Biological rhythms and chronotherapeutics in depression.

Depressive syndromes are frequent and heterogeneous brain conditions with more than 90% of patients suffering from sleep complaints. Better characterizing this "sleep" domain may allow to both better treat acute episodes with existing chronotherapeutics, but also to prevent the manifestation or recurrences of mood disorders. This work aims to i) review theoretical and fundamental data of chronotherapeutics, and ii) provide practical recommendations. Light therapy (LT) can be used as a first-line monotherapy of moderate to severe depression of all subtypes. LT can be also used as a combination with antidepressant to maximize patients' response rates, which has a clear superiority to antidepressant alone. Sleep deprivation (SD) is a rapid and powerful chronotherapeutic with antidepressant responses within hours in 45-60% of patients with unipolar or bipolar depression. Different strategies should be combined to stabilize the SD antidepressant effect, including concomitant medications, repeated SD, combination with sleep phase advance and/or LT (triple chronotherapy). Melatonin treatment is of interest in remitted patients with mood disorder to prevent relapses or recurrences, if a complaint of insomnia, poor sleep quality or phase delay syndrome is associated. During the acute phase, melatonin could be used as an adjuvant treatment for symptoms of insomnia associated with depression. The cognitive behavioral therapy for insomnia (CBT-I) can be recommend to treat insomnia during euthymic phases. The Interpersonal and social rhythm therapy (IPSRT) is indicated for the acute treatment of bipolar depression and for the prevention of mood episodes. Chronotherapeutics should always be associated with behavioral measures for healthy sleep.

Therapeutics on the clock: Circadian medicine in the treatment of chronic inflammatory diseases.

The circadian clock is a collection of endogenous oscillators with a periodicity of ~ 24 h. Recently, our understanding of circadian rhythms and their regulation at genomic and physiologic scales has grown significantly. Knowledge of the circadian influence on biological processes has provided new possibilities for novel pharmacological strategies. Directly targeting the biological clock or its downstream targets, and/or using timing as a variable in drug therapy are now important pharmacological considerations. The circadian machinery mediates many aspects of the inflammatory response and, reciprocally, an inflammatory environment can disrupt circadian rhythms. Therefore, intense interest exists in leveraging circadian biology as a means to treat chronic inflammatory diseases such as sepsis, asthma, rheumatoid arthritis, osteoarthritis, and cardiovascular disease, which all display some type of circadian signature. The purpose of this review is to evaluate the crosstalk between circadian rhythms, inflammatory diseases, and their pharmacological treatment. Evidence suggests that carefully rationalized application of chronotherapy strategies - alone or in combination with small molecule modulators of circadian clock components - can improve efficacy and reduce toxicity, thus warranting further investigation and use.

Cronoterapia con fármacos antihipertensivos y glaucoma / Chronotherapy with anti-hypertensive drugs and glaucoma

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Respuesta: Cronoterapia con fármacos antihipertensivos y glaucoma / Reply: Chronotherapy with anti-hypertensive drugs and glaucoma

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Circadian Rhythm in Cytokines Administration.

In recent times, a number of diseases involving immune system dysfunction have appeared. This increases the importance of research aimed at finding and developing optimized methods for immune system correction. Numerous studies have found a positive effect in using cytokines to treat a variety of diseases, yet the clinical use of cytokines is limited by their toxicity. Research in the field of chronotherapy, aimed at designing schedules of medicine intake using circadian biorhythms of endogenous production of factors, and receptors' expression to the factors on the target cells, as well as chronopharmacodynamics and chronopharmacokinetics of medicines may contribute to the solution of this problem. Advantages of chronotherapy include a greater effectiveness of treatment, reduced dose of required drugs, and minimized adverse effects. This review presents data on the presence of circadian rhythms of spontaneous and induced cytokine production, as well as the expression of cytokine receptors in the healthy body and in a number of diseases. The article reviews various effects of cytokines, used at different times of the day in humans and experimental animals, as well as possible mechanisms underlying the chronodependent effects of cytokines. The article presents the results of chronotherapeutic modes of administering IL-2, interferons, G-CSF, and GM-CSF in treatment of various types of cancer as well as in experimental models of immune suppression and inflammation, which lead to a greater effectiveness of therapy, the possibility of reducing or increasing the dosage, and reduced drug toxicity. Further research in this field will contribute to the effectiveness and safety of cytokine therapy.

Influência dos ritmos circadianos na temperatura corporal, no sistema cardiovascular, no desempenho psicomotor e neuromuscular / Influence of circadian rhythms in body temperature, cardiovascular system, psychomotor and neuromuscular performance

Objetivo. El ritmo circadiano consiste en los cambios cíclicos que ocurren en el período de 24 h, pudiendo interferir en el desempeño humano. El objetivo del presente fue comparar los resultados de las variables fisiológicas, neuromusculares y del tiempo de reacción obtenidos en diferentes horarios del día. Método. Los 30 voluntarios (15 hombres y 15 mujeres) realizaron un conjunto de pruebas por la mañana (10 h), tarde (16 h) y noche (20 h). Las variables analizadas fueron la temperatura corporal (temperatura oral), la frecuencia cardíaca, la presión arterial (sistólica y diastólica), el tiempo de reacción, la flexibilidad, la agilidad, la velocidad, la potencia muscular y la fuerza muscular. Resultados. En la mayoría de las variables estudiadas no fue constatada la variación circadiana. Sin embargo, en el grupo masculino, la temperatura corporal fue estadísticamente mayor por la tarde (36,3 ± 0,4 °C) y por la noche (36,4 ± 0,3 °C) en comparación con la mañana (35,9 ± 0,5 °C), y la agilidad fue estadísticamente menor (lo que refleja un mayor rendimiento) por la tarde (10,9 ± 0,8 s) en comparación con la mañana (11,4 ± 0,8 s). Mientras que en el grupo de mujeres, la presión arterial sistólica fue estadísticamente mayor por la mañana (111,7 ± 7 mmHg) en comparación con la tarde (107,7 ± 7 mmHg) y la impulsión vertical fue estadísticamente mayor por la tarde (37,3 ± 6,5 cm) en comparación con la mañana (35,3 ± 7,1 cm). Conclusión. Los datos sugieren que la respuesta de la mayoría de las variables estudiadas no sufren la influencia de la hora del día (10, 16 e 20 h)(AU)

Objective. The circadian rhythm consists on the cyclic changes that occur in the 24 h period, which might interfere in the human performance. The purpose of this study was to compare the results of the physiologic and neuromuscular variables and of the reaction time obtained in different times of the day. Method. The 30 volunteers (15 men and 15 women) performed a battery of tests in the morning (10 h), in the afternoon (16 h) and at night (20 h). The analyzed variables were the body temperature (oral temperature), heart rate, blood pressure (systolic and diastolic), reaction time, flexibility, agility, velocity (30 m sprint), the muscle power (medicine ball throw, long and sargent jump) and muscle strength. Results. In the majority of the studied variables there was no circadian variation. However, for the male group, body temperature was statiscally higher in the afternoon (36.3 ± 0.4 °C) and at night (36.4 ± 0.3 °C) compared morning (35. 9 ± 0.5 °C) and agility was statiscally lower (reflecting higher performance) in the afternoon (10.9 ± 0.8 sec) compared morning (11.4 ± 0.8 sec). While in the female group, systolic blood pressure was statiscally higher in the morning (111.7 ± 7 mmHg) compared afternoon (107.7 ± 7 mmHg) and vertical jump was statiscally higher in the afternoon (37.3 ± 6.5 cm) compared morning (35.3 ± 7.1 cm). Conclusion. The data suggest that the response of the majority of the studied variables, do not suffer influence of the time of day (10, 16 and 20 h)(AU)

Ritmicidad circadiana y adicción / Circadian rhythmicity and addiction

El estudio de los aspectos cronobiológicos relacionados con la adicciónes un campo de reciente desarrollo que ha recabado datos tanto básicos como clínicos de interés. El consumo de drogas afecta negativamente la expresión rítmica circadiana, produciendo un aplanamiento de las funciones y un retraso de los valores máximos, pudiendo incluso desembocar en un estado de desincronización del control endógeno. Además, los genes reloj Clock y Per2 se han mostrado asociados con la vulnerabilidad a la adicción, el primero regulando directamente la actividad dopaminérgica en el sistema de la recompensa y el segundo participando en la sensibilidad y abstinencia a las drogas. La tipología circadiana vespertina también se ha perfilado como una diferencia individual a tener en cuenta como factor de riesgo en el desarrollo de adicción a drogas. Finalmente, la reorganización de la ritmicidad circadiana con hábitos horarios regulares ajustados al ciclo luz oscuridad, la exposición a luz natural o artificial y la administración de melatonina pueden ser estrategias a utilizar en el tratamiento de las drogodependencias (AU)

The chronobiological aspects of addiction constitute a recently developed field of study that has obtained interesting data from both ibasic and clinical research. Drug consumption has a negative effect on the expression of circadian rhythmicity, since it produces a flattening of the functions and a delay of maximal values, and can even cause a state of desynchronization of endogenous control. Moreover, it has been shown that the clock-genes Clock and Per 2 are associated with vulnerability to addiction, the first gene directly regulating dopaminergic activity in the reward system and the second participating in the sensitivity to and abstinence from drugs. The evening circadian typology has also been proposed as an individual difference to be taken into account as a risk factor in the development of drug addiction. Finally, the reorganization of circadian rhythmicity with regular daily schedules adjusted to the cycle of light-darkness, exposure to natural or artificial light, and the administration of melatonin may be useful strategies in the treatment of drug addictions (AU)

Advances in the management of insomnia.

Insomnia is a prevalent disorder, altering night time sleep, daytime mood and performance. Current treatment strategies, used separately or in combination, include pharmacological, circadian, behavioural and cognitive therapy. An increased diversity of available hypnotics with different potency, pharmacodynamic and pharmacokinetic profiles and improved side effect profiles provides more flexibility in designing individual treatment strategies. Melatonin, a pineal hormone with acute sleep-promoting and chronobiotic properties, allows additional possibilities in treating insomnia and circadian sleep disorders. Current studies of processes involved in normal sleep regulation and pathophysiology of insomnia should result in the development of new medications based on physiological mechanisms of sleep.

Chronomic community screening reveals about 31% depression, elevated blood pressure and infradian vascular rhythm alteration.

Depression, which is a risk factor for cardiac morbidity and mortality, is not an unusual occurrence among individuals with coronary heart disease (CHD), but evidence concerning its role in the pathogenesis of this condition is less clear. Ambulatory blood pressure monitoring (ABPM) has become an important tool in the diagnosis and management of hypertension. Several previous studies have indicated that various kinds of target organ damage and cardiovascular morbidity are more strongly associated with a diagnosis by ABPM than through spot-checks in a clinical setting. This study investigated whether depressive mood was associated with changes in the about-weekly (circaseptan) and half-weekly (circasemiseptan) variations in blood pressure (BP) and heart rate (HR), including a BP surge on Mondays, in community-dwelling subjects monitored chronomically for the time structure (chronome) of their BP and HR variabilities. From April 2001 to April 2003, 217 subjects (85 men and 132 women; mean age: 56.8 +/- 11.3 yr) from U town, Hokkaido (latitude: 43.45 degrees N, longitude: 141.85 degrees E), self-monitored their BP and HR for 7 days starting around 11 a.m. on Thursday, and took readings at 30-minute intervals between 7 a.m. and 10 p.m., then at 60-minute intervals between 10 p.m. and 7 a.m. The data were retrieved and analyzed on a PC with appropriate commercial software (TM-2430-15; A&D Co., Japan). Subjects were asked about 15 items on a depression rating scale through a self-administered questionnaire. When the score amounted to 5 or higher, subjects were considered to be depressive. Student's t-test, a one-way analysis of variance (ANOVA), and cosinor methods with parametric tests were also used. A p-value below 0.05 was considered to indicate statistical significance (below 0.10: borderline statistical significance). Depression rating scales were obtained for 192 out of the 217 subjects enrolled in this study. Depression scores were (>) 5 in 72 subjects. The average values of systolic (S) and diastolic (D) BP were statistically significantly higher in depressed subjects (SBP: 129.2 vs 124.5 mmHg; p = 0.034; DBP: 79.0 vs 76.5 mmHg; p = 0.041). The 7-day average for HR did not differ between subjects with depression scores of < 5 or > 5. DBP dipping was less in the depressed subjects (16.30 vs 18.22%; p = 0.048). The dipping ratios of SBP and HR showed no statistically significant difference. In the group with depression scores of < 5, HR variability (estimated by the SD of HR and HR dip) was higher during vacations and lower on Mondays. The 24-h BP measures showed a novelty effect and a surge on Mondays. In the depressed group, a prominent circaseptan rhythm appeared to replace the novelty effect, vacation dip, and Monday surge. The results of this investigation indicate the clinical importance of the monitoring of depressed subjects. Fewer than 7 days of monitoring means a greater risk of false diagnosis, and thus a therapeutic decision including potentially unnecessary or inappropriate long-term treatment. Records shorter than 7 days would not have detected circaseptan BP dysrhythmia associated with a depressive state. Prominent circaseptans can provide new indications on the mechanisms underlying the strong relation between depression and adverse cardiac events. Future studies should aim at determining whether the treatment of depression, especially from the standpoint of a chronodiagnosis and chronotherapy, can reduce the incidence of adverse cardiac events, and whether this depends upon restoring normal BP and HR variability, i.e. anormal BP and HR chronome.

100 or 30 years after Janeway or Bartter, Healthwatch helps avoid 'flying blind'.

Longitudinal records of blood pressure (BP) and heart rate (HR) around the clock for days, weeks, months, years, and even decades obtained by manual self-measurements (during waking) and/or automatically by ambulatory monitoring reveal, in addition to well-known large within-day variation, also considerable day-to-day variability in most people, whether normotensive or hypertensive. As a first step, the circadian rhythm is considered along with gender differences and changes as a function of age to derive time-specified reference values (chronodesms), while reference values accumulate to also account for the circaseptan variation. Chronodesms serve for the interpretation of single measurements and of circadian and other rhythm parameters. Refined diagnoses can thus be obtained, namely MESOR-hypertension when the chronome-adjusted mean value (MESOR) of BP is above the upper limit of acceptability, excessive pulse pressure (EPP) when the difference in MESOR between the systolic (S) and diastolic (D) BP is too large, CHAT (circadian hyper-amplitude tension) when the circadian BP amplitude is excessive, DHRV (decreased heart rate variability) when the standard deviation (SD) of HR is below the acceptable range, and/or ecphasia when the overall high values recurring each day occur at an odd time (a condition also contributing to the risk associated with 'non-dipping'). A non-parametric approach consisting of a computer comparison of the subject's profile with the time-varying limits of acceptability further serves as a guide to optimize the efficacy of any needed treatment by timing its administration (chronotherapy) and selecting a treatment schedule best suited to normalize abnormal patterns in BP and/or HR. The merit of the proposed chronobiological approach to BP screening, diagnosis and therapy (chronotheranostics) is assessed in the light of outcome studies. Elevated risk associated with abnormal patterns of BP and/or HR variability, even when most if not all measurements lie within the range of acceptable values, becomes amenable to treatment as a critical step toward prevention (prehabilitation) to reduce the need for rehabilitation (the latter often after costly surgical intervention).

Chronotherapeutic approach to design a thermoresponsive membrane for transdermal drug delivery.

In this review, the concepts of chronobiology, circadian rhythm, chronopharmacology, homeostasis and chronotherapy are taken into account to approach the optimal drug therapy, in which the timing of drug administration plays an important role. Based on these considerations, our laboratory has developed a thermo-responsive membrane by entrapping a single or binary liquid crystal to achieve an on-off switching drug delivery for transdermal application via the externally repeated cycle of temperature change, which may simulate the dosing time of therapeutic needs for human body.

[New trends in chronopharmacology]. / Novye tendentsii v khronofarmakologii.

The article discusses the main trends of modern pharmacology associated with the use of new experimental models, the choice of adequate objects of study, the creation of original drug forms.