Circadian administration

The cytotoxic effect of the circadian administration of 5-FU depends on a variety of factors, which we consider in turn below. These factors include the mean duration D of the cell cycle phases, the variability V of cell cycle phase durations, entrainment by the circadian clock, and timing of the daily peak in 5-FU. For definiteness we consider the case where the cell cycle length, in the absence of entrainment, is equal to 22 h. 

Garcia-Borreguero D., Larrosa O., Saiz T. et al. (2001). Circadian variation in neuroendocrine response to the administration of L-dopa in patients with restless legs syndrome a pilot study. Sleep 24(suppl.), (A16-A17). 

Melatonin secretion is synchronized to the light/dark (LD) cycle, with a nocturnal maximum (in young humans, about 200 pg/ml plasma) and low diurnal baseline levels (about 10 pg/ml plasma). Studies have supported the value of the exogenous administration of melatonin in circadian rhythm sleep disorders, insomnia, cancer, neurodegenerative diseases, disorders of the immune function, and oxidative damage (Karasek et al. 2002 Pandi-Perumal et al. 2005, 2006 Srinivasan et al. 2005a,b, 2006 Hardeland et al. 2006). 

O Dell LE, Koob GF (2007) Nicotine deprivation effect in rats with intermittent 23-hour access to intravenous nicotine self-administration. Pharmacol Biochem Behav 86 346-353 O Dell LE, Chen SA, Smith RT, Specie SE, Balster RL, Paterson NE, Markou A, Zorrilla EP, Koob GF (2007) Extended access to nicotine self-administration leads to dependence Circadian measures, withdrawal measures, and extinction behavior in rats. J Pharmacol Exp Ther 320 180-193... 

The ultradian sleep—wake and temperature rhythm produced by 3rd ventricle infusion of TGFa closely resembles the effect of a focal excitotoxic lesion of SPZ neurons (Lu et al 2001). This ultradian rhythm is normally suppressed by circadian control and is disinhibited when SPZ neurons fail to relay SCN circadian information to sleep—wake circuits. Our results indicate that chronic TGFa administration uncouples SPZ neurons from sleep-regulatory circuits and that SPZ neurons expressing the EGFR transmit circadian information from the SCN to sleep—wake centres, in addition to likely regulating circadian locomotor activity. 

Various studies have been undertaken to identify clinical or paraclinical covariates associated with 5-FU PK variability, and the influences of age, sex, circadian rhythms, doses, and routes of administration on 5-FU PK have been well characterized (78,9,10,11,12). 

Frequently, the constant release of a drug from pharmaceutical dosage forms enables one to obtain a suitable pharmacological and therapeutic response. However, for therapy of certain pathologies, i.e. some heart and rheumatic diseases, or in the utilization of some drags such as contraceptive steroids and antibiotics, it would be more useful to obtain different plasma levels of the active principle at different times related to painful symptoms or circadian rhythms, etc. In these cases the desired therapeutic results can usually be obtained with frequent administration of conventional dosage forms which lead to a prompt absorption of the active principle. This kind of drag treatment is often compromised by a lack of full compliance by the patient. Until now there have been few systems that allow the release of the active principle in successive pulses at precise and well-controlled time periods [11,12]. 

The dose and frequency of administration required to achieve effective therapeutic blood and tissue levels vary in different patients because of individual differences in drug distribution and rates of drug metabolism and elimination. These differences are determined by genetic factors and nongenetic variables, such as age, sex, liver size, liver function, circadian rhythm, body temperature, and nutritional and environmental factors such as concomitant exposure to inducers or inhibitors of drug metabolism. The discussion that follows summarizes the most important of these variables. 

Wyatt JK, Cajochen C, Ritz-De Cecco A, Czeisler CA, Dik DJ. Low-dose repeated caffeine administration for circadian-phase-dependent performance degradation during extended wakefulness. Sleep 2004 27(3) 374—381. 

One further treatment that has been studied extensively to achieve resynchronization of the circadian system is the administration of melatonin. Endogenous melatonin is secreted from the pineal gland, primarily across the nocturnal or dark period. It has been proposed to play a role in the control of the circadian system (reviewed in Ref. 174) and potentially in the initiation of sleep (175,176). Studies that have administered exogenous melatonin, primarily during the daytime, have reported both chronobiotic (177) and soporific effects (178). Melatonin administration has been successful in studies examining the reentrainment of the circadian system after transmeridian flight or shiftwork (179). Similarly, the effectiveness of melatonin in reentraining the circadian system of those with DSPS to a normal day has been studied. 

Phase advances of the circadian system and sleep-wake activity have been reported in a number of studies, with daily administration of melatonin (180-183). Termination of melatonin administration resulted in a reversal of the phase advances, with subjects reverting to their preadministration phase. Therefore, continued administration of melatonin may provide a means for those with DSPS to maintain a normal phase, and avoid the associated sleep deprivation due to having to live on a normal schedule. It is important to note, however, that at present the effective dose of melatonin to be administered and the safety of long-term melatonin administration have yet to be established (184). Therefore, melatonin should be thought of as a research compound and not a clinical solution to DSPS. 

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