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The chronotherapy of corticosteroids: practical application of chronobiologic findings to nursing.

In this paper evidence is presented pointing to the significance of when to treat along with why, what, and how much. Because of the circadian organization of the pituitary-adrenal axis, the long-term management of steroid-dependent patients must recognize and take into consideration the advantages of chronotherapy with corticosteroids. Thus, when corticosteroids are administered either daily or on alternate days, adrenal suppression and possibly growth disturbance can be minimized by timing to the circadian crest in adrenocortical function. As more findings are accumulated from ongoing and planned investigations, it can be expected that in the near future chronotherapeutics will become established in the practice of clinical and hospital nursing.

17-Ketosteroids

Nomifensine chronopharmacology, schedule-shifts and circadian temperature rhythms in di-suprachiasmatically lesioned rats--modeling emotional chronopathology and chronotherapy.

Some emotional disorders are associated with alterations of biological rhythm characteristics ('echronism'). Chronotherapy aims empirically to 1. optimize the kind and timing of conventional psychopharmacologic treatment and, need be, to use such old or new molecules in the rational endeavor to 2. correct (disease-determining) rhythm alteration directly. With respect to the first aim, a reduction by timing of undesired pharmacodynamic effects, as well as an amplification of empirically desired ones, can be dramatically illustrated by circadian rhythms in tolerance to many drugs affecting the central nervous system of rodents. A more rational approach is aimed at correcting ecchronism. The new antidepressant drug, nomifensine, achieves this task in rats with bilateral suprachiasmatic lesions, exhibiting in the telemetered core temperature an echronism of varying degrees. In this model system for the chronobiotic treatment of ecchronism, the properly timed administration of nomifensine speeds the adjustment of bilaterally (suprachiasmatically) lesioned rats to a shift in the synchronizing light-dark schedule. With methodologic provisions, notably for treatment timed by pertinent marker rhythms, nomifensine deserves clinical tests in psychochronotherapy.

Animals

Chronotherapy of malaria: improved efficacy of timed chloroquine treatment of patients with Plasmodium falciparum infections.

The effect of routine treatment with chloroquine (10 mg/kg on days 1 and 2 and 5 mg/kg on day 3) on parasitaemia and parasitaemic profile of patients infected with Plasmodium falciparum was studied. As with P. vinckei petteri, the mid-term trophozoites of P. falciparum were the most susceptible stages to chloroquine treatment. It is suggested that, in order to diminish the frequency of drug administration and to lower the risks of chemoresistance developing, treatment should be diversified, using the drug which is most effective on the parasite stages present in the peripheral blood.

Animals

Chronotherapy with immune checkpoint inhibitors: The knowns, the unknowns, and the contested.

Emerging data indicate that immune checkpoint inhibitors can exhibit time-of-day-dependent effects in pre-clinical models. Furthermore, multiple retrospective clinical trials associate earlier anti-tumor treatment timing with improved outcomes. However, key questions remain regarding the reproducibility of these findings, the underlying mechanisms, and their clinical implications. This commentary discusses these open questions and provides an outlook on the field.

Journal Article

The chemical principles of chronotherapy as established from an in vitro model of circadian concentration rhythms.

A model reaction for investigating the effects of chemical parameters on circadian rhythms is suggested. Its main advantage is that oscillations occur on a minute scale rather than daily and so accelerate studies. Some factors were found to increase the period of amplitude of the oscillations, others decreased them. The chemical principles prevailing during such oscillations are itemized. The effects of adding poisons or drugs are also noted and a computer calculation has been used to show that desferrioxamine B treatment for serum iron removal could be 65 percent more effective if administered at the correct point in the circadian cycle.

Circadian Rhythm

[Circadian rhythm of blood pressure in renovascular hypertensive goats treated with captopril].

Blood pressure (BP) was recorded directly and automatically by a microcomputer aid system for 48 h in normotensive and Goldblatt hypertensive goats. By population-mean cosinor fitting, significant circadian rhythms were found for SBP and DBP in both groups of goats. The BP during nighttime was higher than that during daytime in our goats. An angiotensin converting enzyme inhibitor, captopril, was given to hypertensive goats with usual schedule of drug administration (25mg, t.i.d) or form of chronotherapy (62.5 mg, given before the acrophase of BP, q.n). BP significantly decreased throughout the whole day in both treated groups. But there was no statistical difference of cosinor parameters between the effects of BP in these two groups. BP could be decreased by the method of chronotherapy with less amount of drug and less frequency of drug administration.

Animals

Use of ambulatory blood pressure monitoring in the management of antihypertensive therapy.

The recent development of ambulatory blood pressure (ABP) monitoring techniques has improved recording of blood pressure in therapeutic trials and in the clinical setting. The application of ABP differs according to which of these 2 applications is being considered. In therapeutic trials, a placebo control is required. The large quantity of precise data acquired with ABP monitoring allows the study of a limited number of patients; it also allows individual study of patients with a 'white coat' response (i.e. elevated blood pressure in response to examination by the clinician). Analysis of data from ABP monitoring may include the following: comparison of mean blood pressure values over 24 hours, daytime or night-time, or over any other selected time period; 24-hour blood pressure profiles, or analysis hour-by-hour, giving true chronotherapy, and providing data regarding the wearing-off of a drug effect or loss of therapeutic control; analysis of blood pressure at particular times, such as on waking; or specific examination of nonresponders. In individual patients, ABP monitoring should be reserved for specific indications. It can be used before initiation of treatment to confirm the necessity for treatment, especially in the context of hypertension at rest or the 'white coat' effect. With established treatment, ABP monitoring can be used in patients with resistant hypertension, in severe hypertension to examine loss of blood pressure control over time or inversion of the day/night cycle, and in patients with a specific illness, e.g. diabetes, in order to obtain the lowest blood pressure readings possible. Examination of these factors assists clinicians to accurately decide upon the timing and frequency of antihypertensive therapy.

Blood Pressure Monitors

Chronobiology in the diagnosis and treatment of mesor-hypertension.

An elevation of systolic and diastolic bloodpressure to values regarded as abnormal ones on the basis of conventional criteria was recognized by self-measurement. For both systolic and diastolic blood pressure, the overall means adjusted for rhythms, the so-called mesors, also were elevated in the light of their response to treatment: these mesors were found to be lowered with statistical significance when values during treatment were compared by an objective test with values measured before treatment. Individualized rhythmometry quantitatively characterizes a predictalbe portion of the variability in human blood pressure and tests for the statistical significance of changes in blood pressure as a function of the treatment and also as a function of the circadian timing of such treatment. The case report thus illustrates an individualized chronotherapy of systolic and diastolic mesor-hypertension, diagnosed retrospectively from the tested effect of hydrochlorothiazide. In the case reported, and perhaps routinely, computer-analyzed self-measurements can serve 1) to prescribe the right kind and amount with the right timing, for a given therapy, and 2) for diagnosis and prevention as well (Meyer et al.; Halberg et al.).

Blood Pressure

Immunocytoma effect upon circadian variation in murine urinary excretion of beta-aminoisobutyric acid, beta-alanine, phenylalanine and tyrosine.

Under the conditions of disynchronization by the manipulation of both the alternation of light and darkness and the availability and unavailability of food, circadian rhythms characterize the excretion of several amino acids by inbred LOU rats bearing an immunocytoma. Large amplitude rhythms can be demonstrated for urinary beta-aminoisobutyric acid, beta-alanine, phenylalanine and tyrosine. Under the same conditions of disynchronization, control animals excrete the same compounds also with a marked circadian variation but at an invariably lower average rate. These excretory rhythms, along with those demonstrated earlier for polyamines and light-chains, are of interest as potential markers for the chronotherapy of cancer.

Amino Acids

Autorhythmometry: leads from single-sample medical check-ups toward a health science of time series.

Starting from the definition of health as given by the WHO, the authors emphasize that rhythms of biological variables should be taken into account if one is to arrive at a positive and individual definition of the concept of health. The evaluation of a single datum spot check of physiological functions does not permit to quantify health in dynamic terms whereas this may become possible when the rhythmic quality of these variables, according to a spectrum of characteristic frequencies, has been assessed. Rhythmometry provides for appropriate reference standards as regards both the population in general and the physical conditions of the same subject during certain spans in the (prospective) life history (spans selected according to consideration of risk and hence cost and benefit at a given age). The authors therefore stress the importance of rhythmometry, thanks to which the time course and other peculiarities of any biological phenomenon can be evaluated by obtaining serial measurements, objectively quantifying their characteristic features, and working out special models with the aid of computers. Of special interest, particularly for the evaluation of reference standards, is autorhythmometry (AR), to be used at least for certain variables. This is the method by which each subject studies himself, performing a certain number of measurements in the course of the day (or month or year) of his body temperature, blood pressure, cardiac rhythm, grip strength, etc. In AR, the subject takes an active part in the study of his condition of health and it has been shown that in the majority of cases these measurements are done with the utmost accuracy and precision, providing that the purpose of the operations to be performed has been adequately explained. The wide spread use of AR, during more or less extended periods in a lifetime, would permit the assessment of the normal situation for each individual and thus offer the possibility of diagnosing any disorder at its very beginning; it would thus be of great prophylactic value. The authors refer to the example of arterial blood pressure; widely different values for the normal levels can be found in the texts of different authors. They also show that a certain presure may be normal for a given subject at a certain time of day and be a sign of illness for another subject, or even for the same subject at a different ime. The authors suggest the introduction of AR in the curriculum of secondary schools and into the routine for outpatients and inpatients. This practice would increase the availability of information on public health at a lower cost. AR may be very usefully applied to chronotherapy: it is a well-known fact that there are rhythms of sensitivity and therefore rhythms of toxic as well as therapeutic effects for various drugs. These can be dove-tailed in such a way as to work out, for individual cases, a time for administration at which the therapeutic effect is at its maximum and the toxic one at its minimum...

Animals