within cancer cells. Methods We examined the circadian clock’s impact on the timing of cell death and cell division in curcumin-treated C6 rat glioma cells through continuous video microscopy for several days. To evaluate its persistence and distribution in cancer cells, curcumin was localized within cell compartments by imaging its autofluorescence. Finally, HPLC and spectroscopy were used to determine the relative stabilities of the curcumin congeners demethoxycurcumin and bisdemethoxycurcumin that are present in turmeric. Results Circadian rhythms in cell death were observed in response to low (5 μM) curcumin, reaching a peak several hours before the peak in rhythmic expression of mPER2 protein, a major circadian clock component. These results revealed a sensitive phase of the circadian cycle that could be effectively targeted in patient therapies based on curcumin or its analogs. Curcumin fluorescence was observed in cell compartments at least 24 h after treatment, and the two congeners displayed greater stability than curcumin in cell culture medium. Conclusions We propose a mechanism whereby curcuminoids act in a sustained manner, over several days, despite their tendency to degrade rapidly in blood and other aqueous media. During cancer therapy, curcumin or its analogs should be delivered to tumor cells at the optimal phase for highest efficacy after identifying the circadian phase of the cancer cells. We confirmed the greater stability of the curcumin congeners, suggesting that they may produce sustained toxicity in cancer cells and should be considered for use in patient care. Electronic supplementary material The online version of this article (doi:10.1186/s12885-016-2789-9) contains supplementary material, which is available to authorized users.

A rough 24-hour cycle driven endogenously in biochemical, physiological or behavioral processes is called circadian rhythm. Chronobiology is the study of biological temporal rhythms. For decades, we know that the biological rhythm and the drug metabolism are also affected from daylight and chronopharmacology became recognized by scientists in the early 1970s. Its lateral branch chronocopharmacokinetics is the study of rhythmic, predictable-in-time differences in the pharmacokinetics of drugs. Chronopharmacokinetic studies are performed at every step of the biotransformation i.e., absorption, distribution, metabolism and excretion. Feeding schedules, sex and phenotype must be taken into consideration while applying pharmacotherapy to increase the efficiency and to decrease side effects. The impact of drugs on circadian rhythm should be not neglected. On the other hand, new special drug delivery systems can be used to synchronize drug concentrations according to circadian rhythms. "Chronopharmaceuticals" can identify the proper dosing time and this amelioration will lead to improved progress and diffusion of pharmacotherapy. Chronopharmaceuticals coupled with nanotechnology could be the future of drug delivery systems, and lead to safer and more efficient disease therapy in the future. In this review, we will discuss the pharmacokinetic effects of circadian rhythm and its toxicological outcomes. Besides, we will try to give some practical points for clinical pharmacist/pharmacy practitioners, concerning chronopharmacokinetics.

High incidence of cardiovascular diseases globally, including arterial hypertension (AH) and coronary artery disease (CAD), as well as a considerable social impact made by the diseases and their complications, call for finding new ways to improve effectiveness of treatment [1].

Background and objectives: In chronopharmacology the biological rhythm variations caused by drug administration is assessed. Evaluation of the time of drug administration and the qualitative and quantitative effects of reactions to drugs is called chronopharmacodynamics. In this study, we assessed the chronopharmacodynamics of intrathecal co-administration of sufentanyl and bupivacaine in surgical operations of lower extremities. Methods: In 2006, patients aged 20-50 with ASA physical status of I and II, who underwent surgical operation of lower extremities were entered into this prospective study. The patients received a slow intrathecal injection of 10 μg sufentanyl and 15 mg bupivacaine into subarachnoid of third and fourth lumbar spaces in 30 seconds. After the operation, the time of first pain sensation and the visual analogue scale (VAS) score, as the measure of severity of pain, were recorded. Results: 115 patients were studied in this project. The pain-free interval was considered as the time between injection and patient’s demand for pain relief. This interval was 746 (± 322) minutes. The average score of pain severity on VAS at the time of demand for pain relief was 24.7 (± 9.3). The average pain-free duration in patients injected about noon or at midnight was significantly longer than the pain-free interval of other patients. Conclusion: The results show that intrathecal co-administration of sufentanyl and bupivacaine at noon or midnight (conforming to the circadian rhythm) causes better pain-relief with longer duration in comparison with other times of the day or night. Keywords: Chronopharmacology, Sufentanyl, Bupivacaine, Pain, Postoperative

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. The optimization of drug effects and/or minimization of toxicity by timing medications with regard to biological rhythms is known as chronotherapeutics. While chronotherapeutical approaches have been particularly successful in the treatment of hypertension, allergies and some forms of cancer, a time-dependent pharmacological approach can be also effective when dealing with sleep disruptions like insomnia. A large proportion of patients under benzodiazepine (BZD)/Z drug treatment fail to achieve a complete and sustained recovery and are left with residual symptoms, like tolerance or dependency, that make relapse or recurrence more likely, and poorer quality of life a reality. Thus the chronic and extensive use of BZD/Z drugs has become a public health issue and has led to multiple campaigns to reduce both prescription and consumption of BZD/Z-drugs. This short review discusses available data on the efficacy of melatonin to reduce chronic BZD use in insomnia patients. Fil: Golombek, Diego Andres. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnologia; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Pandi Perumal, Seithikurippu R.. Somnogen Canada; Canadá Fil: Brown, Gregory M.. University of Toronto; Canadá Fil: Cardinali, Daniel Pedro. Pontificia Universidad Católica Argentina "Santa María de los Buenos Aires". Instituto de Investigaciones Biomédicas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; Argentina. Pontificia Universidad Católica Argentina "Santa María de los Buenos Aires". Facultad de Ciencias Médicas. Departamento de Docencia e Investigación; Argentina

The relevance of gemcitabine timing for chronotherapeutic optimisation was investigated. Healthy mice received multiple doses of gemcitabine (120, 160 or 200 mg kg(-1) injection (inj)(-1)) at one of six circadian times (3, 7, 11, 15, 19 or 23 h after light onset--HALO) on days 1, 4, 7 and 10 or a single dose of gemcitabine (400 mg kg(-1)) at 11 or 23 HALO+/-cisplatin (5 mg kg(-1) at 1 min, 4 or 8 h later). Mice bearing Glasgow osteosarcoma received multiple doses of gemcitabine (200 mg kg(-1) inj(-1)) at 11 or 23 HALO+/-cisplatin (5 mg kg(-1) inj(-1) at 1 min or 4 h later) on days of 10, 13, 16 and 19 following tumour inoculation. A circadian rhythm in body weight loss was statistically validated, with 1030 HALO corresponding to the least toxic time (95% CL, 0800 to 1300). Gemcitabine dosing produced least body weight loss and least neutropenia after injection at 11 vs 23 HALO, whether the drug was given alone or with cisplatin (P=0.001). Gemcitabine-cisplatin tolerability was improved by dosing gemcitabine at 11 HALO and CDDP at 15 HALO (P0.001). The administration of this schedule to tumour-bearing mice increased median survival three-fold as compared to treatments where both drugs were given simultaneously at 11 or 23 HALO (P=0.02). The optimal schedule would correspond to the delivery of gemcitabine upon awakening and cisplatin near mid-activity in cancer patients.

El tratamiento de los crecimientos neoplásicos malignos en caninos, incluye diferentes alternativas, entre las cuales se encuentra la quimioterapia. Sin embargo, los fármacos tradicionalmente utilizados presentan altos niveles de toxicidad, debido a su baja selectividad sobre células cancerosas. Los principales efectos adversos de estos compuestos son trastornos gastrointestinales, depresión de la medula ósea, alteraciones de la conducta, alopecia y un potencial carcinogénico, entre otros. En la actualidad, diferentes grupos de investigación en el mundo han estado dedicados al desarrollo de nuevas moléculas derivadas de canabinoides y/o endocanabinoides, basados en la reconocida actividad antineoplásica del tetrahidrocanabinol y de la anandamida. Los ensayos hasta ahora reportados permiten concluir que dichos compuestos ofrecen una mayor selectividad de acción sobre las células enfermas, lo cual se traduce en un menor abanico de riesgos tóxicos. Por otra parte, se ha demostrado que los tratamientos farmacológicos en cualquier patología deberían ceñirse a los ritmos biológicos con el fin de obtener una mejor respuesta terapéutica y un menor grado de efectos colaterales. El objetivo de este artículo es dar a conocer los beneficios de un futuro tratamiento antineoplásico inspirado en el comportamiento de los canabinoides y endocanabinoides en la evolución de las enfermedades neoplásicas. There are several alternatives for treating malign neoplastic growths in dogs, including chemotherapy; however, traditionally used drugs have high levels of toxicity due to their low selectivity regarding cancer cells. These compounds' main adverse effects involve gastrointestinal disorders, bone marrow suppression (myelotoxicity), behavioral alterations, alopecia and carcinogenic potential. Research groups around the world are currently working on developing new drugs from cannabinoids and/or endocannabinoids-derived molecules, based on tetrahydrocannabinol and anandamide's known anti-neoplastic activity. Trials reported to date have led to concluding that such compounds offer greater selectivity regarding action on unhealthy cells, thereby representing a lower range of toxic risks. It has been shown that pharmacological treatment regarding any disease should adhere to biological rhythms to obtain a better therapeutic response and incur fewer collateral effects. This article was thus aimed at ascertaining the benefits of future antineoplastic treatment inspired by the behavior of cannabinoids and endocannabinoids in the evolution of neoplastic diseases. O tratamento de tumores malignos em cães, inclui diversas alternativas, entre as quais está a quimioterapia. Embora, as drogas convencionalmente usadas têm níveis elevados de toxicidade, devido à sua baixa selectividade sobre células cancerosas. Os principais efeitos adversos desses compostos são distúrbios gastrointestinais, depressão da medula óssea, distúrbios comportamentais, alopecia e um potencial carcinogénico, entre outras. Atualmente, diferentes grupos de pesquisa no mundo têm se dedicado ao desenvolvimento de novas moléculas derivadas de canabinóides e/ou endocanabinóides, baseados na conhecida atividade antineoplásica do tetrahidrocanabinol e da anandamida. Os experimentos relatados até agora levam à conclusão de que estes compostos oferecem uma maior seletividade de ação nas células doentes, o que resulta num menor intervalo de riscos tóxicos. Além disso, foi demonstrado que os tratamentos farmacológicos em qualquer doença deveríam estar em conformidade com os ritmos biológicos, a fim de obter uma melhor resposta terapêutica e um menor grau de efeitos colaterais. O objetivo deste artigo é apresentar os benefícios de um futuro tratamento antineoplásico inspirado no comportamento dos canabinóides e endocannabinoides na evolução das doenças neoplásicas.

Die pharmakologische Wirkung von Rolipram, einem Phosphodiesterase 4 Hemmer, wird an männlichen WISTAR-Ratten mit einer Dosis von 2,5 mg/kg Körpergewicht untersucht. Der Versuchsablauf ist gekennzeichnet durch eine über insgesamt 24 Stunden in jeweils zweistündigem Abstand durchgeführte jeweils sechzigminütige Verhaltensbeobachtung, die unter einem 12/12 Stunden Hell-Dunkel Beleuchtungsregime erfolgt. Die Tiere erhalten eine begleitende Temperaturmessung und anschließende Blutentnahme zur Messung von Melatonin (MEL), Corticosteron (COR) und Glukose (GLU). Es erfolgt eine punktuelle Untersuchung der Parameter ohne den Anspruch, eine circadiane Rhythmik longitudinal beschreiben zu wollen. Das untersuchte Verhalten wird in die Gruppen substanztypisches Verhalten, Explorations-, Maintenanceverhalten und Wachheitszustand aufgeteilt. In der Dunkelphase (D-Phase) wird zur Verhaltensbeobachtung die Farbe „Rot“ ausgewählt. Sie ist in einem Beleuchtungsversuch ausgewählt worden, da sie die untersuchten Parameter nicht beeinflusst. Rolipram bewirkt eine deutlich beleuchtungsabhängige Induktion von substanztypischem Verhalten. Ein Schlafzustand kann bei den Rolipram- behandelten Tieren nicht mehr beobachtet werden. Das Spontanverhalten wird bei der gewählten Dosis fast vollständig unterdrückt. Es kann überwiegend nur substanzinduziertes Verhalten beobachtet werden. Ein aussagekräftiger Vergleich zwischen Rolipramwirkung und Spontanverhalten kann zu den untersuchten Zeitpunkten daher nicht mehr durchgeführt werden. Bei Thermoregulation und Hormonkonzentrationen können aussagekräftige Daten nach 75 Minuten erhoben werden, die jeweils wie bei einer Sollwertverstellung die Substanzwirkung anzeigen. Es sind anhand der Ergebnisse vier übergeordnete Tendenzen zu erkennen: 1) Rolipram zeigt seine maximale Wirkung zu Beginn der Hellphase, einem Zeitraum der verminderten Vigilanz der nachtaktiven Tiere. Der Vigilanzzustand wird durch den Rückgang bei den Explorations- und Maintenanceparametern sowie einem anhaltenden Wachheitszustand ohne physiologische Verhaltensaktivität beschrieben. 2) Die Änderungen des spontanen physiologischen Verhaltens werden nur bei den Kontrolltieren beobachtet, die alle einen ungestörten Verhaltensablauf während der Beobachtungen zeigen. Dies entspricht den bisher in der Literatur beschriebenen Aktivitätszuständen in Hell- und Dunkelphasen, da es nach Unterdrückung durch Rolipram zu diesen Zeiten kein solches Verhalten mehr gibt. 3) Durch die Stimulation der COR-Sekretion und der an sie peripher gekoppelten Erhöhung der Glukosekonzentration sind Trends zur Induktion der LHPA-Achse zu erkennen. Sie ermöglichen einen Rückschluss auf die Beeinflussung weiterer vorhandener, zentraler Regelkreise. 4) Die Körpertemperatur (KT) als robuster Parameter für tageszeitliche Schwankungen zeigt unbeeinflusst eine der Literatur entsprechende tageszeitliche Veränderung, unter Rolipram erfolgt eine Absenkung wieder wie bei einer Sollwertänderung. In der Auswertung ist im Detail eine tageszeitlich abgestufte Wirkung unter Rolipram zu beobachten. Dabei zeigen sich sowohl bei den substanztypischen, als auch anderen Verhaltensparametern vom Zeitpunkt und Beleuchtungszustand abhängige Veränderungen. Die Regulation des beobachteten Verhaltens und der gemessenen Hormone scheint mit einer Veränderung von Gehalten oder Verfügbarkeit zentraler Monoamine und deren Regulation einherzugehen. Rolipram greift durch seinen bisher beschriebenen Wirkmechanismus in diese Regulation ein und beeinflusst sie zu bestimmten Zeitpunkten besonders intensiv. Bezogen auf die Auswirkungen in einem Depressionsmodell bietet sich damit erstmalig ein belegbarer Ansatz für die Beschreibung einer tageszeitlich abhängigen Wirkung der Substanz. Zwischen der experimentellen Wirkung am Tier und den möglichen Auswirkungen am Menschen können sinnvolle Vergleiche gezogen werden, da die Regelprozesse durch homologe Genprodukte beteiligter Enzyme in den unterschiedlichen Spezies gleichförmig gesteuert werden. Dies kann auf eine chronopharmakologisch begründbare Therapiewirkung hindeuten, was in weiteren Untersuchungen und in anderen für diese Substanz verwendeten Modellen zu bestätigen sein wird. Damit sind das gewählte Modell und die Anwendung einer Untersuchungsmethode eines zusammengesetzten theoretischen Tages in der Lage, substanztypische Effekte als tageszeitlich abhängig zu beschreiben. Die Planung und Anwendbarkeit ähnlicher Untersuchungen wird zukünftig erleichtert. Durch die Unterdrückung des Spontanverhaltens erscheint das gewählte Modell unter Rolipram in generellen Untersuchungen zur circadianen Rhythmik eher nicht geeignet. Die unterschiedliche Auslösbarkeit des substanztypischen Verhaltens kann Aufschluss zu möglichen therapeutischen Wirkungen und den Zeitpunkten ihrer maximalen Wirkung geben. Die Festlegung von wirksamen, aber nebenwirkungsarmen Verabreichungszeitpunkten am Menschen kann gezielt erfolgen, indem die jeweiligen Zeitpunkte durch die jeweils gewollten Haupt- und Nebeneffekte festgelegt werden können. Die erhaltenen Ergebnisse liefern einen deutlichen Zuwachs an detaillierten Informationen zur tageszeitlichen Abhängigkeit von Verhalten und Hormonen unter Rolipram in einem Depressionsmodell., The pharmacologic effect of rolipram, a phosphodiesterase (PDE) 4 inhibitor, is investigated on male Wistar rats with a dose of 2.5 mg/kg body weight. The study is defined by a repeated monitoring of behaviour during hourly intervals every two hours of a whole day with a 12/12 hour lighting regime. Animals receive an additional body temperature monitoring and blood collection for measurement of melatonin, corticosterone and glucose. The study is not to describe a longitudinal rhythmic activity over a whole day but to do this on selected date. Investigated behaviour can be divided into substance behaviour, explorative and maintenance behaviour and monitoring of vigilance. Behaviour monitoring during darkness is possible by using dim red light, which is documented without effect on investigated parameters. Rolipram effects a distinct light-dependent induction of substance typical behaviour. Sleeping behaviour is not detected under rolipram treatment. Spontaneous behaviour is nearly completely suppressed with the investigated dose. A qualified comparison between rolipram effect and spontaneous behaviour is therefore not possible. Data concerning thermal regulation and hormone concentrations are sufficiently available after 75 minutes and show an effect like an adjustment of test values. Results show four superior trends: 1) Rolipram has its maximum effect at the beginning of the light phase with the typically reducing vigilance of nocturnal animals. Rolipram vigilance is best described by reduction of explorative and maintenance behaviour with a prolonged status of alertness without any physiological behavioural activity. 2) Changes of spontaneous behaviour are detected at naïve animals only, which present a completely undisturbed range of behavioural parameters during the whole study. This depicts typical behavioural activities in light and dark phase like in literature, which were completely abolished by rolipram treatment. 3) Stimulation of COR secretion and its peripherally coupled elevation of glucose concentrations show trends of inducing LHPA axis. They allow a conclusion to interfere other central regulatory circuits. 4) Body temperature as robust parameter of circadian changes shows a daily variation as described in literature. Rolipram again lowers temperature like an adjustment of test value. In detail rolipram indicates a graduated effect during time. Differences in substance and behaviour parameters depend on moment and lighting conditions. Regulation of observed behaviour and measured hormones seem to come along with change of concentrations or availabilities of centrally available monoamines and their regulation. Rolipram influences with its already described modes of action this regulation and impacts it exceedingly at certain moments. Referring to effects in a depression model the description delivers at first time a documented impact on rhythmic daily effects of this substance. Between experimental effects on animals and possible effect on man a qualified comparison is possible, because regulatory processes are controlled by homologous gene products of affected enzymes. This indicates a chronopharmacological established effect of treatment, which has to be lined out by further investigations and different models used to describe the effects of this substance. Chosen model and implementation of a study method which constructs a homogenous and theoretically complete day gives chance to describe typical substance effects as circadian dependent. Planning and use of similar studies will be easier in future. Suppressing spontaneous behaviour indicates a minor usability of this model for general applicability in investigations. Different triggering of typical rolipram behaviour implies the possibility to define different therapeutic effects and fixed dates of application. Definitions of distinct application dates can be specifically planned considering possible main and side effects at certain times. The obtained results cause a considerably growth of detailed information of a circadian dependent effect of rolipram on behaviour and hormones in a depression model.

The paper deals with the chronobiological specific characteristics of uropoiesis and their pathological disorders. Knowledge of these data is the basis for efficacy and safety of pharmacotherapy of the renal disease. The paper presents the experience (experimental and clinical) of effective and safe farmacocorrections (nephropathological conditions) with due regard for the time of the circadian period and season of the year., В данной статье приведены хронобиологические особенности мочеобразования и их нарушения при патологии. Знания эти являются основой для эффективности и безопасности фармакотерапии заболеваний почек. В статье представлен опыт (экспериментальный и клинический) эффективной и безопасной фармакокоррекции (нефропатологических состояний) с учетом времени суток и сезонов года., У даній статті наведені хронобіологічні особливості сечоутворення та їх порушення при патології. Знання цих даних є основою для ефективності та безпеки фармакотерапії захворювань нирок. У статті представлено досвід (експериментальний і клінічний) ефективної і безпечної фармакокорекції (нефропатологічних станів) з урахуванням часу доби і сезонів року.

The circadian timing system controls several temporal aspects of physiology and behaviour in laboratory animals and humans. The disruption of the circadian timing system results in the occurrence of alterations at various levels of organisation: central coordination, circadian physiology, molecular clocks and signalling pathways. In particular, a circadian disruption induced by long-haul flights across several time-zones or by shift work is associated with the appearance of systemic symptoms, such as fatigue, mood disorders and appetite loss. These symptoms, related to circadian disruption, are also frequently found in cancer patients, as a consequence of their neoplastic disease or its treatment. My PhD work is part of the research regarding the role of the circadian timing system in the development of the symptoms associated with cancer and its treatment, in tumor progression and in patients’ survival. Its perspective is to identify novel therapeutic options. In particular, the general objectives of this thesis consist in the definition of the relationships between symptoms and circadian function of patients before and during chemotherapy, and in the quantification of the clinical impact of circadian disruption on quality of life and survival. I have focused in particular on patients with metastatic colorectal cancer, third cancer for incidence and mortality. These studies confirm the role of the circadian timing system in the occurrence of systemic symptoms in cancer patients, without treatment or during it. This study is currently ongoing in collaboration with the NIH in the United States. In conclusion, this work leads me to propose an innovative therapeutic approach aimed at shielding and/or restoring the integrity of the circadian timing system. This novel strategy should improve the therapeutic index of chemotherapy, by increasing its efficacy and decreasing its toxicity, still reducing the occurrence of symptoms, preserving the quality of life and prolonging the survival of cancer patients. The implementation of this strategy relies on the non-invasive monitoring of biomarkers of the circadian timing system and on the personalization of chronotherapy delivery., L'objectif principal de ma thèse est l’exploration de l’impact clinique d’une perturbation du système circadien chez les patients cancéreux. J’ai démontré une relation robuste entre le rythme d'activité-repos et survie, symptômes et qualité de vie. J’ai mis en évidence et caractérisé la dynamique du système circadien des patients sous chimiothérapie. J’ai montré qu’une bonne tolérance conditionnait l’efficacité de la chronothérapie. Ces résultats me conduisent à proposer de cibler le système circadien pour améliorer les symptômes des patients et l’efficacité des traitements anticancéreux.

INTRODUCTION: It has been known for a long time that the efficiency and toxicity of drugs change during a 24-h period. However, the molecular mechanisms involved in these processes have started to emerge only recently. AREAS COVERED: This review aims to highlight recent discoveries showing the direct role of the molecular circadian clock in xenobiotic metabolism at the transcriptional and post-transcriptional levels in the liver and intestine, and the different ways of elimination of these metabolized drugs via biliary and urine excretions. Most of the related literature focuses on transcriptional regulation by the circadian clock of xenobiotic metabolism in the liver; however, the role of this timing system in the excretion of metabolized drugs and the importance of the kidney in this phenomenon are generally neglected. The goal of this review is to describe the molecular mechanisms involved in rhythmic drug metabolism and excretion. EXPERT OPINION: Chronopharmacology is used to analyze the metabolism of drugs in mammals according to the time of day. The circadian timing system plays a key role in the changes of toxicity of drugs by influencing their metabolisms in the liver and intestine in addition to their excretion via bile flow and urine.

Pharmacological treatments of hypertension are associated with a reduction in cardiovascular risk. The blood pressure of both normotensive and hypertensive patients has a particular pattern associated to the biological clock set according to a circadian rhythm. One of the aims of this study was to test the long acting anti-hypertensive medications, atenolol and perindopril for their chronopharmacological properties in their effect on systolic and diastolic blood pressure levels over a period of 24 hours when administered in the morning or evening. Other aims were to compare blood pressure control in patients on atenolol and perindopril with control and normotensive patients and to obtain hourly systolic and diastolic blood pressure values using the ambulatory blood pressure monitor. An ambulatory blood pressure monitor was applied to the recruited patients for 24 hours and results analysed. Atenolol provides better blood pressure control during the early morning following a morning dose, whilst it results in an elevated blood pressure during the early morning when administered in the evening. Evening administered perindopril did not result in optimum blood pressure control throughout the 24h whilst morning administration resulted in an elevated early morning peak during the critical early morning period., peer-reviewed

Durante los últimos 40 años, se ha demostrado que las funciones fisiológicas oscilan durante ciclos de 24 horas (circadianos), menos de 24 (ultradianos) y mayores de 24 horas (infradianos), denominados ritmos biológicos (cronobiología). El presente artículo hace énfasis en cómo los ritmos biológicos pueden incidir en la respuesta a los medicamentos y la terapéutica (cronofarmacología y cronoterapia). Esta variable de estudio podría ofrecer nuevos márgenes en la eficacia y seguridad de los medicamentos y hacer un uso más racional de ellos. During the last 40 years it has been demonstrated that the physiological and patophysiological functions oscillate during cycles of 24 hours (circadian), less than 24 hours (ultradian) and more than 24 hours (infradian), which are called biological rhythms (chronobiology). The present article focuses on how these biological rhythms could be affecting the response to drugs and therapeutics (chronopharmacology, chronoterapy). This study variable could offer new margins for the efficacy and safety of medicines and makes a more rationale use of them.

RESUMEN: En la Universidad de los Llanos, fue realizado un experimento con el objetivo de evaluar el efecto del grano de soya integral tostado sobre los parámetros productivos de codornices japonesas durante 24 semanas, la fase experimental se dividió en 6 periodos de 28 días cada uno. Las codornices fueron distribuidas en un diseño experimental Completamente al azar, distribuidos en 5 tratamientos, 5 repeticiones y 10 codornices por repetición, la unidad experimental estuvo constituida por la jaula. Fueron formuladas 5 dietas experimentales con 0, 5, 10, 15 y 20% de inclusión de grano de soya integral tostado. El grano de soya fue sometido a tostado a 120ºC, durante 2 minutos. Las dietas experimentales estaban compuestas de maíz, harina de arroz, harina de carne, torta de soya, vitaminas, minerales y grano de soya integral tostado. Las codornices fueron alojadas en jaulas distribuidas en baterías, agua y alimento fue suministrado a voluntad. Los resultados fueron sometidos a análisis de varianza. Los resultados de postura fueron 63,02; 62,9; 60,09; 62,22 y 59,75%; de peso del huevo 10,45; 10,45; 10,48; 10,53 y 10,42 g; de consumo de ración diario 24,63; 23,91; 24,12; 23,52 y 24,65 g; de Kg. de ración/docenas de huevo 0,46; 0,46; 0,48 y 0,49; de Kg. de ración/Kg. de huevo producido 3,74; 3,64; 4,12; 3,67 y 4,13; de huevos con cáscara rota 0,46; 0,80; 0,52; 0,56 y 0,66%; de huevos entelados 1,50; 1,72; 1,40; 1,56 y 2,28 para los tratamientos con 0 (testigo), 5; 10; 15 y 20% de inclusión de grano de soya integral tostado.En conclusión: la inclusión de diferentes niveles de grano de soya integral tostado en la ración de codornices japonesas, no presentó diferencias significativas para las variables consumo de ración, postura, peso del huevo, conversión alimenticia y presentación de huevos rotos y entelados. El tratamiento conteniendo 15% de grano de soya integral tostado expresó la mejor conversión alimenticia (Kg. de ración/docenas de huevo producidas).PALABRAS CLAVE: Codornices, soya tostada, alimentación, conversión.ABSTRACT: SOYBEAN GRAIN WHOLE TOASTED IN FEED QUAIL. At Universidad de Los Llanos, was made a research with the objective to evaluate the effect of the inclusion of grain whole soybean Toasted on the parameters productive of Japanese quails during 24 weeks, in six periods of 28 days. The quails were in a completely randomized experimental design with five treatments of grain whole Soybean Toasted (SIT), five repetitions for treatment and 10 birds for repetition, the experimental unit was the cage. Were formulated five diets experimental with increasing levels of soybean (0%, 5%, 10%, 15% and 20%). The grain of soybean was toasted to 120°C, for two minutes. Experimental diets were composed by corn, rice, soybean meal, vitamin, mineral and grain of soybean. The quail were allotted in cage and submitted ad libitum fed and water. The results of egg production were 63,02; 62,9; 60,09; 62,22 and 59,75%; egg weight 10,45; 10,45; 10,48; 10,53 and 10,42g; feed intake 24,63; 23,91; 24,12; 23,52 and 24,65g; feed to egg dozen ratio 0,46; 0,46; 0,48 and 0,49; feed to egg mass ratio 3,74; 3,64; 4,12; 3,67 and 4,13; eggs with shell broken 0,46; 0,80; 0,52; 0,56 and 0,66%; eggs without shell 1,50; 1,72; 1,40; 1,56 y 2,28 for treatments with 0 (control), 5; 10; 15 and 20% of grain whole soybean toasted.It was concluded that the grain of soybean toasted in the diet had not different significant (P>0,05) in intake of food, ratio Kg of diet/dozen of eggs, eggs production, eggs weight, eggs with shell broken. The treatment with 15% of grain de soybean was the best feed conversion (Kg of diet/dozen of eggs).KEY WORDS: Conversion, Quail, Fed, Soybean toasted RESUMEN: En la Universidad de los Llanos, fue realizado un experimento con el objetivo de evaluar el efecto del grano de soya integral tostado sobre los parámetros productivos de codornices japonesas durante 24 semanas, la fase experimental se dividió en 6 periodos de 28 días cada uno. Las codornices fueron distribuidas en un diseño experimental Completamente al azar, distribuidos en 5 tratamientos, 5 repeticiones y 10 codornices por repetición, la unidad experimental estuvo constituida por la jaula. Fueron formuladas 5 dietas experimentales con 0, 5, 10, 15 y 20% de inclusión de grano de soya integral tostado. El grano de soya fue sometido a tostado a 120ºC, durante 2 minutos. Las dietas experimentales estaban compuestas de maíz, harina de arroz, harina de carne, torta de soya, vitaminas, minerales y grano de soya integral tostado. Las codornices fueron alojadas en jaulas distribuidas en baterías, agua y alimento fue suministrado a voluntad. Los resultados fueron sometidos a análisis de varianza. Los resultados de postura fueron 63,02; 62,9; 60,09; 62,22 y 59,75%; de peso del huevo 10,45; 10,45; 10,48; 10,53 y 10,42 g; de consumo de ración diario 24,63; 23,91; 24,12; 23,52 y 24,65 g; de Kg. de ración/docenas de huevo 0,46; 0,46; 0,48 y 0,49; de Kg. de ración/Kg. de huevo producido 3,74; 3,64; 4,12; 3,67 y 4,13; de huevos con cáscara rota 0,46; 0,80; 0,52; 0,56 y 0,66%; de huevos entelados 1,50; 1,72; 1,40; 1,56 y 2,28 para los tratamientos con 0 (testigo), 5; 10; 15 y 20% de inclusión de grano de soya integral tostado.En conclusión: la inclusión de diferentes niveles de grano de soya integral tostado en la ración de codornices japonesas, no presentó diferencias significativas para las variables consumo de ración, postura, peso del huevo, conversión alimenticia y presentación de huevos rotos y entelados. El tratamiento conteniendo 15% de grano de soya integral tostado expresó la mejor conversión alimenticia (Kg. de ración/docenas de huevo producidas).PALABRAS CLAVE: Codornices, soya tostada, alimentación, conversión.ABSTRACT: SOYBEAN GRAIN WHOLE TOASTED IN FEED QUAIL. At Universidad de Los Llanos, was made a research with the objective to evaluate the effect of the inclusion of grain whole soybean Toasted on the parameters productive of Japanese quails during 24 weeks, in six periods of 28 days. The quails were in a completely randomized experimental design with five treatments of grain whole Soybean Toasted (SIT), five repetitions for treatment and 10 birds for repetition, the experimental unit was the cage. Were formulated five diets experimental with increasing levels of soybean (0%, 5%, 10%, 15% and 20%). The grain of soybean was toasted to 120°C, for two minutes. Experimental diets were composed by corn, rice, soybean meal, vitamin, mineral and grain of soybean. The quail were allotted in cage and submitted ad libitum fed and water. The results of egg production were 63,02; 62,9; 60,09; 62,22 and 59,75%; egg weight 10,45; 10,45; 10,48; 10,53 and 10,42g; feed intake 24,63; 23,91; 24,12; 23,52 and 24,65g; feed to egg dozen ratio 0,46; 0,46; 0,48 and 0,49; feed to egg mass ratio 3,74; 3,64; 4,12; 3,67 and 4,13; eggs with shell broken 0,46; 0,80; 0,52; 0,56 and 0,66%; eggs without shell 1,50; 1,72; 1,40; 1,56 y 2,28 for treatments with 0 (control), 5; 10; 15 and 20% of grain whole soybean toasted.It was concluded that the grain of soybean toasted in the diet had not different significant (P>0,05) in intake of food, ratio Kg of diet/dozen of eggs, eggs production, eggs weight, eggs with shell broken. The treatment with 15% of grain de soybean was the best feed conversion (Kg of diet/dozen of eggs).KEY WORDS: Conversion, Quail, Fed, Soybean toasted

Submitted by Vitor Silverio Rodrigues (vitorsrodrigues@reitoria.unesp.br) on 2014-05-27T11:18:13Z No. of bitstreams: 0Bitstream added on 2014-05-27T14:38:54Z : No. of bitstreams: 1 2-s2.0-0030988290.pdf: 202428 bytes, checksum: 4f98f023c630dc264c1f5618abc7fed6 (MD5) Made available in DSpace on 2014-05-27T11:18:13Z (GMT). No. of bitstreams: 0 Previous issue date: 1997-05-01 Fencamfamine (FCF) is a central stimulant that facilitates central dopaminergic transmission through inhibition of dopamine uptake and enhanced release of the transmitter. We evaluated the changes in the inhibition of uptake and the release of striatal [ 3H]-dopamine at 9:00 and 21:00 h, times corresponding to maximal and minimal behavioral responses to FCF, respectively. Adult male Wistar rats (200-250 g) maintained on a 12-h light/12-h dark cycle (lights on at 7:00 h) were used. In the behavioral experiments the rats (N = 8 for each group) received FCF (3.5 mg/kg, ip) or saline at 9:00 or 21:00 h. Fifteen minutes after treatment the duration of activity (sniffing, rearing and locomotion) was recorded for 120 min. The basal motor activity was higher (28.6 ± 4.2 vs 8.4 ± 3.5 s) after saline administration at 21:00 h than at 9:00 h. FCF at a single dose significantly enhanced the basal motor activity (38.3 ± 4.5 vs 8.4 ± 3.5 s) and increased the duration of exploratory activity (38.3 ± 4.5 vs 32.1 ± 4.6 s) during the light, but not the dark phase. Two other groups of rats (N = 6 for each group) were decapitated at 9:00 and 21:00 h and striata were dissected for dopamine uptake and relase assays. The inhibition of uptake and release of [ 3H]-dopamine were higher at 9:00 than at 21:00 h, suggesting that uptake inhibition and the release properties of FCF undergo daily variation. These data suggest that the circadian time-dependent effects of FCF might be related to a higher susceptibility of dopamine presynaptic terminals to the action of FCF during the light phase which corresponds to the rats' resting period. Departamento de Farmacologia Inst. de Cie. Biomédicas Universidade de São Paulo, 05508-900 São Paulo, SP Depto. Principios Ativos, N. Faculdade de Cie. Farmaceuticas Universidade Estadual Paulista, 14801-902 Araraquara, SP Depto. Principios Ativos, N. Faculdade de Cie. Farmaceuticas Universidade Estadual Paulista, 14801-902 Araraquara, SP

For many decades, researchers are aware of the importance of circadian rhythm in physiological/biochemical properties and drug metabolism. Chronopharmacology is the study of how the effects of drugs vary with biological timing and endogenous periodicities. It has been attaching substantial attention in the last years. Chronopharmacodynamics mainly deals with the biochemical and physiological effects of drugs on the body, the mechanisms of drug action, the relationship between drug concentration and effect in relation to circadian clock. In this review, we will focus on mammalian circadian pharmacodynamics and discuss new chronotherapy approaches. Moreover, we will try to highlight the chronopharmacodynamics of cardiovascular drugs, anti-cancer drugs, analgesics and non-steroidal anti-inflammatory drugs (NSAIDs) and give some practical concerns for clinical pharmacists and pharmacy practitioners, concerning this issue.

Merel Boom*, Joost Grefkens*, Eveline van Dorp, Erik Olofsen, Gertjan Lourenssen, Leon Aarts, Albert Dahan, Elise SartonDepartment of Anesthesiology, Leiden University Medical Center, Leiden, The Netherlands; *These authors contributed equally to this workAbstract: Chronopharmacology studies the effect of the timing of drug administration on drug effect. Here, we measured the influence of 4 timing moments on fentanyl-induced antinociception in healthy volunteers. Eight subjects received 2.1 µg/kg intravenous fentanyl at 2 pm and 2 am, with at least 2 weeks between occasions, and 8 others at 8 am and 8 pm. Heat pain measurements using a thermode placed on the skin were taken at regular intervals for 3 hours, and verbal analog scores (VAS) were then obtained. The data were modeled with a sinusoid function using the statistical package NONMEM. The study was registered at trialregister.nl under number NTR1254. A significant circadian sinusoidal rhythm in the antinociceptive effect of fentanyl was observed. Variations were observed for peak analgesic effect, duration of effect, and the occurrence of hyperalgesia. A peak in pain relief occurred late in the afternoon (5:30 pm) and a trough in the early morning hours (5:30 am). The difference between the peak and trough in pain relief corresponds to a difference in VAS of 1.3–2 cm. Only when given at 2 am, did fentanyl cause a small but significant period of hyperalgesia following analgesia. No significant changes were observed for baseline pain, sedation, or the increase in end-tidal CO2. The variations in fentanyl’s antinociceptive behavior are well explained by a chronopharmacodynamic effect originating at the circadian clock in the hypothalamus. This may be a direct effect through shared pathways of the circadian and opioid systems or an indirect effect via diurnal variations in hormones or endogenous opioid peptides that rhythmically change the pain response and/or analgesic response to fentanyl.Keywords: chronopharmacology, opioid, fentanyl

Circadian rhythms describe physiological systems that repeat themselves with a cycle of approximately 24 h. Our understanding of the cellular and molecular origins of these oscillations has improved dramatically, allowing us to appreciate the significant role these oscillations play in maintaining physiological homeostasis. Circadian rhythms allow living organisms to predict and efficiently respond to a dynamically changing environment, set by repetitive day/night cycles. Since circadian rhythms underlie almost every aspect of human physiology, it is unsurprising that they also influence the response of a living organism to disease, stress, and therapeutics. Therefore, not only do the mechanisms that maintain health and disrupt homeostasis depend on our internal circadian clock, but also the way drugs are perceived and function depends on these physiological rhythms. We present a holistic view of the therapeutic process, discussing components such as disease state, pharmacokinetics, and pharmacodynamics, as well as adverse reactions that are critically affected by circadian rhythms. We outline challenges and opportunities in moving toward personalized medicine approaches that explore and capitalize on circadian rhythms for the benefit of the patient.

Предоставление в распоряжении лечащего врача современной аналитической методики, дает возможность проверить применяемые до сих пор дозировки лекарственных препаратов и по-новому освещает некоторые вопросы фармакотерапии. Для достижения максимального терапевтического эффекта при минимальных токсических эффектах, контроль концентрации лекарственных веществ необходимо осуществлять в месте действия препарата. Эта задача решается с помощью контролируемой фармакотерапии. При использовании препаратов с узким терапевтическим коридором, таких как дигоксин -это особенно важно. Значительная часть препаратов не требует контролируемой терапии с определенными концентрации препарата в сыворотке крови. Такими препаратами являются соединения с большим интервалом между токсической и терапевтической дозами, а также лекарственные средства, действие которых можно легко определить клинически (мочегонные, гипотензивные средства). При отсутствии высокой корреляции между концентрацией препарата в крови и фармакологическим эффектом (соединения бета-адреноблокаторов, амиодарон), контролируемая терапия также не проводится. Лечение при контролируемой концентрации препарата способствует рациональной и более безопасной терапии, при условии умелой интерпретации измеренной концентрации. Ошибки, как правило, являются следствием неправильного забора крови или неправильной оценки клинической ситуации., Providing the attending physician with a modern analytical technique makes it possible to check the dosages of medicines used so far and in a new light covers some issues of pharmacotherapy. To achieve the maximum therapeutic effect with minimal toxic effects, the concentration of drugs must be controlled at the site of action of the drug. This problem is solved with the help of controlled pharmacotherapy. When using drugs with a narrow therapeutic corridor, such as anticonvulsants, antiarrhythmic drugs, antibiotics, immunosuppressants, antiepileptic drugs, this is especially important. A significant part of the drugs does not require controlled therapy with certain concentrations of the drug in the blood serum. Such drugs are compounds with a large interval between toxic and therapeutic doses, as well as drugs whose effect can be easily determined clinically (diuretics, antihypertensives). In the absence of a high correlation between the concentration of the drug in the blood and the pharmacological effect (beta-adrenoblocker compounds, amiodarone), controlled therapy is also not carried out. Treatment with a controlled concentration of the drug contributes to a rational and safer therapy, provided that the measured concentration is skillfully interpreted. Errors are usually the result of improper blood sampling or an incorrect assessment of the clinical situation., №12(180) (2020)

Approximately one-third of patients with epilepsy continue to have seizures despite antiepileptic therapy. Many seizures occur in diurnal, sleep/wake, circadian, or even monthly patterns. The relationship between biomarkers and state changes is still being investigated, but early results suggest that some of these patterns may be related to endogenous circadian patterns whereas others may be related to wakefulness and sleep or both. Chronotherapy, the application of treatment at times of greatest seizure susceptibility, is a technique that may optimize seizure control in selected patients. It may be used in the form of differential dosing, as preparations designed to deliver sustained or pulsatile drug delivery or in the form of 'zeitgebers' that shift endogenous rhythms. Early trials in epilepsy suggest that chronopharmacology may provide improved seizure control compared with conventional treatment in some patients. The present article reviews chronopharmacology in the treatment of epilepsy as well as future treatment avenues.

La cronobiología es la disciplina que ha estudiado la organización temporal de los procesos que ocurren en los seres vivos, los mecanismos que las originan y sus alteraciones. En 1832, Agustín de Candolle demostró que bajo condiciones constantes el período de los ciclos de movimientos de las plantas duraba unas 24 horas, con lo que añadió una evidencia de la naturaleza endógena de los ritmos biológicos. En los mamíferos, se ha estimado que aproximadamente el 10 % del genoma está bajo un control circadiano. Desde la década de los años 70´s se observó que la respuesta inmune dependía de la hora del día en la cual se analizaba y que la susceptibilidad a las infecciones dependía también de la hora en la cual el organismo fuera infectado. Recientemente se ha establecido una relación entre el ciclo circadiano y la respuesta inmune. Este trabajo trata las ventajas del conocimiento del ritmo circadiana de los mecanismos inmunitarios y la importancia del uso de la cronoterapia sobre los osciladores de las células del sistema inmune en los trastornos inmunitarios, lo cual pudiera evitar complicaciones en los pacientes.