On methods for testing and achieving cancer chronotherapy.
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Animals↗
Biomedical subjects
F Halberg
Publications and source records attributed to F Halberg.
Rhythmometry gauges treatment of mesor-hypertension in the seventh and eight decades of life.
Autorhythmometry of blood pressure by an individual over an age-span of 67 to 72 years showed a strong circadian rhythm superimposed upon significant circaseptan and circannual rhythms. Automatic BP monitoring with an Arteriosonde throughout 24-hour spans on 4 separate occasions, before and during treatment, also indicated a prominent circadian BP rhythm and a treatment-related reduction in circadian mesor. The concept of a blood pressure mesor reference for the antimesor-hypertensive treatment constitutes a valuable guideline in the control of "familial" mesor-hypertension.
Aged↗
Schedule shifts, life quality and quantity--modeled by murine blood pressure elevation and arthropod life span.
During the span from 50 to 100 days and beyond, the male stroke-prone Okamoto rat develops systolic blood pressure measures in excess of 200 mm Hg. In the course of developing such a marked elevation in systolic blood pressure mean, this intermittently handled male Okamoto rat exhibits a statistically significant circadian rhythm with large amplitude. This amplitude may represent, at least in part, a response to intermittent handling; it is several times larger than the amplitude for spontaneously mesor-hypertensive (but not stroke-prone) female animals of the same age.
Aging↗
Time-qualified reference intervals - chronodesms.
Methods are presented for qualifying clinical reference intervals, for individuals as well as peer groups, according to circadian and other rhythms, using chronobiologically-defined single samples or time series.
Biological Clocks↗
[Circadian periodicity and stomach ulcer. An animal experiment model for the detection of rhythm factors in the genesis of civilization diseases].
Against the background of clinical experience attesting to the role of the circadian and circannual rhythm stage in gastric ulcerogenesis, animal experiments provide a model where by circadian stage and sex are both revealed as determinants of gastric ulcerogenesis. Experiments on the genetically mesor-hypertensive Okamoto rat demonstrate the critical interaction of multiple loads in ulcerogenesis, in keeping with a report by Glavin and Mikhail. While stimulation by single loads of a certain intensity--immobilization, food deprivation or cooling--did not regularly lead to the production of gastric ulcers, the combination of these same loads did so as a function of circadian state at the beginning of exposure time.
Animals↗
Chronobiologic optimization of aging.
Chronobiologic facts, concepts and methods are relevant to gerontology and geriatrics. Circadian and other rhythms are prominent sources of predictable variation requiring a reassessment of the "normal range" at all ages. Changes in the characteristics (e.g., the amplitude) of these rhythms during aging emphasize the need for careful evaluation of time dependency in research and clinical practice. Manipulation of periodic environmental factors that synchronize circadian rhythms can affect lifespans in plants and animals, further supporting the suggestion of an interaction between rhythms and senescence.
Aged↗
Implications of biologic rhythms for clinical practice.
The fact that many bodily functions display rhythmicity has an important bearing on resistance to toxins, response to drug or irradiation, and weight gain or loss according to when food is ingested. Though considerable clinical research remains to be done, "chronobiology" has already made available techniques for establishing predictable human rhythms, opening the way to more specific treatment of many condtions.
Adrenal Glands↗
[Glossary of chronobiology (author's transl)].
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Animals↗
Survival and cure of leukemic mice after circadian optimization of treatment with cyclophosphamide and 1-beta-D-arabinofuranosylcytosine.
When cyclophosphamide and 1-beta-D-arabinofuranosylcytosine were administered to mice previously given injections of L1210 leukemia cells, the combination was more effective than either drug given alone. The effectiveness of the 2 drugs in combination was strongly influenced by the stage of the circadian system at which the drugs were administered. With the use of a chronobiological (sinusoidal) approach, in comparison with one or two conventional treatment schedules, it was possible to demonstrate an overall lower toxicity as monitored by death or weight loss. In general, mean survival times and cures (when obtained) were circadian stage dependent; for example, in 1 study the cure rate was 94% in mice treated at 1 circadian stage, but only 44% in those treated at another stage. It cannot be overemphasized, however, that just as the "right" timing can enhance (with statistical significance) both the tolerance to chemotherapeutic agents and the rate of cure in leukemic mice, so can the "wrongly" timed (wrongly placed) ara-C sinusoid or "wrongly" timed cyclophosphamide enhance toxicity and host death rate.
Animals↗
Weight and metabolic changes induced by low carbohydrate-high fat diets in man and in rat.
Weight loss and potential toxicity of low carbohydrate-high fat diets were examined in 8 volunteer medical students given either a high fat diet or a high carbohydrate diet for 15 days, as well as in 36 Sprague-Dawley rats fed for 5 weeks a series of low carbohydrate diets (less than 1%), varying in protein and lipid proportions. A weight loss occurred with the low carbohydrate-high fat diets; serum cholesterol level increased in both man and rat; plasma triglycerides rose in man. In rat, we found an increase in hepatic lipid levels as in plasma ketone and non-esterified fatty acid concentrations. These effects seemed to be related to the increase in lipid intake rather than the lack of carbohydrates.
Adipose Tissue↗
Timing of single daily meal influences relations among human circadian rhythms in urinary cyclic AMP and hemic glucagon, insulin and iron.
Relations among circadian rhythms in serum iron, glucagon and insulin and urinary cyclic AMP excretion differ drastically when diurnally active, nocturnally resting human adults consume all daily food for one week as breakfast only and for another week as dinner only - a finding of interest to diverse fields, e.g., for optimizing certain kinds of therapy or for a better utilization of calories.
Circadian Rhythm↗
The circadian periodicity of urinary 17-ketosteroids, corticosteroids, and electrolytes in congenital adrenal hyperplasia.
The circadian periodicity of adrenal function in patients with congenital virilizing adrenal hyperplasia (CAH) was examined by measuring the urinary 17-ketosteroids, 17-hydroxycorticosteroids, sodium, and potassium. Patients with the salt-losing and the non-salt-losing types were studied with and without treatment. Cosine curves were fitted to the data by the least-squares method to determine the mesors, amplitudes, and acrophases of the variable for each patient. The data reveal distinct circadian rhythms for all variables measured whether or not the patient was receiving treatment. The acrophases for 17-ketosteroids and 17-hydroxycorticosteroids were between 1500 and 1800 h. These acrophases are about 6 h later than those for normal subjects. The treatment on a fixed daytime schedule for many years may have shifted the natural rhythm.
17-Hydroxycorticosteroids↗
Close reproduction by different laboratories of characteristics of circadian rhythm in 1-beta-D-arabinofuranosylcytosine tolerance by mice.
The tolerance of BALB/c X DBA/2 F1 mice to the popular cytostatic drug 1-beta-D-arabinofuranosylcytosine (ara-C) was tested in two laboratories about 1000 km apart. According to the same plan and on the same days in Little Rock, Ark., and Minneapolis, Minn., nine groups of 20 mice each received four courses of ara-C treatment, with 4-day intervals between them beginning February 7, 1973. In each course, a total dose of 240 mg/kg was divided among eight separate injections administered at 3-hr intervals. One group of mice received equal doses of ara-C every 3 hr (the homeostatic schedule). The eight other groups in each location received the same total dose per course but in gradually increasing and decreasing doses (the sinusoidal schedule). The timing of the highest doses on the latter schedule differed among the eight groups (by integer multiples of 3 hr). As predicted from earlier work, survival times after treatment with ara-C on different sinusoidal schedules differed drastically. However, the timing of the sinusoidal schedules yielding the longest survival was similar in the two locations. The survival times from all sinusoidal treatments from a given location were fitted by a 24-hr cosine curve. The timing of the rhythm in tolerance as a whole as thereby computed as the lag from local midnight of the peak in the cosine curve best fitting all data. The timing of this tolerance rhythm (briefly, circadian chronotolerance), computed separately for data from Arkansas and Minnesota, agreed within 1 hr. There also was close agreement in the results obtained by the 2 laboratories in mean survival time; the percentage of survivors when mice were treated according to certain of the selected sinusoidal schedules was much greater than for mice treated on the homeostatic schedule. This large and reproducible difference in tolerance and the similar timing of the overall fitted function describing chronotolerance in the hands of different investigators underlines the urgency of testing potential benefits from timed clinical treatment.
Animals↗
Circadian rhythmic plaque-forming cell response of spleens from mice immunized with SRBC.
Studies under controlled conditions of lighting and temperature revealed clear evidence of circadian periodicity with respect to the number of PFC present in the spleens of BALB/c mice 3 or 4 days after immunization with SRBC. Striking differences in proliferative responses of spleen lymphocytes to PHA or Con A were also observed at two different circadian times. Large proliferative responses occurred at the time when injection of antigen and/or sampling for PFC yielded a low PFC formation (early in the daily dark span) and small proliferative responses occurred at the time when antigen injection and sampling yielded high formation of PFC (early in the daily light span). These findings indicate that care should be taken to control the circadian timing of stimulation and sampling in studies of immune responses, and that rhythmically varying aspects constitute a new dimension of immunologic processes awaiting further analysis in both the circadian and weekly spectral regions.
Animals↗
[Circadian rhythms in the urinary excretion of salicylate (chronopharmacokinetics) in healthy adults].
Six healthy adults volunteered to ingest a 1 g solution/24 h of sodium salicylate in a study consisting of 4 standardized tests. The difference between tests was the timing of drug absorption: 07(00), 11(00), 19(00) and 23(00) respectively. The 4 separate tests were performed at least 1 week apart. Subjects; synchronization : diurnal routine activity with light-on at 07(00) and light-off at 23(00) Urine was collected at four-hour intervals, for 48 hours following drug ingestion. By the mean cosinor summary of least squares fits of a 24-hour cosine curve, or by other testing, a within-day difference is established for several chronopharmacokinetic parameters characterizing urinary salicylate excretion. By criteria including the height of the peak excretion, the span necessary to reach the peak, etc., it is shown that, as compared to drug administration at other times, salicylate is excreted faster into the urine, reaches higher values sooner and falls off faster when the drug is ingested between 19(00) and 23(00).
Adult↗
Biological rhythms.
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Adrenal Cortex Hormones↗
Circadian rhythms in mice fed a single daily meal at different stages of lighting regimen.
Circadian rhythms in systemic and cellular variables were studied in three groups of mice on different schedules of daily food accessibility: (1) only during the first 4 hours of the 12-hour light span; (2) only during the first 4 hours of the 12-hour dark span; and (3) at all times. The amplitudes of circadian variation in rectal temperature, serum corticosterone, and liver glycogen were increased by "meal-feeding" in either early light or early darkness. The overall averages of corticosterone and glycogen were also increased by meal-feeding at either stage of the lighting regimen. The time of peak values in temperature, corticosterone, and glycogen were determined by the time of food presentation, regardless of its relation to the lighting regimen. On the other hand, the interval between food presentation and peak values in the corneal mitotic index was greater when feeding was restricted to early darkness. These differences among the three groups of animals resulted in different relations among varibles at any given interval after feeding onset. Such effects concerning total bodily function, energy storage, hormonal regulation, and basic cellular processes indicate the pertinence of meal timing to nutritional research and practice.
Animal Nutritional Physiological Phenomena↗