[Medical advertising and chronopharmacology].
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Biomedical subjects
F Lévi
Publications and source records attributed to F Lévi.
Circulating CALLA-positive lymphocytes exhibit circadian rhythms in man.
Common acute lymphoblastic leukemia antigen (CALLA) is a polypeptide with a molecular weight of 100,000 daltons (P100). It has been mainly found on the membrane of leukemic lymphoblasts, but not on that of normal circulating lymphocytes. Circadian rhythmicity in circulating CALLA-positive (CALLA+) lymphocytes was investigated in five healthy male subjects. Blood was sampled every 4 h for 24 h in each subject. Seven times series were obtained (three for the same subject). Leukocyte and differential counts were determined, and mononucular cells (greater than 95% lymphocytes) were isolated in Ficoll-Paque gradient. CALLA+ cells were characterized with both J5 and VILA1 monoclonal antibodies. Other T- and B-cell subpopulations were also determined in the same samples. Up to 1160 +/- 498 (mean +/- 1 S.E.M) J5-labelled CALLA+ lymphocytes per mm3 were found in peripheral blood at night. At this time, circulating VILA1-labelled CALLA+ lymphocytes also reached their peak although with a much lower number (66 +/- 14 cells/mm3). A circadian rhythm (with a period identical to 24h) was statistically validated with several methods for the number of J5-labelled cells, that of VILA1-labelled cells and the J5: VILA1 ratio. The count of J5-labelled CALLA+ cells was correlated with that of total lymphocytes, total T (OKT3+) and inducer T (OKT4+) cells (p less than 0.01), but neither with suppressor/cytotoxic cells (OKT8+) nor with B cells (SIg+, B1+, B2+, or HLA-Dr+). No correlation was found between any of these lymphocyte subpopulation and the count of VILA1-labelled CALLA+ cells. Such results further support the hypothesis that VILA1 and J5 monoclonal antibodies do not bind to the same epitope of the CALLA molecule. The large nocturnal increase in circulating J5-labelled CALLA+ lymphocytes may be accounted for by a release of immature presumably T lymphocytes in the peripheral blood.
Adult↗
Circadian rhythms in competitive sabre fencers: internal desynchronization and performance.
During a 7-10 day span, circadian rhythms of sleep-wake, self-rated fatigue and mood, oral temperature, eye-hand skill and right and left hand grip strength were investigated in eight subjects: five males (21-28 years of age), members of the French sabre fencing team selected for the 1984 Olympic Games in Los Angeles, and three females (19-26 years of age) practicing fleuret (foil) fencing as a sports activity. On the average six measurements/day/variable/subject were performed. The single cosinor method showed that a circadian rhythm was detectable for only 26 out of the 56 time series (46.4%). Power spectrum analysis gave almost the same figure (19 out of 48: 39.5%) with regard to rhythms with tau = 24 hr indicating that with one exception (subject JFL) rhythms were internally desynchronized including differences tau between right and left hand grip strength rhythms for three subjects. Results suggest: (a) a physiologic synchronization of circadian rhythms may be a predictor of good performance; (b) however, internal desynchronization as shown previously may be a trivial phenomenon and thus does not imply in itself alterations of either health or performance; (c) chronobiologic methods should be recommended for a better understanding of changes in performance by those participating in competitive and other sports.
Adult↗
A histological assessment of the four-day subrenal capsule assay (SRCA).
A four-day subrenal capsule assay (SRCA) was developed, since fragments of human tumours implanted under the renal capsule of immunocompetent mice became rejected by the host within six days. The assay requires a histological assessment of both its exploitability and the extent of drug-induced anti-tumour lesions. 45 tumours from 43 patients with solid tumour were submitted to an SRCA in 1410 male B6D2F1 mice. After being biopsied each tumour was dissected by a pathologist, cut into 50 pieces (1.5 mm3), and one piece was implanted under the renal capsule of 35 mice; the mean tumour diameter was measured on day 0. The mice were randomized into groups of 6 to 10 animals each. On days 1, 2 and 3, the mice were treated with either placebo (control group) or with various anticancer agents. On day 4 the animals were sacrificed, the mean tumour diameter measured, the tumour bearing kidney fixed in Bouin's picroformol solution and processed for histological analysis after staining with hematein. Fragments of fresh explants of human tumours retained their proliferative and metabolic capacity: mitoses were observed as well as keratinizing cells in epidermoid carcinomas and melanin-producing cells in melanomas. Proliferation of tumour cells was seen along the renal capsule suggesting their affinity for connective tissue. Capillaries filled with mouse erythrocytes were also seen. No or minimal lymphocytic infiltration was found. Drug oncolytic effects ranged from minor cellular degeneration to almost complete necrosis and were documented by the scoring of histologic lesions.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Circadian rhythm in tolerance of mice for etoposide.
Etoposide (40 mg/kg/day X 3 days and 60 mg/kg/day X 3 days) was best tolerated by male B6D2F1 mice when given in the second half of the rest span of their sleep-wake circadian cycle. Such a time-qualified treatment resulted in increased long-term survival rate, highest peripheral leukocyte count at nadir, and lowest body weight loss, as compared to results from drug dosing in the activity span. Assuming that such results may be extrapolated to human beings, the treatment time of etoposide associated with an optimal tolerance would be located in the second half of the sleeping span (usually near 5.00 hrs).
Animals↗
Interindividual differences in a set of biological rhythms documented during the high arctic summer (79 degrees N) in three healthy subjects.
The High Arctic summer with its permanent sunlight provides a situation in which one of the natural synchronizers, the light-dark alternation, is minimal. During the summers of 1981 and 1982 three healthy right-handed geographers who were performing field studies in Svalbard as part of their own research volunteered to document, 4-6 times per 24 hr for respectively 63, 141 and 147 days, a set of circadian rhythms: self-rated fatigue, oral temperature, grip strength of both hands, heart rate and times of awakening and retiring. Tests were performed before departure from France, in Svalbard (79 degrees N latitude) where their daily activities were often strenuous, and after returning to France. Time series were treated individually according to three methods: display of data as a function of time, cosinor analyses to quantify rhythm parameters, and spectral analyses to estimate component periods of rhythms. Circadian parameters such as period and acrophase of activity-rest, oral temperature and fatigue rhythms were not altered. On the other hand, the circadian rhythm in grip strength was altered: the period differed from 24 hr in one subject, while grip strength acrophase of the left, but not the right, hand of the other two subjects was phase shifted during the sojourn in Svalbard. A prominent circahemidian (about 12 hr) rhythm was observed in two subjects for their heart rate in Svalbard, while a prominent circadian rhythm (differing from exactly 24 hr) was observed in France associated with a small circahemidian component.
Activity Cycles↗
[Circadian rhythm of the grip strength of the right and left hands: desynchronization in some shift workers].
38 male shift workers and former shift workers volunteered to self-measure 4 to 8 times/24 hrs. their oral temperature (OT) as well as right and left hand grip strength (HGS) best performance during a 16 to 30 day span. Time series were analyzed individually according to two methods: day by day circadian acrophase drift and power spectrum. Mainly, but not exclusively, subjects with poor tolerance to shift work exhibited an internal desynchronization with a circadian period tau different from 24 hrs. which was the case for OT as well as right and left HGS; each could be different in tau between one another and from 24 hrs. These results suggest that oscillatory systems may be influenced by the neocortex apparently with difference between right and left side.
Adult↗
Large-amplitude circadian rhythm in helper:suppressor ratio of peripheral blood lymphocytes.
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Circadian Rhythm↗
Clinical chronopharmacology.
Circadian (approximately or equal to 24 h), circannual (approximately or equal to 1 year) and other biological rhythms of endogenous origin, detectable at all levels of organization, constitute a temporal structure in all animal species, including man. Circadian, circannual and other rhythmic changes in biological susceptibility and response of organisms to a large variety of physical as well as chemical agents including medications and foods are rather common phenomena. Modern chronopharmacology investigates drug effects: a) as a function of biological timing and b) upon parameters characterising the endogenous bioperiodicities. A better understanding of periodic and thus predictable changes in drug effects can be attained through consideration of three complementary concepts: the chronokinetics of a drug (rhythmic changes in its pharmacokinetics): the chronesthesy (rhythmic changes in susceptibility of target biosystem to this drug), and the chronergy (the drug-integrated overall effects). One of the aims of chronopharmacology is solving problems of drug optimization. Knowledge of those administration times coinciding with best effectiveness or tolerance is required to optimize both timing(s) and dosage(s) of a medication. Illustrative examples of both experimental and clinical investigative chronopharmacology are corticosteroids and anticancerous agents.
Adult↗
[Morphologic distribution of tumors occuring in the canton of Vaud].
After a short presentation of the methodological aspects of cancer registration and morphological coding, the results concerning cancer of the upper digestive tract, lung, testis and ovary were discussed. Some distributions of the main histological types are analysed by age, sex, site and multiple primaries. Known statistical associations are described between morphology and sex for lung cancer and between morphology and controlateral tumor for ovary.
Adult↗
Chronomodulation of chemotherapy against metastatic colorectal cancer. International Organization for Cancer Chronotherapy.
Toxic effects of 5-fluorouracil (5-FU) and oxaliplatin (L-OHP), two active drugs against metastatic colorectal cancer, varied by 50% or more according to circadian dosing time in mice or rats. Adaptation of chemotherapy delivery to circadian rhythms (chronotherapy) was assessed in fully ambulatory outpatients, using multichannel programmable pumps. These devices allowed us to reliably test the clinical relevance of such a chronotherapy principle. First, single agent 5-day chronomodulated schedules were devised and assessed in Phase I and II trials with 5-fluorouracil (5-FU, peak delivery at 4:00 h) or oxaliplatin (L-OHP, peak at 16:00 h). Both schedules were then combined, folinic acid (FA) being added, synchronous with 5-FU infusion. This three-drug chronomodulated regimen (chrono-FFL) produced a 58% response rate (95% C.I.: 48-68%) in 93 patients with metastatic colorectal cancer, 46 of whom had previously received chemotherapy. In the first European randomised trial in 92 previously untreated patients, chronomodulated three-drug delivery achieved 53% response, as compared to 32% in those patients receiving flat infusion (P = 0.038). These respective figures were confirmed in a subsequent multicentre randomised trial involving 186 additional patients. Since the most active schedule was also the least toxic one by 2- to 10-fold, chrono-FFL was further intensified in three consecutive Phase II trials involving a total of 200 additional patients. Results suggest that both response rate and quality were further improved with such treatment intensification. Thus, chrono-FFL more than doubled the activity of chemotherapy against metastatic colorectal cancer in a multicentre European setting.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Tumori. Chronotherapy Study Group of the European Organization for Research and Treatment of Cancer.
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Antineoplastic Combined Chemotherapy Protocols↗
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↗
[Mechanisms and perspectives in clinical chronopharmacokinetics].
The pharmacokinetic parameters of drugs vary largely and predictably as a function of their dosing time along the 24-hr scale (and also the year and the menstrual cycle) in Man. Such chronopharmacokinetics have been described following single or repeated doses via the oral or the venous route, and whether drug halflife is short or long. Moreover continuous infusion of a drug at a constant rate cannot maintain constant plasma levels. Such phenomena are accounted for by circadian (and other) rhythms which characterize absorption, protein binding, transmembrane flux, as well as liver and kidney metabolism and biliary and urinary excretions. It is anticipated that the knowledge of the physical and chemical properties of a drug and that of the circadian organization of the main physiologic functions involved into its bioavailability will allow to predict its chronopharmacokinetics.
Animals↗
Internal desynchronization of circadian rhythms and tolerance of shift work.
Fifteen male subjects including 12 shift workers (oil refinery operators) volunteered to document circadian rhythms in sleep-wake, grip strength of both hands, peak expiratory flow, heart rate, self-rated drowsiness, fatigue and attention. Each of these variables was measured 4 to 6 times/day for 2 to 3 weeks. In addition, both axillary temperature (with a shielded probe) and wrist activity were almost continuously recorded at 15 min intervals during the same time span. Individual time series were analyzed according to several statistical methods (power spectrum, cosinor, chi 2, etc.), in order to estimate the prominent circadian period tau and to evaluate both individual and subgroup differences with regard to tolerance of shift work, age, duration of shift work. The present study confirms for continuously recorded temperature and wrist activity, grip strength of both hands, heart rate and peak expiratory flow that intolerance of shift work is frequently associated with an internal desynchronization. However, this conclusion cannot be extended to circadian rhythms in self-rated drowsiness, fatigue and attention. The internal desynchronization among several circadian rhythms supports the hypothesis that these latter are driven by several oscillators, with presumable differences between right and left hemispheres as suggested by unequal values of tau in rhythms of both hand grip strength. Since an internal desynchronization can be observed in tolerant shift workers having no complaint, it is likely that symptoms of intolerance are related to the subject's sensitivity to internal desynchronization rather than to the desynchronization itself.
Adult↗
[Biological rhythms, chronotherapy and nitrates].
Mammalian biological functions are organized according to circadian rhythms (lasting about 24 hours). They are coordinated by a biological clock situated in the suprachiasmatic nuclei (SCN) of the hypothalamus. These rhythms persist under constant environmental conditions, demonstrating their endogenous nature. Several genes of the circadian rhythm have been cloned in N. Crassa, Drosophilus and Mice, allowing molecular analysis of circadian functioning. Some rhythms can be altered by disease and drug pharmacology can be influenced by the time of their administration during the day (chronopharmacology). The rhythms of disease and pharmacology can be taken into account to modulate treatment over the 24-hour period (chronotherapy). The knowledge of such rhythms appears particularly relevant for the understanding and/or treatment of hypertension and ischaemic coronary artery disease. In rats and in man, the circadian rhythm of systolic or diastolic blood pressure can be dissociated from the rest-activity cycle, suggesting that it is controlled by an oscillator which can function independently of the SCN, which could justify modification of treatment according to the anomalies of the blood pressure rhythm. The morning peak of myocardial infarction in man is due to the convergence of several risk factors, each of which has a 24-hour cycle: blood coagulability blood, BP, oxygen requirements and myocardial susceptibility to ischaemia. The existence of these rhythms, and the chronopharmacology of cardiovascular drugs such as nitrate derivatives, constitute clinical prerequisites for the chronotherapy of heart disease.
Animals↗