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PubMed1996

[Chronopharmacology and chronotherapy for asthma by using PEF].

Several attempts have recently been made to develop chronotherapy for nocturnal asthma, using theophylline, inhaled corticosteroid, inhaled anticolinergic agent and beta 2-agonist. Pharmacological chronotherapy is the administration of medication according to biological rhythm to maximize pharmacological effects and minimize side effects. The circadian rhythm of biological rhythms is particularly important in understanding the declined changes in lung function of asthmatics at night. Since diurnal variations of PEF obtained from asthmatics, include circadian rhythms at a high rate, it is thought that PEF may be suitable for evaluating the effect of chronotherapy. Chronotherapy of a once-daily evening dose of a new controlled-release theophylline preparation, that achieves to peak blood concentrations at 10-12 hours after dosage, effectively improved the values of PEF and symptoms of nocturnal asthmatics. Hereafter, it is speculated that more effective therapy will be developed by using chronopharmacological designed drugs.

Administration, Oral↗
PubMed1991

Chronotherapy of reversible airways disease with once-daily evening doses of a controlled-release theophylline preparation.

1. Asthma and COPD worsen at night and in the early morning, due to various circadian influences. 2. Uninterrupted sleep, stable lung function over 24 h, and reduced and stable airways responsiveness are primary therapeutic goals in asthma and COPD. 3. Once-daily evening theophylline chronotherapy meets these goals, providing rising blood levels at night and in the early morning, when most needed. 4. This regimen is now indicated for morning and evening dosing for reversible airway obstruction, in the United States and Canada, and marks the first available treatment for these diseases to include dosing time in the therapeutic strategy. It reflects increasing recognition by the medical community of the need to consider the individual patient's timing of symptoms in relation to the kinetics of the drug. 5. Theophylline chronotherapy is as well tolerated as more frequently administered methylxanthine preparations despite the relatively large single doses required by the prolonged dosing interval. The convenience of once-daily administration favors drug-taking compliance. 6. Theophylline chronotherapy does not provide constant blood levels over the 24-h day. Indeed, by improving lung function by means of a larger peak-to-trough difference than associated with twice-daily theophylline, once-daily chronotherapy has altered our thinking about theophylline pharmacodynamics.

Asthma↗
PubMed2005

Combined systemic chronotherapy and hepatic artery infusion for the treatment of metastatic colorectal cancer confined to the liver.

BACKGROUND: The optimal treatment of patients with metastatic colorectal cancer is still a clinical challenge. We describe the use of combined hepatic arterial infusion (HAI) of irinotecan (CPT-11) in conjunction with systemic chronotherapy infusion of 5-fluorouracil (5FU), folinic acid and carboplatin in patients with colorectal liver metastases. METHODS: Twenty-three patients with colorectal cancer and isolated liver metastases were enrolled in this trial. Intraoperative insertion of an intra-arterial catheter into the hepatic artery was accomplished during the colon operation (in cases of synchronous tumor) or as a separate procedure in colorectal cancer patients with newly diagnosed liver metastases. A systemic double-lumen double-chamber port was inserted via the subclavian vein as a separate procedure. The treatment plan included irinotecan given by intra-arterial infusion at 150 mg/m2 for 1 h. After 2 weeks of rest chronomodulated 5FU (700 mg/m(2); peak delivery rate at 04:00 h), leucovorin (175 mg/m2; peak delivery rate at 04:00 h) and carboplatin (40 mg/m2; peak delivery rate at 16:00 h) for 4 days was followed by 10 days' rest and then given again. After 10 days' rest another HAI was introduced using the same method. Each cycle of therapy included 2 HAI courses and 2 chronotherapy courses in between. After 2 complete cycles, patients were evaluated for their response with weekly accessed toxicity recording. RESULTS: Seven women, 8 men, median age 61 years (range 46-72). Eight patients had synchronous colon and hepatic disease and 7 patients had metachronous disease. Ten patients had previously been treated with 5FU and leucovorin while 5 patients were chemonaive. The mean number of cycles were 11.6 per patient (range 8-19). Partial response was achieved in 6 patients (40%) and was followed by laparoscopic radiofrequency ablation in 5 patients (33%). Disease stabilization was observed in 2 patients (13%) and disease progression in 7 patients (47%) mainly after previous chemotherapy failure. Side effects were infrequent and mild including grade 2 GIT complaints (5 patients), RUQ pain during HAI (9 patients) and grade 2 hematological complaints in 2 patients. CONCLUSION: A combined chemotherapy protocol (HAI and chronotherapy) with irinotecan (CPT-11) together with chronomodulated infusion of 5FU, folinic acid and carboplatin can be used in metastatic colorectal patients with a high efficacy rate and minor side effects especially in pretreated patients.

Aged↗
PubMed1998

Using chronotherapy to treat severe sleep problems: a case study.

Chronotherapy was used to treat severe sleep problems (irregular sleep onset times, frequent night and early wakings, and short total sleep times) in a girl with mental retardation. Chronotherapy involved systematically delaying the child's bedtime each night while maintaining a regular schedule during waking hours until an age-appropriate bedtime was achieved. Immediate improvements in the child's sleep pattern were observed with the introduction of treatment, and an age-appropriate bedtime was achieved in 11 days. Four months of follow-up data indicated that improvements maintained in the home. Although chronotherapy was developed specifically for adults with delayed sleep phase insomnia, the current results suggest that the treatment may be useful for other populations and problems.

Child↗
PubMedDate not supplied

Chronotherapy of colorectal cancer metastases.

Chronotherapy has consisted in the adaptation of chemotherapeutic drug delivery to circadian (approximately 24-hour) rhythms. This can be achieved in fully ambulatory patients using multichannel programmable pumps. Up to approximately 1500 patients with metastatic colorectal cancer have been registered in one of 15 trials testing the relevance of this treatment method with 5-fluorouracil +/- leucovorin +/- oxaliplatin. Chronotherapy was shown as significantly less toxic and more effective than constant rate infusion in 2 consecutive multicenter trials. High efficacy and good tolerability permitted secondary surgical resection of previously inoperable metastases, with apparent survival improvement (3-year survival > or = 20%) and cures in some patients. This strategy is currently undergoing further testing within the European Organization for Research and Treatment of Cancer. Nevertheless, combining chronotherapy with surgery of colorectal cancer metastases can be readily offered to patients as a safer therapeutic option for optimizing outcome.

Animals↗
PubMed2001

Chronotherapy and chronotoxicity of the cyclooxygenase-2 inhibitor, celecoxib, in athymic mice bearing human breast cancer xenografts.

PURPOSE: Inhibition of the enzyme cyclooxygenase with celecoxib is cytotoxic in a variety of solid tumor cell lines. Previous work has shown that by charting circadian rhythms, it has been possible to find optimal times to deliver a dose of drug, such that it is most efficacious in killing cancer cells and least harmful to normal tissues. Therefore, we examined the time dependence of toxicity (chronotoxicity) and of antitumor effects (chronotherapy) of celecoxib to determine optimal time of day for dosing with respect to light-dark cycles. EXPERIMENTAL DESIGN: Celecoxib was administered i.p. for 10 days (5 days on, 2 days off, 5 days on) to nude mice bearing s.c. breast xenografts. Body weight, peripheral blood cells, clinical chemistry, and tumor growth were monitored. RESULTS: The highest tolerance (100% survival) was found at 7 HALO and the least occurred at 17 h after light onset (HALO; 10% survival). Chronotherapy at a 20-mg/kg dose varied between the seven HALO evaluated and between the three breast tumors (MCF-7, ZR-75-30, and MDA-MB-468) studied. When the maximum tolerated dose (MTD) of celecoxib was optimized for each HALO, we found that at 7-10 HALO, the MTD was 25 mg/kg, whereas at 17-20 HALO; the MTD was only 10 mg/kg. Tumor regression was observed when dosing was done at 23 HALO to 7 HALO (5 a.m. to 1 p.m.), whereas no therapeutic response was observed when dosing was done at 10-13 HALO (4 p.m. to 7 p.m.), and rapid tumor growth was noted when dosing was done at 17 HALO (11 p.m.). CONCLUSIONS: Tumor growth response to the MTD at each HALO revealed that there was no clear relationship between dose administered and therapeutic response. COX-2 expression was not able to explain either the chronotherapy or the chronotoxicity results obtained.

Animals↗
PubMed1996

[Chronopharmacology and chronotherapy of cancers].

Tolerability of approximately 30 anticancer drugs vary by 50% or more according to circadian rhythms in mice or rats. Despite pharmacokinetics parameters of cytostatic drugs vary according to dosing time in rodents, cellular rhythms appear as the main mechanisms of their chronopharmacology: circadian changes in enzymatic activities involved into fluoropyrimidine (5-fluorouracil-5-FU, or floxuridine-FUdR) catabolism (dehydropyrimidine dehydrogenase) or anabolism (thymidine kinase), rhythms in reduced glutathione, involved into cellular protection against cytotoxic effects of alkylating drugs, platinum complexes and anthracyclines, rhythms in cellular proliferation of rapidly renewing tissues, such as bone marrow or intestinal tract. Furthermore, chemotherapy injection at the least toxic time allows to increase its antitumor efficacy against several transplanted rodent tumor models. Extrapolation of these results for improving therapeutic index of chemotherapy in cancer patients was based upon the hypothesis that rhythms in metabolism or proliferation of healthy tissues were tightly coupled to the circadian sleep-wakefulness cycle, both in rodents and in man. Programmable-in-time pumps allowed to test the clinical relevance of chronotherapy principle in patients with cancer metastases. Phase I clinical trials with 5-FU, FUdR, oxaliplatin-L-OHP, interferon-alpha and doxorubicin suggested that circadian-based chronomodulation of chemotherapy delivery rate both improved drug tolerability and allowed to increase its safe dose. Antitumor activity of such chronomodulated regimens, usually involving several drugs, appeared as superior to that achieved by standard protocols in Phase II clinical trials, especially in patients with renal cell cancer receiving FUdR and in patients with colorectal cancer treated with 5-FU, folinic acid (FA) and L-OHP (so called chrono-FFL regimen). A randomized european multicenter trial validated the clinical relevance of the chronotherapy principle in 278 patients with metastatic colorectal cancer: chrono-FFL was compared to flat FFL infusion and resulted in 2 to 10 times fewer severe toxic effects and a near-doubling of its antitumor efficacy, objective response rate being 51% with chrono-FFL and 30% with flat FFL (p < 0.001). These results have warranted to test further the relevance of chronotherapy in patients with breast, lung or pancreatic cancer metastases and to develop basic research on the role of biological rhythms upon cancer processes.

Animals↗
PubMed1999

A multicenter evaluation of intensified, ambulatory, chronomodulated chemotherapy with oxaliplatin, 5-fluorouracil, and leucovorin as initial treatment of patients with metastatic colorectal carcinoma. International Organization for Cancer Chronotherapy.

BACKGROUND: The combination of 5-fluorouracil (5-FU), leucovorin (LV), and oxaliplatin (I-OHP) was shown to be both more active against metastatic colorectal carcinoma and better tolerated if the drug delivery rate was chronomodulated according to circadian rhythms rather than constant. This allowed the authors to intensify the three-drug chronotherapy regimen and to assess its activity as the initial treatment of metastatic colorectal carcinoma patients in ten centers from four countries. METHODS: Patients with previously untreated and inoperable measurable metastases from colorectal carcinoma received a daily administration of chronomodulated 5-FU (700 mg/m2/day, peak delivery rate at 04:00 hours), LV (300 mg/m2/day, peak delivery rate at 04:00 hours), and 1-OHP (25 mg/m2/day, peak delivery rate at 16:00 hours) for 4 days every 14 days. Intrapatient escalation of 5-FU dose was performed if toxicity was less than World Health Organization (WHO) Grade 2. RESULTS: Of 90 enrolled patients, 35 had a WHO performance status of 1 or 2; 49 had metastases in > or = 2 organs. The liver was involved in 79 patients, 30 of whom had clinical hepatomegaly. The main dose-limiting toxicities were WHO modified Grade 3 or 4 diarrhea (41% of patients, 8.2% of courses), stomatitis (30% of patients, 5.1% of courses), and Grade 2 cumulative peripheral sensory neuropathy (19% of patients after 12 courses). Two patients died with severe gastrointestinal toxicity. Using the intent-to-treat method, the overall objective response rate was 66% (95% confidence limits, 56-76%). Surgical removal of previously inoperable metastases was successful in 31 patients (34%). Histologic necrosis of metastases was >90% in 7 patients and complete in 1 patient. The median progression free survival and survival durations were 8.4 months (range, 5.9-10.9 months) and 18.5 months (range, 13.2-23.8 months), respectively, with 38% of the patients alive at 2 years of follow-up. CONCLUSIONS: The objective response rate appeared to be approximately 3-fold as high as that achieved with current 5-FU-based regimens and translated into an approximately 50% increase in median survival. The hypothesis that this intensified, ambulatory, chronotherapy regimen can increase survival currently is being investigated in a multicenter randomized study conducted by the European Organization for Research and Treatment of Cancer Chronotherapy Study Group.

Aged↗
PubMed1987

[Chronoprevention and chronotherapy of bronchial asthma].

Chronobiological investigation of external respiratory function parameters was conducted in 93 patients with preasthma and bronchial asthma and in 13 healthy persons. The peculiarities of circadian organization of external respiratory parameters which were used for administration of chronotherapy were revealed in the patients. Some time before the appearance of maximum deterioration of indices under study, mostly indices of bronchial permeability, drugs (broncholytics, inhalation steroids and intal) were administered. Objective and subjective methods of assessment of bronchial permeability using a diary of self-evaluation were compared. The substitution of laboratory investigation for self-evaluation will make it possible to widely use chrono-diagnosis and chronotherapy for patients with bronchial asthma, and chronotherapy was found to be more effective than commonly used therapeutic schemes.

Adolescent↗
PubMed1994

Chronotherapy of cancer: biological basis and clinical application.

Chronotherapy-administration of drugs according to biological rhythms-has recently followed a development similar to that of new drugs. Clinical phase I, II and III trials could reliabily be performed thanks to the avialability of specific tools for chronotherapy, e.g. programmable-in-time-pumps. In standardized and selected mice or rats, the toxicity of approximately 30 anticancer agents (anthracylines, Pt complexes, fluoropyrimidines, nitrosoureas, as well as TNF, IL-2 ...) varied 2 to 10 fold according to drug dosing time along the 24 h time scale, as a result of endogenous circadian rhythms. Dosing-time dependent changes in pharmacokinetics or tissue uptake of drug do not suffice to explain 24 hr rhythms in drug pharmacodynamic effects. Thus, cellular rhythms in target tissues, including enzymatic activities, reduced glutathione, cell division cycle, ... appear as the major mechanisms of rhythms in the cytotoxicity of cytostatic compounds. These "peripheral" mechanisms are coordinated or reset by central biological clocks. In cancer patients, the continuous infusion of 5-fluorouracil, adriamycin or vindesine at a constant rate resulted in large 24-hr changes in plasma drug levels. Mechanisms involve circadian changes in drug metabolism (e.g., dehydropyrimidine dehydrogenase for 5-FU), disposition (blood flow) or excretion (urine output). Extrapolation of times of least toxicity from nocturnally-active rodents to diurnally-active patients has been attempted through referring them to the sleep-wakefulness cycle of the considered species. Chronotherapy has allowed to significantly decrease drug toxicity and/or increase dose intensity of adriamycin, fluorouracil, FUdR, oxaliplatin and alpha-interferon.(ABSTRACT TRUNCATED AT 250 WORDS)

Antineoplastic Agents↗
PubMed2003

Cancer chronotherapy: principles, applications, and perspectives.

BACKGROUND: Cell physiology is regulated along the 24-hour timescale by a circadian clock, which is comprised of interconnected molecular loops involving at least nine genes. The cellular clocks are coordinated by the suprachiasmatic nucleus, a hypothalamic pacemaker that also helps the organism adjust to environmental cycles. The rest-activity rhythm is a reliable marker of the circadian system function in both rodents and humans. This circadian organization is responsible for predictable changes in the tolerability and efficacy of anticancer agents, and possibly also may be involved in tumor promotion or growth. METHODS: Expected least toxic times of chemotherapy were extrapolated from experimental models to human subjects with reference to the rest-activity cycle. The clinical relevance of the chronotherapy principle (i.e., treatment administration as a function of rhythms) has been investigated previously in randomized multicenter trials. RESULTS: In the current study, chronotherapeutic schedules were used to safely document activity of the combination of oxaliplatin, 5-fluorouracil, and leucovorin against metastatic colorectal carcinoma and to establish new medicosurgical management for this disease, and were reported to result in unprecedented long-term survival. CONCLUSIONS: Chronotherapy concepts appear to offer further potential to improve current cancer treatment options as well as to optimize the development of new anticancer or supportive agents.

Animals↗
PubMed2000

Chronotherapy with 5-fluorouracil, folinic acid and carboplatin for metastatic colorectal cancer; an interesting therapeutic index in a phase II trial.

The aim of this study was to develop a phase II study gauging the contribution of a daily low-dose of carboplatin combined with 5-fluorouracil (5-FU) and folinic acid (FOL) in a chronotherapy schedule for advanced colorectal cancer patients. 60 patients with metastatic colorectal cancer were included in a phase II trial in which 50% of patients had received prior chemotherapy of up to three regimens. Treatment consisted of a combination of 5-FU (700 mg/m(2)/day) and FOL (300 mg/m(2)/day) infused from 10.00 pm to 10. 00 am peaking at 4.00 am with carboplatin infused from 10.00 am to 10.00 pm at 40 mg/m(2)/day with a peak at 4.00 pm. 4-day courses were repeated every 2 weeks in an ambulatory setting with a programmable pump. Patients experienced excellent tolerance (grades III-IV%): diarrhoea, 8.1; nausea/vomiting, 4.8; mucositis, 3.2; skin or neurological 1.7; granulocytes 29.0; platelets and haemoglobin (Hb) 9.7. Major tumour responses were observed in 47% of cases, 4 complete response (CR), 24 partial response (PR); 3 CR and 6 PR (69%) were recorded in 13 previously untreated patients; 11 (18%) underwent subsequent surgical resection of residual metastases. Median survival was 14.6 months with 22% patients surviving over 2 years (35% survival for responders versus 0 for non-responders). In conclusion, this chronotherapy determined administration of 5-FU/FOL and carboplatin yielded an excellent therapeutic index for the combination and warrants further evaluation in the first-line treatment of metastatic colorectal cancer.

Adult↗
PubMed2001

Circadian chronotherapy for human cancers.

Cell physiology is regulated by a 24-hour clock, consisting of interconnected molecular loops, involving at least nine genes. The cellular clock is coordinated by the suprachiasmatic nucleus, a hypothalamic pacemaker which also helps the organism to adjust to environmental cycles. This circadian organisation brings about predictable changes in the body's tolerance and tumour responsiveness to anticancer agents, and possibly also for cancer promotion or growth. The clinical relevance of the chronotherapy principle, ie treatment regimens based upon circadian rhythms, has been demonstrated in randomised, multicentre trials. Chronotherapeutic schedules have been used to document the safety and activity of oxaliplatin against metastatic colorectal cancer and have formed the basis for a new approach to the medicosurgical management of this disease, which achieved unprecedented long-term survival. The chronotherapy concept offers further promise for improving current cancer-treatment options, as well as for optimising the development of new anticancer or supportive agents.

Antineoplastic Agents↗
PubMed1996

Using drug chronotherapy to wean patients from mechanical ventilation.

Discontinuation of positive pressure mechanical ventilation results in decreased intrathoracic pressure. Although there has been extensive research into factors associated with weaning adults from mechanical ventilatory support, little attention has been paid to the role of left ventricular performance. Research also has not focused on interventions that might optimize ventricular performance. The purpose of this article is to explore the potential effect of cardiac dysfunction in weaning and the role of drug chronotherapy as a strategy to modify patients' responses to weaning from mechanical ventilatory support. Biophysical principles involved are reviewed, and the development of a chronotherapeutic intervention is described. Two case examples illustrate the use of drug chronotherapy during the weaning process.

Aged↗
PubMed2004

Chronotherapy of hypertension.

PURPOSE OF REVIEW: Blood pressure displays appreciable predictable-in-time circadian variation. The chronotherapy of hypertension takes into account the clinically relevant features of the 24-h pattern of blood pressure, e.g. the accelerated morning rise and nighttime decline during sleep, plus potential administration circadian time determinants of the pharmacokinetics and dynamics of antihypertensive medications. RECENT FINDINGS: Significant administration-time differences in the kinetics (i.e. chronokinetics) plus the beneficial and adverse effects (termed chronodynamics) of antihypertensive drugs are well known. Thus, bedtime, but not morning, dosing with cilnidipine significantly reduces nocturnal blood pressure. In addition, the dose-response curve, therapeutic coverage, and efficacy of the doxazosin gastrointestinal therapeutic system are all markedly dependent on the circadian time of drug administration. Moreover, valsartan administration at bedtime as opposed to upon awakening results in improved diurnal/nocturnal blood pressure ratio, such that the dosing time of valsartan can be chosen in relation to the dipper status of any given patient to improve therapeutic benefit and reduce cardiovascular risk. SUMMARY: Nocturnal hypertension, which is characterized by the loss or even reversal of the expected 10-20% sleep-time blood-pressure decline, increases the risk of cardiac and cerebrovascular events. Chronotherapy provides a means of individualizing treatment of hypertension according to the circadian profile of blood pressure of each patient. The chronotherapeutic strategy constitutes a new option to optimize blood-pressure control and to reduce risk.

Antihypertensive Agents↗
PubMed2006

Chronotherapy using corticosteroids for multiple sclerosis relapses.

BACKGROUND: The activity of the immune system displays a circadian rhythm. In diseases characterised by aberrant immune activity, chronotherapy (a treatment regimen tailored to diurnal body rhythms) may increase the efficiency, safety and tolerability of drugs. AIM: To compare the outcomes of intravenous corticosteroid administration during the day or night, for treatment of acute multiple sclerosis relapses. METHODS: 17 patients with multiple sclerosis were included in the study. Clinical assessment of disability was performed at trial entry, and at days 7 and 30 from the initiation of treatment. Adverse events and preference of night-time versus daytime treatment were assessed at the end of the treatment course. RESULTS: After night-time treatment, clinical recovery was significantly (p<0.001) enhanced and the mean number of side effects was significantly (p = 0.007) lower. Furthermore, most patients expressed a preference for night-time versus daytime treatment. CONCLUSIONS: The study suggests a potential benefit for implementation of chronotherapy using steroid treatment for acute multiple sclerosis relapse, with implications for other immune-mediated disorders.

Acute Disease↗
PubMed2005

[Chronobiology, chronotherapy and vascular risk].

The importance of rhythmic activities in humans, and their influence on the diseases are underscored. Clinical chronology is fundamental in order to interpret the physiopathological basis of temporary variations. Knowing the variability of the biological processes also makes it possible improving the effect of drugs utilized and minimize their adverse effects. This is the objective of Chronotherapy. We apply chronology and Chronotherapy in cardiovascular diseases, since many of them adjust their prevalence for specific rhythms. One thinks about the mechanisms or factors that favor cardiovascular diseases, especially those related to the circadian variations of blood pressure. We also review the variations in the pharmacokinetics of the drugs used in the treatment of cardiovascular diseases, delving further into the analysis of its effects according to their administration schedule. We can conclude that the use of those drugs according to the chronological knowledge makes possible to achieve better results in the control of cardiovascular diseases, and a greater safety in its use.

Cardiovascular Diseases↗
PubMed2002

[Effects of aspirin standard therapy and chronotherapy on circadian organization of hemocoagulation in patients with insulin-dependent diabetes mellitus].

24-h profile of hemocoagulation was assessed in 30 patients with insulin-dependent diabetes mellitus type 1 aged 17-37 years. The patients were randomized into 2 groups, 15 patients each. Patients of group 1 received aspirin by conventional scheme: 125 mg 3 times a day for 16 days. Patients of group 2 received aspirin as preventive chronotherapy: once a day in a dose 125 mg for 16 days two hours before the acrophase of platelet aggregation rhythm--at 22 p.m. Parameters of plasmic and platelet hemostasis in blood samples were measured at 3.00, 7.00, 11.00 a.m., 15.00, 19.00, 23.00. The above chronobiological information was processed by Kosinor-analysis according to F. Halberg. Before the treatment, hypercoagulation with night rise as well as external and internal desynchronism of the hemostasis circadian rhythms were observed. Conventional aspirin treatment improved hemostasis but influenced acrophases minimally. Aspirin chronotherapy promoted normalization of circadian organization of hemocoagulation.

Adolescent↗