Circadian pattern

The circadian pattern of pineal NAT activity and consequently melatonin secretion is controlled by the suprachiasmatic nuclei (SCN) as it is abolished by lesions of the SCN, the major circadian oscillator (Klein and Moore 1979). Thus, the environmental L/D cycle acts as the pervasive and pre-eminent Zeitgeber that regulates melatonin synthesis (Scheer and Czeisler 2005). 

Erratic DPD activity is a major cause of the marked pharmacokinetic variability of 5-FU. Drug-drug interactions (47,48), circadian patterns (12,49,50), and inter-gender (7,8) inter-ethnic differences (51,52,53,54,55) have been identified as putative causes for profound variations in DPD activities. Consequently, population studies of DPD activities displayed extremely wide ranges of values (17,56,57). 

The past 20 years have witnessed a broad interest in the role of the hypothalamic-pituitary-adrenal axis in the psychobiology of affective disorders. In depressed patients, increases in serum cortisol are frequently reported in addition to disruptions of circadian patterns of cortisol secretion... 

It has been claimed that melatonin contributes significantly to blood serum TAC. Both melatonin and TAC in human serum were found to exhibit the same circadian pattern of changes, with nocturnal peak values at 01 00 hr. Exposure of volunteers to light at night decreased both TAC and melatonin. Removal of melatonin from sera collected at night decreased the TAC value of the samples to basal daytime... 

It is useful to compare the circadian patterns of 5-FU delivery with the more conventional constant infusion drug-delivery pattern, in which the amount of 5-FU delivered over the 24-h period is the same as for the circadian delivery schedules. The quantity of 5-FU (Qsfu) delivered over 24 h according to the semi-sinusoidal schedule defined by Eq. (3) is given by Eq. (5) ... 

To investigate the effect of the peak time of circadian delivery of 5-FU, we compare in Fig. 10.4a four circadian schedules with peak delivery at 4 a.m., 10 a.m., 4 p.m., and 10 p.m., for a cell cycle variability of 15%. The data on cumulated cell kill by 5-FU indicate a sharp difference between the circadian schedule with a peak at 4 a.m., which is the least toxic, and the other schedules. This difference is even more striking when cells are better synchronized, for smaller values of variability V (data not shown). The most toxic circadian schedules are those with a peak delivery at 4 p.m. or 10 a.m. We compare in Fig. 10.4b the least and most toxic circadian patterns of 5-FU delivery with the continuous infusion of 5-FU. Continuous delivery of 5-FU appears to be slightly more toxic than the circadian pattern with a peak at 4 p.m. 

The cases of peak delivery at 10 a.m. (Fig. 10.5b) or 10 p.m. (Fig. 10.5d) are intermediate between the two preceding cases. Overlap between the peak of 5-FU and the peak of cells in S phase is only partial, but it is still greater in the case of the peak at 10 a.m., so that this pattern is the second most toxic, followed by the circadian delivery centered around 10 p.m. The comparison of the four panels Fig. 10.5a-d explains the results of Fig. 10.4a on the marked differences in cytotoxic effects of the four 5-FU circadian delivery schedules. The use of the cell cycle automaton helps clarify the dynamic bases that underlie the distinctive effects of the peak time in the circadian pattern of anticancer drug delivery. 

The case of the continuous infusion of 5-FU is considered in Fig. 10.5e. Because the total amount of 5-FU administered over 24 h is the same as for the circadian semi-sinusoidal patterns, the level of 5-FU - and hence the cytotoxic effect of the drug - is sometimes below and sometimes above that reached with the circadian schedule. The numerical simulations of the automaton model indicate that the cytoxicity is comparable to that observed for the most toxic circadian pattern, with peak delivery of 5-FU at 4 p.m. 

Numerical simulations therefore indicate that the least damage to the cells occurs when the peak of 5-FU circadian delivery is at 4 a.m., and when cells are well synchronized, i.e., when cell cycle variability V is lowest. In contrast, when the peak of 5-FU circadian delivery is at 4 p.m., cytotoxicity is enhanced when cells are well synchronized. The cytotoxic effect of the drug, therefore, can be enhanced or diminished by increased cell cycle synchronization, depending on the relative phases of the circadian schedule of drug delivery and the cell cycle entrained by the circadian clock. Continuous infusion of 5-FU is nearly as toxic as the most cytotoxic circadian pattern of anticancer drug delivery. 

We compared the effect of the continuous administration of 5-FU with various circadian patterns of 5-FU delivery peaking at 4 a.m, 10 a.m., 4 p.m., or 10 p.m. in the presence of entrainment by the circadian clock, by measuring the normalized, cumulative number of cells killed by 5-FU (Fig. 10.4). Several conclusions can be drawn from this comparison. First, the various circadian patterns of 5-FU delivery have markedly different cytotoxic effects on diurnally active cancer patients the least toxic pattern is that which peaks at 4 a.m., while the most toxic one is that which peaks at 4 p.m. The other two patterns peaking at 10 a.m. or 10 p.m. exert intermediate cytotoxic effects. Conventional continuous infusion of 5-FU is nearly as toxic as the circadian pattern of 5-FU delivery peaking at 4 p.m. 

The cell cycle automaton model permits us to clarify the reason why circadian delivery of 5-FU is least or most toxic when it peaks at 4 a.m. or 4 p.m., respectively. Indeed, the model allows us to determine the position of the peak in S-phase cells relative to that of the peak in 5-FU. As shown in Fig. 10.5, 5-FU is least cytotoxic when the fraction of S-phase cells oscillates in antiphase with 5-FU (when 5-FU peaks at 4 a.m.) and most toxic when both oscillate in phase (when 5-FU peaks at 4 p.m). Intermediate cytotoxicity is observed for other circadian patterns of 5-FU (when the drug peaks at 10 a.m. or 10 p.m.), for which the peak of 5-FU partially overlaps with the peak of S-phase cells. For the continuous infusion of 5-FU, the peak in S-phase cells necessarily occurs in the presence of a constant amount of 5-FU. Hence, the constant delivery pattern is nearly as toxic as the circadian pattern peaking at 4 p.m. 

The results of simulations indicate that, when the circadian delivery of 5-FU peaks at 4 a.m., differential effects of the drug on a population of healthy cells and on a population of tumor cells may be observed depending on whether the two cell populations are entrained or not by the circadian clock [33]. Another source of differential effect pertains to the degree of variability, given that, as previously noted, synchronization of the cells minimizes cytotoxic damage when the circadian 5-FU modulated delivery pattern peaks at 4 a.m. The results are markedly different when the circadian pattern of 5-FU delivery peaks at 4 p.m. [33]. Then the cytotoxic effect of the drug on the two populations is the inverse as that predicted for the circadian pattern peaking at 4 a.m. The effect of variability therefore depends on the circadian pattern of 5-FU delivery and on the possibility of entrainment of the cell cycle by the circadian clock. 

To some extent the idea of resonance is also present in the case of circadian 5-FU delivery. Indeed, the circadian patterns of 5-FU which peak at 4 a.m. or 4 p.m. correspond to oscillations that are, respectively, in antiphase or in corresponding phase with the circadian variation of the fraction of cells in S phase. This effect can be seen even for cell cycle durations that differ from 24 h, because of the entrainment of the cell cycle by the circadian clock. 

Altinok, A., Levi, F., Goldbeter, A. A cell cycle automaton model for probing circadian patterns of anticancer drug delivery. Adv. Drug Deliv. Rev. 2007,... 

Acute dystonic reactions are dramatic, acute-onset muscular spasms that occur within the first 24-48 hours after starting therapy, or in a few cases when the dosage is increased. A circadian pattern of acute dystonic reactions has been described (198). Men are more susceptible than women to this reaction, and the young more so than the elderly (199). Drug-induced dystonia can also be... 

Mazurek MF, Rosebush PI. Circadian pattern of acute, neuroleptic-induced dystonic reactions. Am J Psychiatry 1996 153(5) 708-10. 

Lu, S., Xu, R., Jia, J.W., Pang, J., Matsuda, S.P. and Chen, X.Y (2002) Gloning and functional characterization of a beta-pinene synthase from Artemisia annua that shows a circadian pattern of expression. Plant Physiol., 130,477-86. 

The timing of corticosteroid administration has been pinpointed to interact with the diurnal rhythm of the hypothalamic-pituitary-adrenal axis in humans (Meibohm et al 1997). Dose timing has a pivotal effect on the safety profile and consequently the risk-benefit ratio of inhaled corticosteroids. In humans, maximum adrenal suppression occurs with the administration of aerosolized corticosteroids in the early morning hours, whereas endogenous cortisol production is least disrupted by administration in the afternoon. The circadian pattern results from the... 

Eastell R, Calvo MS, Burr it MF, Offord KP, Russell RG, Riggs BL. Abnormahties in circadian patterns of bone resorption and renal calcium conservation in type I osteoporosis. J Clin Endocrmol Metab 1992 74 487-94. 

An understanding of the progression of the response in the absence of drug is essential for the proper application of the model. For example, endogenous cortisol (24, 54-56) and osteocalcin (57) levels in plasma follow a circadian pattern that can be htted with a cosine function. 

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