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Biomedical subjects

F Lévi

Publications and source records attributed to F Lévi.

At least 91 records · Page 5Linked to original sources
PubMed1990

Phase I trial of 5-day continuous venous infusion of oxaliplatin at circadian rhythm-modulated rate compared with constant rate.

The toxic effects and tissue uptake of both cisplatin and oxaliplatin--[(1R, 2R)-1,2-cyclohexanediamine-N,N'] [oxalato(2-)-O,O']platinum--were previously shown to vary similarly according to dosing time in mice. A 4-hour infusion of cisplatin resulted in fewer side effects and allowed administration of higher doses at 16 hours than at 4 hours in patients with cancer. We hypothesized that the continuous venous infusion of oxaliplatin for 5 days would be less toxic and would deliver a higher dose to the patient if the drug were infused at a circadian rhythm-modulated rate (peak at 16 hr; schedule B) rather than at a constant rate (schedule A). We tested this hypothesis in a randomized phase I trial. We escalated the dose of oxaliplatin to the patient by 25 mg/m2 per course. Courses were repeated every 3 weeks. An external, multichannel, programmable-in-time pump was used for the infusions. Toxicity was assessable for 94 courses in 23 patients (12 patients with breast carcinoma, nine with hepatocellular carcinoma, and two with cholangiocarcinoma). The incidence of neutropenia of World Health Organization grades II-IV and the incidence of distal paresthesias were 10 or more times higher (P less than .05) with schedule A than with schedule B. In addition, vomiting was 55% higher (P = .15) with schedule A than with schedule B. Furthermore, with schedule B, the mean dose of oxaliplatin (P less than .001) and its maximum tolerated dose (P = .06) could be increased by 15% over those doses with schedule A. An objective response was achieved in two of the 12 patients with previously treated breast cancer. We recommend that the dose of oxaliplatin for phase II trials be 175 mg/m2, delivered according to the circadian rhythm-modulated rate.

Adult↗
PubMed1990

Chemotherapy of advanced ovarian cancer with 4'-O-tetrahydropyranyl doxorubicin and cisplatin: a randomized phase II trial with an evaluation of circadian timing and dose-intensity.

The efficacy and toxicity of the new anthracycline, 4'-0-tetrahydropyranyl doxorubicin (THP) (50 mg/m2 intravenous [IV] bolus) in association with cisplatin (100 mg/m2 IV as a 4-hour infusion) was assessed in 31 patients with advanced ovarian carcinoma. Twenty-eight patients were assessable for toxicity among whom 25 were assessable for response (International Federation of Gynecology and Obstetrics [FIGO] stage IIIa, four patients; IIIb, 15 patients; IV, six patients). Nine patients had received prior treatment. Patients were randomized to receive schedule (sch) A (THP at 6 hours, then cisplatin from 16 to 20 hours) or sch B (THP at 18 hours, then cisplatin from 4 to 8 hours). Sch A was hypothesized as less toxic since THP was best tolerated in the late rest span and cisplatin near the middle of the activity span in experimental studies. The rate of clinical complete response (CR) was 52%, that of partial response (PR) was 12%, and the overall clinical response rate (CR plus PR) was 64% (sch A, 73%; sch B, 57%). Median progression-free survival and survival times were, respectively, 10 and 19 months. Of 12 patients in clinical CR evaluated at second-look laparotomy, four had a pathological CR (33%), and three had microscopic residual disease (MD). The overall rate of pathological CR was 16%. Sch A was associated with less neutropenia (P = .10), thrombocytopenia (P less than .01), anemia (P less than .01), and renal toxicity (P less than .05) than sch B. Of four patients withdrawn for toxicity, three were on sch B (one death). Mean dose intensities (DIs) of THP and cisplatin, respectively, decreased by 30% and 47% over the five initial courses. Such decrease was significantly more pronounced for sch B than for sch A in previously untreated patients (P from 2-way analysis of variance [ANOVA] less than .01). THP-cisplatin is active against advanced ovarian cancer, and its toxicities can be significantly decreased by dosing THP in the early morning and cisplatin in the late afternoon as compared with THP in the evening and cisplatin the next morning.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1990

The influence of the athymic mutation nude on the components of the circadian rhythm of activity in mice.

The mutation known as nude brings about the lack of a thymus gland in mice. This immunodeficiency akes it possible to graft normally unaccepted, human cancerous tumors onto the mouse. Consequently, this animal is frequently used as a model for evaluating anti-cancer therapies. The effect of this mutation on biological rhythms constitutes a necessary step before using this model for cancer chronotherapy research. We evaluated the circadian and ultradian components of the rest-activity cycle in the following strains of mice: C57BL/6 with homozygous nu/nu, heterozygous nu/+, thymectomised +/+, and sham-operated +/+. The amount of activity was reduced in nu/nu as compared to the other groups. Nonetheless, neither the nude mutation nor thymectomy yielded any notable change in the circadian rhythm of activity.

Activity Cycles↗
PubMed1990

Stable circadian mechanisms of toxicity of two platinum analogs (cisplatin and carboplatin) despite repeated dosages in mice.

The toxicities and tissue uptake of cisplatin (CDDP) and carboplatin (CBDCA) vary largely according to the time of injection of a single dose. Repeated dosages may alter the mechanisms involved with such circadian-dependent toxicity. Weekly i.v. injections of CDDP (5 mg/kg) or CBDCA (50 mg/kg) were given over 2 months to 288 male B6D2F1 mice standardized by an alternation of 12 hr of light and 12 hr of darkness at any one of three circadian dosing times (0, 8 or 16 hr after light onset--HALO). Survival; body weight; complete blood cell counts; histologic lesions in kidney, liver, spleen, bone marrow and intestinal tract; platinum concentration in kidney, spleen and colon were determined every 2 weeks throughout treatment. Thrombocytopenia was 10-fold larger following CBDCA as compared with CDDP. Severe bone marrow necrosis was cumulative following CDDP, but reversible following CBDCA. Leukopenia and bone marrow lesions were, respectively, half as severe following the dosing of either drug at 16 HALO compared with 0 or 8 HALO. Cortical tubular necrosis was observed in CDDP-treated mice. It was cumulative and half as extensive after drug dosing at 16 HALO, as compared with 0 or 8 HALO (P less than or equal to .05). Total Pt accumulation in all three tissues was 3- to 4-fold higher following repeated dosages of CDDP as compared with CBDCA. Tissue Pt uptake was halved after CDDP or CBDCA dosing at 16 HALO as compared with 8 HALO (P less than or equal to .01). Dosing either Pt complex at the appropriate time is even more critical if administrations are to be repeated. Mechanisms appear to involve the circadian rhythm-dependent ability of target tissues to take up the drug.

Animals↗
PubMed1989

Circadian rhythm in toxicities and tissue uptake of 1,2-diamminocyclohexane(trans-1)oxalatoplatinum(II) in mice.

Mechanisms involved in the circadian rhythm in murine tolerance for the new platinum analogue, 1,2-diamminocyclohexane(trans-1)oxalatoplatinum(II) (1-OHP) were sought in 404 male C57BL/6 x DBA/2 F1 mice standardized by 12 h light-12 h dark. A potentially lethal dose of 1-OHP (17 mg/kg i.v.) resulted in 76% long-term survival at 15 h after light onset (HALO) (activity span) as compared to 24% after treatment at 7 HALO (rest span) (chi 2 21.3; P less than 0.001). A total of 204 mice received the same dose of 1-OHP at one of three circadian stages (0, 8, or 16 HALO). No renal toxicity was encountered. Bone marrow and jejunal villi constituted the chief targets of 1-OHP toxicity at this dosage and schedule. Hematological tolerance as gauged by leukocyte counts was optimal when the drug was given at 16 HALO (P from analysis of variance, less than 0.001). Jejunal lesions were less severe after 1-OHP dosing at 16 HALO as compared to 8 HALO (P less than 0.001). Total platinum concentrations were determined in 18 tissues 24 h after 1-OHP dosing. The highest levels of platinum were found in the spleen on day 1 as well as on day 5 following 1-OHP treatment. Despite the fact that the highest platinum concentrations in tissues usually corresponded to drug dosing at 8 HALO, no correlation was documented between such variables and tissue toxicity. Tissue pharmacokinetics of 1-OHP contribute only in part if at all to the circadian rhythm in hematological and jejunal toxicity of this drug.

Animals↗
PubMed1989

Control of a murine plasmacytoma with doxorubicin-cisplatin: dependence on circadian stage of treatment.

In anticipation of the development of clinical chronotherapy and in order to pick clinical test times for doxorubicin and cisplatin trials, two large studies were performed on rats bearing a transplanted plasmacytoma. The circadian timing of each of two anticancer drugs given at precisely equal dose intensities was expected to improve therapeutic benefit over conventionally given (time-unqualified) treatment. In each chronotherapeutic study, maximal benefit and minimal toxic effects were found when cisplatin was administered in the middle to latter part of the daily activity (dark) span, while doxorubicin was administered near the end of the daily resting (light) span for these nocturnally active rodents living on a 12-hour-12-hour or 8-hour-16-hour light-dark schedule. This was true whether doxorubicin or cisplatin was given first and whether there was a lag of only a few hours or a few days between the administration of these two agents.

Animals↗
PubMed1989

[The significance of chronopharmacology for oncology].

Many physiological variables in hemato-oncology, e.g. the function of liver and kidney and hematopoiesis, show circadian changes. Consequently, the metabolism, elimination and myelotoxicity of cytostatic drugs are subjected to circadian variations in animal and man. Moreover, preliminary clinical data suggest that an optimal circadian timing may even increase the efficacy of anticancer chemotherapy. The recent development of programmable infusion pumps provided a reliable tool for the application of cytostatic drugs at any time of day. As a consequence, controlled clinical trials on the temporal optimization of anticancer chemotherapy seem now to be necessary and feasible.

Animals↗
PubMed1988

Circadian rhythm-varying plasma concentration of 5-fluorouracil during a five-day continuous venous infusion at a constant rate in cancer patients.

A circadian rhythm in the plasma concentration of 5-fluorouracil (5-FUra) is demonstrated in seven patients receiving this drug as a continuous venous infusion at a constant rate for 5 days. All patients had stage C bladder carcinoma and received cis-diamminedichloroplatinum(II) (45-91 mg/m2) on day 1 as a 30-min venous infusion at 5 p.m. Continuous venous infusion of 5-FUra (450-966 mg/m2/day) was started on day 2 at 8:30 a.m. via a volumetric pump and lasted for 5 days (until day 6). Blood samples were obtained on EDTA every 3 h on days 2, 4, and 6 on each patient (20 samples/patient). 5-FUra plasma concentration was determined by high performance liquid chromatography. Data were analyzed by both multiple analysis of variance and cosinor. Mean lowest and highest values (+/- SEM) were, respectively, 254 +/- 33 ng/ml at 1 p.m. and 584 +/- 160 ng/ml at 1 a.m. (F = 2.3; P less than 0.03). Because of large intersubject differences in 24-h mean plasma concentration, data were also expressed as percentages of each patient's 24-h mean. Both analysis of variance and cosinor analysis further validated (P less than 0.0001) a circadian rhythm with a double amplitude (total extent of variation) of 50% of the 24-h mean and an acrophase located at approximately 1 a.m. (estimated time of peak). Such findings warrant a thorough scrutiny at the chronopharmacology of anticancer drugs when designing continuous infusion schedule. A circadian modulation of the infusion rate of this drug may further optimize the therapeutic index of such treatment modality.

Aged↗
PubMed1988

Alteration of period and amplitude of circadian rhythms in shift workers. With special reference to temperature, right and left hand grip strength.

48 male shift workers in various industries volunteered to document circadian rhythms in sleeping and working, oral temperature, grip strength of both hands, peak expiratory flow and heart rate. All physiological variables were self-measured 4 to 5 times a day for 2 to 4 weeks. Individual time series were analyzed according to several statistical methods (power spectrum, cosinor, chi squares, ANOVA, correlation, etc.) in order to estimate rhythm parameters such as circadian period (tau) and amplitude (A), and to evaluate subgroup differences with regard to tolerance to shift work, age, duration of shift work, speed of rotation and type of industry. The present study confirms for oral temperature and extends to other variables (grip strength of both hands, heart rate) that intolerance to shift work is frequently associated with both internal desynchronization and small circadian amplitude. The internal desynchronization among several circadian rhythms supports the hypothesis that these latter are driven by several oscillators. Many differences were observed between circadian rhythms in right and left hand grip strength: circadian tau in oral temperature was correlated with that in the grip strength of the dominant hand but not with that of the other hand; changes in tau s of the non-dominant hand were age-related but did not correlate with temperature tau; only the circadian A of the non-dominant hand was associated with a desynchronization. Thus, circadian rhythms in oral temperature and dominant hand grip strength may be driven by the same oscillator while that of the non-dominant hand may be governed by a different one. Internal desynchronization between both hand grip rhythms as well as desynchronization of performance rhythms reported by others provide indirect evidence that circadian oscillator(s) may be located in the human cerebral cortex.

Adult↗
PubMed1988

Circadian time dependence of murine tolerance for carboplatin.

A large amplitude circadian rhythm in murine tolerance for the anticancer agent, carboplatin (cyclobutane dicarboxylatoplatinum II, CBDCA) was demonstrated. Two studies were performed in a total of 266 male B6D2F1 mice standardized by LD 12:12. In the first experiment CBDCA (80 mg/kg/day) was administered intravenously (iv) daily for three consecutive days at all six circadian stages (3, 7, 11, 15, 19, or 23 hr after light onset, HALO). CBDCA dosing at 15 HALO resulted in 58% long-term survivors as compared to 0% after treatment at 3 or 23 HALO (chi 2 = 28; p less than 0.001). In the second experiment, CBDCA (72 or 80 mg/kg/day X 3 days, iv) was administered at any of three circadian stages (0, 8, or 16 HALO). Mice were killed, blood was collected, and seven tissues were obtained 5 and 10 days after the first dose, in order to determine serum urea and creatinine concentrations, leukocyte and red blood cell counts, and to evaluate histologic lesions. No renal toxicity was encountered. Bone marrow and colon mucosa were the major target tissues of CBDCA in these dosages and schedules. CBDCA dosing at 16 HALO was least toxic to the bone marrow as assessed by peripheral leukocyte count and histologic score (p from ANOVA less than 0.05). Histologically assessed lesions of the colon mucosa were less severe after CBDCA dosing at 16 HALO as compared to those at 8 HALO, and significantly so for the lowest dosage tested (p approximately 0.05). Uptake of CBDCA 24 hr after the third dose ranged from 23 micrograms/g of dry tissue in the colon to 7 micrograms/g in the duodenum. Mean tissue concentrations increased between Day 4 and Day 10 for the liver and spleen, and remained similar for the kidney. No consistent circadian dependence was found with regard to Day 4 mean Pt uptake in different tissues, whereas the lowest Day 10 Pt concentrations corresponded to CBDCA dosing at 16 HALO for all tissues investigated. Toxicity did not appear to be directly related to the total platinum concentration in these tissues.

Animals↗
PubMed1988

Circadian and seasonal rhythms in murine bone marrow colony-forming cells affect tolerance for the anticancer agent 4'-O-tetrahydropyranyladriamycin (THP).

The proliferative status of both bone marrow myeloid precursor cells (GM-CFUc) and stromal cells from the microenvironment are organized along circadian and circannual time scales in male B6D2F1 mice. Such temporal structure profoundly affects the in vitro susceptibility of myeloid precursors for the anticancer agent, 4'-O-tetrahydropyranyl adriamycin. These results account in part for the large-amplitude circadian rhythms that characterize host tolerance for chemotherapy. They also provide evidence that the time of bone marrow sampling from a donor may influence its engraftment into the recipient.

Animals↗
PubMed1987

Clinical chronopharmacology with special reference to NSAIDs.

Both drug disposition and effects vary as a function of dosing time. A chronotherapeutic study was therefore undertaken with sustained-release indomethacin (ISR) to quantitate any potential therapeutic gain from an optimal time of administration. Four studies were performed on a total of 517 patients with osteoarthritis of the hip or knee. Each patient took the same dose of ISR at 8:00 am for one week, 12:00 noon for one week and 8:00 pm for one week. In addition to conventional evaluation criteria, patients performed self-rating of pain on visual analogue scales. Overall, there were 44 withdrawals (29 associated with morning ingestion). At group level, time-dependent differences in drug effectiveness were small, although large inter-individual differences were documented. Evening ingestion was most effective in patients with predominant nocturnal or morning pain; conversely, morning or noon ingestion was most effective in patients with maximum afternoon or evening pain. A four-fold improvement in tolerance and a doubling of analgesic effectiveness resulted from varying the ingestion time. Chronotherapeutic studies should therefore include careful longitudinal documentation of pertinent marker rhythms such as self-rating of pain.

Animals↗
PubMed1987

[Chronobiology and cancer].

Circadian rhythms characterize murine tolerance for 18 anticancer agents, including radiations and chemotherapeutic drugs. Such rhythms usually exhibit a large amplitude. Moreover, the circadian time of highest host tolerance for several cytostatics was similar to that of their optimal antitumor effectiveness in four different experimental models. Mechanisms of such rhythms involve predictable temporal changes in drug pharmacokinetics as well as rhythms in the susceptibility of both tumor and host tissues. Studies performed in mice or rats led to an adequate prediction of the optimal time to administer adriamycin, 4'tetrahydropyranyl-adriamycin and cis-dichlorodiammine platinum, provided that the rest-activity cycle of either species be considered. Since the dosing time of these agents also influenced largely the extent of human tolerance for these drugs, the extension of circadian timed therapy appears as inescapable. Programmable delivery systems have been developed to render such goal feasible, and their need has been emphasized in preliminary studies. Since interindividual differences may characterize, to some extent, host chronotolerance, and to a larger extent, tumor chronosusceptibility, a circadian monitoring of marker variables ("marker rhythms") constitutes a further challenge for individualizing cancer chronotherapy.

Animals↗
PubMed1986

Ultradian, circadian and circannual rhythms of blood glucose and injected insulins documented in six self-controlled adult diabetics.

The aim of the study was to document during one to two years individual rhythmic patterns in blood glucose and injected insulin in self-controlled insulin dependent (C-peptide negative) diabetics with home blood glucose monitoring. Two females and four males with diurnal activity from 0700 to 2300 self-determined their blood glucose three to six times a day over a period of 12-27 months. Circadian and ultradian rhythms were analysed for each subject on a monthly basis to document annual rhythms. Blood glucose (BG) estimated circadian acrophases were located between 2200 and 0300 for all patients and months with few exceptions. A correlation was found between circadian mesors and amplitudes of BG in four subjects. Annual changes in BG were validated for each subject with large interindividual differences in peak times. The individual mean of injected insulin (II) varied from 40 to 80 iU with annual changes validated for each subject. A group pattern was observed with a peak time either in the autumn (four patients) or in the summer (two patients). A circadian rhythm of II was detected in almost all monthly means and for all patients. Locations of computed peak time phi of II exhibited a great stability for a given individual but large interindividual differences. Thus the rather constant phi location of BG for all subjects contrasted with interindividual differences in phi locations of II. These results suggest that rhythmic changes in BG and II should be recognized when forming a realistic strategy for timing and dosing time(s) of insulin.

Activity Cycles↗
PubMed1986

Interindividual differences in the circadian hematologic time structure of cancer patients.

The complete hematologic blood cell count of 11 patients with advanced cancer were determined on 14 occasions, every 4 hr over 36-48 hr. Oral temperature was also measured at the same times as blood sampling. Five patients had breast cancer, five had ovarian cancer and one a leiomyosarcoma. Circadian rhythms were detected by the cosinor method for seven hematologic variables (red blood cells, hemoglobin, hematocrit, white blood cells, neutrophils, lymphocytes, platelets) and for oral temperature in the whole group of patients. All acrophases were located between 1300 and 1700 hr, except for lymphocytes (2100 hr). A rhythm with a period of 8 hr was validated for lymphocytes and monocytes. Validated or estimated amplitudes and acrophases were closely similar in both breast and ovarian cancer subgroups. Individual cosinor analyses documented large differences from patient to patient, which were accounted for by differences in performance status. Thus, subjects with poor performance status and rapidly progressive disease had very few validated rhythms as compared to those patients with good performance status. As a result a statistically significant correlation was found between the number of validated hematologic circadian rhythms and the performance status (r = -0.88; P less than 0.01).

Adult↗