[Chronotherapy of affective disorders: principles and clinical aspects]. / Chronotherapie affektiver Störungen: Grundlagen und klinische Aspekte.

BACKGROUND: Chronobiological processes play a critical role in the initial manifestation and course of affective disorders. Chronotherapeutic agents aim to improve sleep-wake cycle disturbances and affective symptoms by modulating the chronobiological neuronal circuitry. OBJECTIVE: To review the different chronotherapeutic procedures, the current evidence situation and recommendations for clinical applications. METHOD: Narrative review. RESULTS: Chronotherapeutic interventions for patients with affective disorders can be nonpharmacological, e.g., light therapy, sleep deprivation, sleep phase advance and dark therapy, pharmacological in the form of melatonin and psychological consisting of interpersonal and social rhythm therapy or cognitive behavioral therapy for insomnia modified for patients with bipolar disorder. Nearly all these interventions show promising data regarding their efficacy in acute depressive or manic episodes or as maintenance therapy. For melatonin, there is less evidence for improvement of affective symptoms than for stabilizing the sleep-wake cycle. Some interventions are well-suited for an outpatient setting, e.g., light therapy, dark therapy and psychotherapy, while others, such as triple chronotherapy consisting of sleep deprivation, sleep phase advance and light therapy, are more suited for in-patient treatment. CONCLUSION: Chronotherapeutic interventions are versatile in their application and can be combined with each other and used concomitantly with classical psychopharmacotherapy. With a benign side effect profile and good evidence for efficacy, they could play an important role in the treatment of affective disorders; however, this potential is used too rarely in the clinical context.

Inhibition of Glycolysis Suppresses Cell Proliferation and Tumor Progression In Vivo: Perspectives for Chronotherapy.

A high rate of glycolysis is considered a hallmark of tumor progression and is caused by overexpression of the enzyme 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3). Therefore, we analyzed the possibility of inhibiting tumor and endothelial cell metabolism through the inhibition of PFKFB3 by a small molecule, (E)-1-(pyridin-4-yl)-3-(quinolin-2-yl)prop-2-en-1-one (PFK15), as a promising therapy. The effects of PFK15 on cell proliferation and apoptosis were analyzed on human umbilical vein endothelial cells (HUVEC) and the human colorectal adenocarcinoma cell line DLD1 through cytotoxicity and proliferation assays, flow cytometry, and western blotting. The results showed that PFK15 inhibited the proliferation of both cell types and induced apoptosis with decreasing the Bcl-2/Bax ratio. On the basis of the results obtained from in vitro experiments, we performed a study on immunodeficient mice implanted with DLD1 cells. We found a reduced tumor mass after morning PFK15 treatment but not after evening treatment, suggesting circadian control of underlying processes. The reduction in tumor size was related to decreased expression of Ki-67, a marker of cell proliferation. We conclude that inhibition of glycolysis can represent a promising therapeutic strategy for cancer treatment and its efficiency is circadian dependent.

Interleukin-2 chronotherapy for metastatic renal cell carcinoma: Results of a phase I-II study.

BACKGROUND: Interleukin-2 (IL-2) was the cornerstone treatment for metastatic renal cell carcinoma (RCC) until the advent of tyrosine kinase inhibitors, but it still has therapeutic value. As a single bolus of IL-2 causes toxicity, there is interest in administration regimens with better tolerability and efficacy. Chronotherapy is the administration of therapy according to the circadian rhythm's influence on the immune and hormonal systems. This phase I-II trial evaluated the safety of IL-2 chronotherapy in metastatic RCC patients and determined the maximum tolerated dose. The secondary objective was to identify prognostic factors for survival. METHODS: Three chronomodulation schedules (5:00-13:00, 13:00-21:00, and 21:00-5:00) were tested. Each schedule was an 8-h IL-2 infusion, with a Gaussian distribution of drug concentration peaking at 4 h. To identify the maximum tolerated dose, the dose for different patients was escalated from 2 MIU/m2 (level I) to 18.6 MIU/m2 (level VI). RESULTS: Thirty patients were enrolled and completed treatment. Two patients were treated at 5:00-13:00, 15 at 13:00-21:00, and 13 at 21:00-5:00. Nine cases of grade 3 toxicity occurred in 7 patients at the highest dose (18.6 MIU/m2); no grade 4 toxicity occurred. The maximum tolerated dose was 14.0 MUI/m2. Patients were followed for a median of 16 months (range, 2-107). One patient was lost to follow-up, 3 patients were alive at last contact, and 26 patients died. Six patients achieved long-term survival (≥48 months). There was one complete response, four partial responses, 11 cases of stable disease and 14 of progressive disease. The response rate was 16% (5/30) and disease-control rate was 53% (16/30). Median progression-free survival was 4.5 months, and median overall survival was 14.5 months. Kaplan-Meier analyses revealed significant associations between overall survival and ECOG performance score (0 vs. 1-2), MSKCC score (0-2 vs. ≥ 3), IMDC risk score (0-2 vs. ≥ 3), IL-2 dose level (IV-VI vs. I-III), and prolactin (increase vs. no increase), and but not for chronotherapy schedule. CONCLUSION: IL-2 chronotherapy appears to be safe, moderately toxic and active in metastatic RCC. It may represent a new modality of IL-2 administration for these patients.

[Triple Chronotherapy approach for reducing depressive symptoms and suicidal intent in hospitalized patients: Study protocol of a Randomized Controlled Trial]. / La Triple Chronotherapy come approccio per la riduzione della sintomatologia depressiva e dell'intenzionalità suicidaria in pazienti ospedalizzati: Protocollo di studio di un Trial Clinico randomizzato controllato.

BACKGROUND: Depressive disorders are a relevant burden for public health due to their prevalence and high levels of associated disability and mortality. Recent studies suggest that the combination of multiple chronotherapuetic interventions may reveal effective in the rapid improvement of depressive symptoms. OBJECTIVES: This paper describes the protocol of a study that aims to test the efficacy of a triple chronotherapy intervention (combined total sleep deprivation, light therapy and sleep phase advance) in the improvement of depressive symptoms in individuals diagnosed with unipolar or bipolar depression. METHODS: A randomized controlled trial will be conducted in patients hospitalized with a unipolar or bipolar depression at the Servizio Psichiatrico di Diagnosi e Cura inpatient unit of the San Paolo - ASST Santi Paolo e Carlo Hospital in Milan, Italy. Individuals will be randomly assigned to the intervention (triple chronotherapy add-on to standard pharmacological treatment) or to the "control" group (standard pharmacological treatment). RESULTS: Enrolment began in December 2018 and will end in October 2020, or at any earlier point in which the expected sample size will be reached. The study protocol has already been approved by the local ethics committee and is registered as EudraCT 2019-000892-18. Outcome analyses aim to verify whether triple chronotherapy produces a rapid and stable improvement in depressive symptoms in individuals hospitalized for an acute unipolar or bipolar depressive episode.

Chronopharmacology: Appraising the Influence of Biorhythms on the Efficacy and Safety of Antihypertensive Drugs.

This review is dedicated to chronopharmacology and chronotherapeutics of hypertension interventions. The aim of chronopharmacology is to determine the most suitable time for administration of a drug to enhance efficacy and safety, prevent tolerance, and minimize the untoward effects of the given therapy. In other words, chronotherapeutics and chronopharmacology optimize drug therapy through matching the disease rhythms to drug availability. Chronobiological principles to optimize the therapeutic effects of antihypertensive drugs attained significance a few decades ago. Circadian rhythm plays a pivotal role in the regulation of blood pressure and expresses as a contender for application of chronotherapeutics. Changes in the normal circadian rhythmic pattern of blood pressure also foretell the risk for developing cardiovascular events. This review highlights studies conducted on the chronopharmacology of different antihypertensive drug classes and prospective areas of chronotherapy to make it comprehensible for application in clinical practice to achieve optimum control of hypertension.

Radiation chronotherapy-clinical impact of treatment time-of-day: a systematic review.

PURPOSE: Many brain tumor patients suffer from radiation-induced toxicities. Chronotherapy is a treatment modality that utilizes circadian rhythms to optimize the effect on tumor while minimizing negative outcomes on healthy tissue. This review aims to systematically examine the literature on the application of a radiation chronotherapeutic for all cancers and determine the possible advantages of incorporating a circadian-based fixed time-of-day for radiotherapy into CNS cancers. METHODS: A systematic review of the literature was conducted in two electronic databases from inception to February 1, 2019. Primary research manuscripts were screened for those related to adult human subjects exposed to ionizing radiation using the chronotherapy technique. RESULTS: Nine manuscripts were included in the review from 79 eligible articles. Three were prospective randomized trails and 6 were retrospective reviews. This survey revealed that overall survival and tumor control do not have consistent effects with only 60% and 55.5% of paper which included the variables having some significance, respectively. Treatment symptoms were the primary endpoint for both the prospective trials and were examined in 3 of the retrospective reviews; effects were observed in sensitive tissue for all 5 studies including mucosal linings and skin basal layer. CONCLUSIONS: Existing literature suggests that the application of radiation chronotherapy may reduce negative symptom outcome within highly proliferative tissues. Further examination of radiation chronotherapy in well-designed prospective trials and studies in brain tumor patients are merited.

Augmentation of Pharmacotherapy by Sleep Deprivation with Sleep Phase Advance in Treatment-Resistant Depression.

INTRODUCTION: The aim was to assess the efficacy of total sleep deprivation (TSD) with sleep phase advance (SPA) in treatment-resistant depression (TRD) and associated biochemical factors. METHODS: We studied nine males and 12 females, aged 49±14 years, with treatment-resistant unipolar or bipolar depression, receiving antidepressant and mood-stabilizing drugs. The four-day schedule included single TSD and three consecutive nights with SPA. Biochemical markers were measured on the day before and on 1st, 7th and 14th day after the TSD. RESULTS: Ten subjects met criteria for response, defined as a reduction of ≥50% in the Hamilton Depression Rating Scale, on the 14th day. Concentrations of cortisol at baseline were lower in responders, and they decreased during therapy in both groups. In responders, there was an increase of interleukin-10 (IL-10) and IL-1ß on the 14th day. DISCUSSION: Our preliminary study demonstrated the efficacy of pharmacotherapy augmentation by TSD and SPA in half of the patients with TRD. The main biochemical factors related to clinical response included status of cortisol and increase in IL-10 and IL-1ß levels.

Hypertension: New perspective on its definition and clinical management by bedtime therapy substantially reduces cardiovascular disease risk.

Diagnosis of hypertension-elevated blood pressure (BP) associated with increased cardiovascular disease (CVD) risk-and its management for decades have been based primarily on single time-of-day office BP measurements (OBPM) assumed representative of systolic (SBP) and diastolic BP (DBP) during the entire 24-hours span. Around-the-clock ambulatory blood pressure monitoring (ABPM), however, reveals BP undergoes 24-hours patterning characterized in normotensives and uncomplicated hypertensives by striking morning-time rise, 2 daytime peaks-one ~2-3 hours after awakening and the other early evening, small midafternoon nadir and 10-20% decline (BP dipping) in the asleep BP mean relative to the wake-time BP mean. A growing number of outcome trials substantiate correlation between BP and target organ damage, vascular and other risks is greater for the ABPM-derived asleep BP mean, independent and stronger predictor of CVD risk, than daytime OBPM or ABPM-derived awake BP. Additionally, bedtime hypertension chronotherapy, that is, ingestion of ≥1 conventional hypertension medications at bedtime to achieve efficient attenuation of asleep BP, better reduces total CVD events by 61% and major events (CVD death, myocardial infarction, ischaemic and haemorrhagic stroke) by 67%-even in more vulnerable chronic kidney disease, diabetes and resistant hypertension patients-than customary on-awaking therapy that targets wake-time BP. Such findings of around-the-clock ABPM and bedtime hypertension outcome trials, consistently indicating greater importance of asleep BP than daytime OBPM or ambulatory awake BP, call for a new definition of true arterial hypertension plus modern approaches for its diagnosis and management.

Circadian rhythm in atopic dermatitis-Pathophysiology and implications for chronotherapy.

Circadian rhythm is a biological clock that controls a wide range of physiological functions throughout the body, including various skin functions. A 24-h diurnal cycle, governed by an endogenous clock in the brain, largely controls cutaneous diurnal rhythm, which external factors, including temperature, humidity, diet, and stress, also modulate locally. Circadian rhythm influences cutaneous blood flow and properties of skin barrier function, such as transepidermal water loss and capacitance, and has important implications in atopic dermatitis (AD). This review explores how aberrations in circadian rhythm may play a role in the pathogenesis of AD and proposes implementation of chronotherapy to improve treatment outcomes in patients with AD.

The effect of chronotherapy on delirium in critical care - a systematic review.

BACKGROUND: Delirium is highly prevalent within critical care and is linked to adverse clinical outcomes, increased mortality and impaired quality of life. Development of delirium is thought to be caused by multiple risk factors, including disruption of the circadian rhythm. Chronotherapeutic interventions, such as light therapy, music and use of eye shades, have been suggested as an option to improve circadian rhythm within intensive care units. AIM: This review aims to answer the question: Can chronotherapy reduce the prevalence of delirium in adult patients in critical care? DESIGN: This study is a systematic review of quantitative studies. RESEARCH METHOD: Six major electronic databases were searched, and a hand search was undertaken using selected key search terms. Research quality was assessed using the critical appraisal skills programme tools. The studies were critically appraised by both authors independently, and data were extracted. Four themes addressing the research question were identified and critically evaluated. FINDINGS: Six primary research articles that investigated different methods of chronotherapy were identified, and the results suggest that multi-component non-pharmacological interventions are the most effective for reducing the prevalence of delirium in critical care. The melatonergic agonist Ramelteon demonstrated statistically significant reductions in delirium; however, the reliability of the results in answering the review question was limited by the research design. The use of bright light therapy (BLT) and dynamic light application had mixed results, with issues with the research design and outcomes measured limiting the validity of the findings. CONCLUSION: Multi-component non-pharmacological interventions, such as noise and light control, can reduce delirium in critical care, whereas other interventions, such as BLT, have mixed outcomes. Melatonin, as a drug, may be a useful alternative to sedative-hypnotics. RELEVANCE TO CLINICAL PRACTICE: Chronotherapy can reduce the incidence of delirium within critical care, although further research is warranted. Staff education is essential in the implementation of chronotherapy.

A circadian gene expression atlas in mammals: implications for biology and medicine.

To characterize the role of the circadian clock in mouse physiology and behavior, we used RNA-seq and DNA arrays to quantify the transcriptomes of 12 mouse organs over time. We found 43% of all protein coding genes showed circadian rhythms in transcription somewhere in the body, largely in an organ-specific manner. In most organs, we noticed the expression of many oscillating genes peaked during transcriptional "rush hours" preceding dawn and dusk. Looking at the genomic landscape of rhythmic genes, we saw that they clustered together, were longer, and had more spliceforms than nonoscillating genes. Systems-level analysis revealed intricate rhythmic orchestration of gene pathways throughout the body. We also found oscillations in the expression of more than 1,000 known and novel noncoding RNAs (ncRNAs). Supporting their potential role in mediating clock function, ncRNAs conserved between mouse and human showed rhythmic expression in similar proportions as protein coding genes. Importantly, we also found that the majority of best-selling drugs and World Health Organization essential medicines directly target the products of rhythmic genes. Many of these drugs have short half-lives and may benefit from timed dosage. In sum, this study highlights critical, systemic, and surprising roles of the mammalian circadian clock and provides a blueprint for advancement in chronotherapy.

Short-term effects of green tea chronotherapy on the metabolic homeostasis of mice on different diets.

Biological rhythms can be defined as changes in physiological or behavioral variables that repeat at certain time intervals. Rhythms that last approximately 24 h are referred to as circadian rhythms. Modern lifestyles have drastically affected human habits, as well as the population's eating habits. These changes have generated an epidemic of metabolic syndromes, such as obesity and diabetes. In an attempt to combat obesity, populations have attempted to use many different herbal remedies and plant-based drugs, the most common of which is Camellia sinensis, or green tea. Most of the studies on the effects of C. sinensis on maintaining body weight have reported the involvement of this substance in lipid oxidation. The objective of this study was to evaluate how the administration of C. sinensis at different times of day influenced changes in body weight, blood glucose levels, and food intake of mice kept under different diet conditions. The structural organization of abdominal adipose tissue was also evaluated, as were certain aspects of lipid metabolism and overall synthetic activity in the liver, adipose tissue, and ovaries. The results obtained suggest that the intake of green tea in the light phase of the day stimulates weight loss, regardless of the diet ingested. Neither glucose levels nor the structural organization of adipose tissue was found to be altered in any of the experimental groups. Neither diet nor the time at which the green tea was administered was found to have any effects on the amount of food the mice consumed. The time at which green tea was consumed and the type of diet both influenced LXRαß nuclear receptor expression, as well as the expression of fibrillarin in the liver and ovaries, although this influence was tissue specific.

Clinical Relevance of the First Domomedicine Platform Securing Multidrug Chronotherapy Delivery in Metastatic Cancer Patients at Home: The inCASA European Project.

BACKGROUND: Telehealth solutions can improve the safety of ambulatory chemotherapy, contributing to the maintenance of patients at their home, hence improving their well-being, all the while reducing health care costs. There is, however, need for a practicable multilevel monitoring solution, encompassing relevant outputs involved in the pathophysiology of chemotherapy-induced toxicity. Domomedicine embraces the delivery of complex care and medical procedures at the patient's home based on modern technologies, and thus it offers an integrated approach for increasing the safety of cancer patients on chemotherapy. OBJECTIVE: The objective was to evaluate patient compliance and clinical relevance of a novel integrated multiparametric telemonitoring domomedicine platform in cancer patients receiving multidrug chemotherapy at home. METHODS: Self-measured body weight, self-rated symptoms using the 19-item MD Anderson Symptom Inventory (MDASI), and circadian rest-activity rhythm recording with a wrist accelerometer (actigraph) were transmitted daily by patients to a server via the Internet, using a dedicated platform installed at home. Daily body weight changes, individual MDASI scores, and relative percentage of activity in-bed versus out-of-bed (I

Chronotherapeutic treatments for depression in youth.

Chronotherapeutics such as wake therapy and bright light therapy are well-established methods in treating adults with depressive disorders and are additionally beneficent for sleep regulation. Few studies concerning chronotherapeutics in juvenile depression exist, though the established treatments are insufficient and sleep disorders often co-occur. In this study, we investigate the impact of two types of chronotherapeutics on depressive symptoms and sleep behavior in a juvenile setting. Juvenile inpatients (n = 62) with moderate to severe depressive symptoms took part in either a combined setting consisting of one night wake therapy followed by 2 weeks bright light therapy or in a setting of bright light therapy alone. Depressive symptoms, general psychopathology, clinical impression and sleep behavior were measured before (T1), directly after (T2) and 2 weeks after intervention (T3). Depressive symptoms decreased while sleep quality increased in both groups. The bright light therapy alone group showed further improvement at T3 in regards to depressive symptoms. Correlation analyses indicated significant negative correlations between sleep quality and awaking after restorative sleep with the depressive symptoms. However, only awaking after restorative sleep had a predictive impact on treatment outcome. The present study provides first evidence for a positive impact of chronotherapeutic interventions on treatment outcome in depressed juvenile inpatients. Bright light therapy seems to stabilize and further enhance reduction of depressive symptoms during follow-up, whereas one night wake therapy does not have an additional long-lasting impact on depressive symptoms and sleep parameters.

[The influence of chronomagnetic therapy on the parameters of the quality of life in the patients presenting with the diseases of the musculoskeletal system at the balneological and health resort-based stage of the rehabilitative treatment].

UNLABELLED: The methods for the rehabilitative treatment play an important role in the management of the patients presenting with the diseases of the musculoskeletal system. One of these techniques is chronomagnetic therapy. AIM: The objective of the present study was to evaluate the influence of chronomagnetic therapy on the patient's quality of life. PATIENTS AND METHODS: The patients of the main group included 30 ones with osteoarthrosis, 30 with rheumatoid arthritis, 20 with ankylosing spondylitis, 6 with podagric arthritis, 6 with psoriatic arthritis, and 6 others with reactive arthritis. Each of these patients every day underwent 10 sessions of chronomagnetic therapy with the use of the Multimag apparatus («Kasimov Instrumental Plant¼, Ryazan). The patients of the comparison group (20 ones presenting with osteoarthrosis, 27 with rheumatoid arthritis, 15 with ankylosing spondylitis, 4 with podagric arthritis, 4 with psoriatic arthritis, and 4 subjects with reactive arthritis) received the identical chronomagnetotherapeutic treatment under the conditions of the «Vulan¼ balneological health resort located at Gelendzhik, Krasnodar Region. RESULTS: The patients of the main group presenting with osteoarthrosis were characterized by the most pronounced manifestations of the role physical and social behaviour and the associated enhancement of pain intensity. The patients with rheumatoid arthritis exhibited well apparent manifestation of role and emotional functioning as well as enhanced vitality. Positive dynamics of these characteristics (role physical and emotional functioning, vital activity) was documented in the patients of the comparison group presenting with osteoarthrosis, ankylosing spondylitis, and rheumatoid arthritis. In this group, the patients with osteoarthrosis, ankylosing spondylitis, and rheumatoid arthritis experienced the improvement of the major parameters of the quality of life characterizing the physical and mental components of the health status. CONCLUSION: The chronomagnetotherapeutic treatment at the stage of rehabilitation of the patients suffering from the diseases of the musculoskeletal system markedly improves the characteristics of physical health the disturbances of which may lead to the development of psycho-somatic disorders. Chronomagnetic therapy of the patients with the diseases of the musculoskeletal system under the conditions of a balneological health resort proved to be more effective in terms of improvement of the parameters of physical and mental health. The result of the subjective evaluation of the health status in such patients can be used as a marker of the effectiveness of chronomagnetic therapy and an indicator of remission of the disease.

Seeing the forest and trees: whole-body and whole-brain imaging for circadian biology.

Recent advances in methods for making mammalian organs translucent have made possible whole-body fluorescent imaging with single-cell resolution. Because organ-clearing methods can be used to image the heterogeneous nature of cell populations, they are powerful tools to investigate the hierarchical organization of the cellular circadian clock, and how the clock synchronizes a variety of physiological activities. In particular, methods compatible with genetically encoded fluorescent reporters have the potential to detect circadian activity in different brain regions and the circadian-phase distribution across the whole body. In this review, we summarize the current methods and strategy for making organs translucent (removal of lipids, decolourization of haemoglobin and adjusting the refractive index of the specimen). We then discuss possible applications to circadian biology. For example, the coupling of circadian rhythms among different brain regions, brain activity in sleep-wake cycles and the role of migrating cells such as immune cells and cancer cells in chronopharmacology.

Chronobiological Therapy for Mood Disorders.

Chronobiological therapies for mood disorders include manipulations of the sleep-wake cycle such as sleep deprivation and sleep phase advance and the controlled exposure to light and darkness. Their antidepressant efficacy can overcome drug resistance and targets the core depressive symptoms including suicide, thus making them treatment options to be tried either alone or as adjunctive treatments combined with common psychopharmacological interventions. The specific pattern of mood change observed with chronobiological therapies is characterized by rapid and sustained effects, when used among themselves or combined with drugs. Effects sizes are the same reported for the most effective psychiatric treatments, but side effects are usually marginal or absent. New treatment protocols are developed to adapt them in different clinical settings. This review deals with the general principles of clinical chronobiology and the latest findings in this rapidly developing field.

Human blood metabolite timetable indicates internal body time.

A convenient way to estimate internal body time (BT) is essential for chronotherapy and time-restricted feeding, both of which use body-time information to maximize potency and minimize toxicity during drug administration and feeding, respectively. Previously, we proposed a molecular timetable based on circadian-oscillating substances in multiple mouse organs or blood to estimate internal body time from samples taken at only a few time points. Here we applied this molecular-timetable concept to estimate and evaluate internal body time in humans. We constructed a 1.5-d reference timetable of oscillating metabolites in human blood samples with 2-h sampling frequency while simultaneously controlling for the confounding effects of activity level, light, temperature, sleep, and food intake. By using this metabolite timetable as a reference, we accurately determined internal body time within 3 h from just two anti-phase blood samples. Our minimally invasive, molecular-timetable method with human blood enables highly optimized and personalized medicine.

[CHRONODIAGNOSTICS AND CHRONOTHERAPY OF COGNITIVE DISORDERS IN ELDERLY SUBJECTS].

Cognitive disorders in elderly subjects with cerebral atherosclerosis confirmed by paraclinical methods and psychological tests are accompanied by sympathicotonia and rhythm desynchronization of RR-intervals in ECG. Biocontrolled IR laser therapy in the projection of frontal and temporal lobes of both hemispheres, internal carotid and vertebral arteries, and superior cervical node reduces sympaticotonia, restores circumhoralian and circadian rhythms of RR-intervals, improved cognitive functions and quality of sleep.

Optimization of irinotecan chronotherapy with P-glycoprotein inhibition.

The relevance of P-glycoprotein (P-gp) for irinotecan chronopharmacology was investigated in female B6D2F1 mice. A three-fold 24h change in the mRNA expression of Abcb1b was demonstrated in ileum mucosa, with a maximum at Zeitgeber Time (ZT) 15 (p<0.001). No rhythm was found for abcb1a in ileum mucosa, or for Abcb1a/b in Glasgow osteosarcoma (GOS), a mouse tumor cell line moderately sensitive to irinotecan. Non-tumor-bearing mice received irinotecan (50mg/kg/day i.v.×4days) as a single agent or combined with P-gp inhibitor PSC833 (6.25mg/kg/day i.p.×4 days) at ZT3 or ZT15, respectively corresponding to the worst or the best irinotecan tolerability. Endpoints involved survival, body weight change and hematologic toxicity. Antitumor efficacy was studied in GOS-bearing mice receiving irinotecan (25, 30 or 40mg/kg/day×4days) and +/-PSC833 at ZT3 or ZT15, with survival, body weight change, and tumor growth inhibition as endpoints. Non-tumor bearing mice lost an average of 17% or 9% of their body weight according to irinotecan administration at ZT3 or ZT15 respectively (p<0.001). Dosing at ZT15 rather than ZT3 reduced mean leucopenia (9% vs 53%; p<0.001). PSC833 aggravated irinotecan lethal toxicity from 4 to ~60%. In tumor-bearing mice, body weight loss was ~halved in the mice on irinotecan or irinotecan-PSC833 combination at ZT15 as compared to ZT3 (p<0.001). PSC833-irinotecan at ZT15 increased tumor inhibition by ~40% as compared to irinotecan only at ZT15. In conclusion, P-gp was an important determinant of the circadian balance between toxicity and efficacy of irinotecan.