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Francis Lévi - One of the best experts on this subject based on the ideXlab platform.

  • Aspects of clinical Chronopharmacology
    2016
    Co-Authors: Alain Reinberg, Michael H. Smolensky, Francis Lévi
    Abstract:

    CE?M&GH Circadian ( = 24 h), circannual ( = 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 inves-tigates drug effects: (a) as a function of biological timing, and (b) upon parameters charac-terizing the endogenous bioperiodicities. A better understanding of periodic and thus pre-dictable 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 biosystems 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 chrono-pharmacology are corticosteroids and anticancerous agents. 0 Chronoeffectiueness, chron-opharrnacokinetics, chronoptimization, human circadian rhythms

  • Identification of Circadian Determinants of Cancer Chronotherapy through In Vitro Chronopharmacology and Mathematical Modeling
    Molecular cancer therapeutics, 2015
    Co-Authors: Sandrine Dulong, Alper Okyar, Annabelle Ballesta, Francis Lévi
    Abstract:

    Cancer chronotherapy aims at enhancing tolerability and efficacy of anticancer drugs through their delivery according to circadian clocks. However, mouse and patient data show that lifestyle, sex, genetics, drugs, and cancer can modify both host circadian clocks and metabolism pathways dynamics, and thus the optimal timing of drug administration. The mathematical modeling of Chronopharmacology could indeed help moderate optimal timing according to patient-specific determinants. Here, we combine in vitro and in silico methods, in order to characterize the critical molecular pathways that drive the Chronopharmacology of irinotecan, a topoisomerase I inhibitor with complex metabolism and known activity against colorectal cancer. Large transcription rhythms moderated drug bioactivation, detoxification, transport, and target in synchronized colorectal cancer cell cultures. These molecular rhythms translated into statistically significant changes in pharmacokinetics and pharmacodynamics according to in vitro circadian drug timing. The top-up of the multiple coordinated Chronopharmacology pathways resulted in a four-fold difference in irinotecan-induced apoptosis according to drug timing. Irinotecan cytotoxicity was directly linked to clock gene BMAL1 expression: The least apoptosis resulted from drug exposure near BMAL1 mRNA nadir (P < 0.001), whereas clock silencing through siBMAL1 exposure ablated all the Chronopharmacology mechanisms. Mathematical modeling highlighted circadian bioactivation and detoxification as the most critical determinants of irinotecan Chronopharmacology. In vitro-in silico systems Chronopharmacology is a new powerful methodology for identifying the main mechanisms at work in order to optimize circadian drug delivery.

  • Optimization of irinotecan chronotherapy with P-glycoprotein inhibition.
    Toxicology and applied pharmacology, 2013
    Co-Authors: Elisabeth Filipski, Elodie Berland, Narin Ozturk, Catherine Guettier, Gijsbertus T. J. Van Der Horst, Francis Lévi, Alper Okyar
    Abstract:

    The relevance of P-glycoprotein (P-gp) for irinotecan Chronopharmacology was investigated in female B6D2F1 mice. A three-fold 24h change in the mRNA expression of Abcb1b was demonstrated in ileum mucosa, with a maximum at Zeitgeber Time (ZT) 15 (p

  • Docetaxel Chronopharmacology in Mice
    Cancer research, 1998
    Co-Authors: Marco Tampellini, Elisabeth Filipski, Xu Hui Liu, Guy Lemaigre, Patricia Vrignaud, Emmanuel François, Marie Christine Bissery, Francis Lévi
    Abstract:

    Abstract Docetaxel tolerance and antitumor efficacy could be enhanced if drug administration was adapted to circadian rhythms. This hypothesis was investigated in seven experiments involving a total of 626 male B6D2F1 mice, synchronized with an alternation of 12 h of light and 12 h of darkness (12:12), after i.v. administration of docetaxel. In experiment (Exp) 1, the drug was given once a week (wk) for 6 wks (20 mg/kg/wk) or for 5 wks (30 mg/kg/wk) at one of six circadian times, during light when mice were resting [3, 7, or 11 hours after light onset (HALO)], or during darkness, when mice were active (15, 19, or 23 HALO). Endpoints were survival and body weight change. In Exp 2 and 3, docetaxel (30 mg/kg/wk) was administered twice, 1 wk apart, at one of four circadian stages (7, 11, 19, or 23 HALO). Endpoints were hematological and intestinal toxicities. In Exp 4, circadian changes in cell cycle phase distribution and BCL-2 immunofluorescence were investigated in bone marrow as possible mechanisms of docetaxel tolerability rhythm. In Exp 5 to 7, docetaxel was administered to mice bearing measurable P03 pancreatic adenocarcinoma (270–370 mg), with tumor weight and survival as endpoints. Mice from Exp 5 and 6 received a weekly schedule of docetaxel at one of six circadian stages (20 or 30 mg/kg/wk at 3, 7, 11, 15, 19, or 23 HALO). In Exp 7, docetaxel (30 mg/kg) was given every 2 days (day 1, 3, 5 schedule) at 7, 11, 19, or 23 HALO. Docetaxel dosing in the second half of darkness (19 or 23 HALO) resulted in significantly worse toxicity than its administration during the light span (3, 7, or 11 HALO). The survival rate ranged from 56.3% in the mice treated at 23 HALO to 93.8 or 87.5% in those injected at 3 or 11 HALO, respectively (Exp 1, P

  • docetaxel Chronopharmacology in mice
    Cancer Research, 1998
    Co-Authors: Marco Tampellini, Elisabeth Filipski, Xu Hui Liu, Guy Lemaigre, Patricia Vrignaud, Emmanuel François, Marie Christine Bissery, Francis Lévi
    Abstract:

    Docetaxel tolerance and antitumor efficacy could be enhanced if drug administration was adapted to circadian rhythms. This hypothesis was investigated in seven experiments involving a total of 626 male B6D2F1 mice, synchronized with an alternation of 12 h of light and 12 h of darkness (12:12), after i.v. administration of docetaxel. In experiment (Exp) 1, the drug was given once a week (wk) for 6 wks (20 mg/kg/wk) or for 5 wks (30 mg/kg/wk) at one of six circadian times, during light when mice were resting [3, 7, or 11 hours after light onset (HALO)], or during darkness, when mice were active (15, 19, or 23 HALO). Endpoints were survival and body weight change. In Exp 2 and 3, docetaxel (30 mg/kg/wk) was administered twice, 1 wk apart, at one of four circadian stages (7, 11, 19, or 23 HALO). Endpoints were hematological and intestinal toxicities. In Exp 4, circadian changes in cell cycle phase distribution and BCL-2 immunofluorescence were investigated in bone marrow as possible mechanisms of docetaxel tolerability rhythm. In Exp 5 to 7, docetaxel was administered to mice bearing measurable P03 pancreatic adenocarcinoma (270-370 mg), with tumor weight and survival as endpoints. Mice from Exp 5 and 6 received a weekly schedule of docetaxel at one of six circadian stages (20 or 30 mg/kg/wk at 3, 7, 11, 15, 19, or 23 HALO). In Exp 7, docetaxel (30 mg/kg) was given every 2 days (day 1, 3, 5 schedule) at 7, 11, 19, or 23 HALO. Docetaxel dosing in the second half of darkness (19 or 23 HALO) resulted in significantly worse toxicity than its administration during the light span (3, 7, or 11 HALO). The survival rate ranged from 56.3% in the mice treated at 23 HALO to 93.8 or 87.5% in those injected at 3 or 11 HALO, respectively (Exp 1, P < 0.01). Granulocytopenia at nadir was -49 +/- 14% at 7 HALO compared with -84 +/- 3% at 19 HALO (Exp 2 and 3, P < 0.029), and severe jejunal mucosa necrosis occurred in 5 of 8 mice treated at 23 HALO as opposed to 2 of 18 receiving docetaxel at 7, 11, or 19 HALO (Exp 2 and 3, P < 0.02). The time of least docetaxel toxicity corresponded to the circadian nadir in S or G2-M phase and to the circadian maximum in BCL-2 immunofluorescence in bone marrow. Docetaxel increased the median survival of tumor-bearing mice in a dose-dependent manner (controls: 24 days; 20 mg/kg weekly, 33 days; 30 mg/kg weekly or day 1, 3, 5 schedule, 44 or 46 days, respectively; Exp 5-7). Survival curves of treated mice differed significantly according to dosing time for each dose and schedule (P from log rank <0.003 to P < 0.03). In Exp 5 and 6, the percentage of increase in life span was largest if docetaxel was administered weekly at 7 HALO (20 mg/kg, 220%; 30 mg/kg, 372%) and lowest after docetaxel dosing at 19 HALO (80% with 20 mg/kg) or at 15 HALO (78% with 30 mg/kg). In Exp 7, (day 1, 3, 5 schedule), docetaxel was most active at 11 HALO (percentage increase in life span, 390%) and least active at 23 HALO (210%). Docetaxel tolerability and antitumor efficacy were simultaneously enhanced by drug dosing in the light span, when mice were resting. Mechanisms underlying the tolerability rhythm likely involved the circadian organization of cell cycle regulation. Docetaxel therapeutic index may be improved with an administration at night in cancer patients, when fewest bone marrow cells are in S or G2-M phase.

Bjorn Lemmer - One of the best experts on this subject based on the ideXlab platform.

  • Signal Transduction and Chronopharmacology of Regulation of Circadian Cardiovascular Rhythms in Animal Models of Human Hypertension.
    Heart failure clinics, 2017
    Co-Authors: Bjorn Lemmer
    Abstract:

    Inbred strains of rats can be used as models of human hypertension to evaluate mechanisms of regulation of the circadian rhythms underlying hypertension. Blood pressure and heart rate rhythms in rodents are endogenous (circadian). Studies have been performed in rats on the turnover of norepinephrine, on processes of signal transduction in the beta-adrenoceptor-adenylate cyclase-cyclic AMP-phosphodiesterase system and in the renin-angiotensin-aldosterone system, and on circadian rhythms in blood pressure and heart rate using radiotelemetry. The findings allowed a better understanding of the circadian phase-dependent kinetics and effects of cardiovascular active drugs (Chronopharmacology) used in humans.

  • Discoveries of rhythms in human biological functions: a historical review.
    Chronobiology international, 2009
    Co-Authors: Bjorn Lemmer
    Abstract:

    Though there are very early and ancient observations on the daily variation in physiological and pathophysiological functions (e.g., bronchial asthma), more detailed and scientific reports were not published until the beginning of the 17th century. The aim of this review is to bring those reports to the attention of researchers of chronobiology and Chronopharmacology. The ancient books and their contents, which constitute the basis for this review, are part of the personal library collection of the author; numerous observations and reports on biologic rhythms in man are presented here for the first time. The intent of this review is to demonstrate that the fields of chronobiology and Chronopharmacology are not only a new and modern branch of science, but that it stands on the shoulders of wonderful and insightful observations and explanations made by our scientific forefathers. It is the hope that the reader will enjoy the richness of the ancient reports that contribute to our present knowledge achieved t...

  • Chronopharmacology of cardiovascular medications
    Biological Rhythm Research, 2007
    Co-Authors: Bjorn Lemmer
    Abstract:

    The cardiovascular system is well organized in time. Mechanisms of regulation and pathophysiological events are not evenly distributed over the 24-h scale. Moreover, certain diseases may even alter...

  • Chronopharmacology and controlled drug release.
    Expert opinion on drug delivery, 2005
    Co-Authors: Bjorn Lemmer
    Abstract:

    Circadian rhythms in the body are well established and are an important factor to consider when administering drugs. Many diseases display symptoms and onset characteristics that are not randomly distributed within 24 h (e.g., coronary infarction, angina pectoris, asthmatic attacks and peptic ulcer perforations); therefore, it is not surprising that the effects and/or pharmacokinetics of drugs can display significant daily variations. Recent data, primarily concerned with the chronopharmacokinetics of antiasthmatics, histamine H2-blockers and cardiovascular active drugs (e.g., propanolol, organic nitrate and nifedipine) are described as representative examples in this review. The data demonstrate that biological rhythms should have been taken into account when evaluating drug delivery systems, galenic formulations and pharmacokinetics as a basis for drug treatment.

  • cardiovascular chronobiology and Chronopharmacology
    2001
    Co-Authors: Bjorn Lemmer
    Abstract:

    Circadian rhythms in the functions of the cardiovascular system are now well established (for reviews see [1–5]). Biological rhythms in heart rate and blood pressure were already described at the end of the eighteenth and during the nineteenth century by Falconer, Autenrieth, Knox, Wilhelm, Zadek, and others (for references see [4]). Following these early reports, numerous and more sophisticated studies have provided convincing evidence for circadian rhythms in heart rate and in blood pressure in both in healthy subjects and in patients suffering from cardiovascular diseases. The development and use of automatic, 24 h, blood pressure monitoring devices has greatly contributed to our present knowledge about circadian rhythms in the cardiovascular system.

Wang Bo - One of the best experts on this subject based on the ideXlab platform.

Akio Fujimura - One of the best experts on this subject based on the ideXlab platform.

  • Chronopharmacology of morphine in mice.
    Chronobiology international, 2005
    Co-Authors: Yimin Cui, Koh-ichi Sugimoto, Nobutaka Araki, Toshiaki Sudoh, Akio Fujimura
    Abstract:

    Dosing-time-dependent changes in the effect and toxicity of morphine were examined in mice housed under alternating 12 h light (07:00 to 19:00 h) and dark (19:00 to 07:00 h) cycles. Morphine (0.5 mg/kg) was injected intraperitoneally (i.p.) in animals to assess its beneficial effect (i.e., protection against the kaolin-induced, bradykinin-mediated, writhing reaction) and its toxicity (i.e., alteration of the hepatic enzymes of aspartate aminotransferase [AST] alanine aminotransferase [ALT], and glutathione [GSH] in separate experiments). The magnitude of the analgesic effect of morphine depended on dosing time, with minimum effect at 02:00 h and maximum effect at 14:00 h. The serum hepatic enzyme levels of AST and ALT increased after dosing morphine (100 mg/kg) at 02:00 and 14:00 h. Time courses of these enzymes did not differ between the two trials. However, hepatic GSH, which is involved in the detoxification of chemical compounds, significantly decreased after i.p. morphine injection at 02:00 but not at 14:00 h. Overall, the results suggest that the analgesic effect of morphine is greater after dosing during the resting than during the activity phase of mice that have been induced with bradykinin-mediated pain. Drug-induced hepatic damage as inferred by GSH alteration, however, may be greater after dosing during the active phase.

  • Chronopharmacology of oral prednisolone in rats.
    Journal of medicine, 2001
    Co-Authors: N Tomizawa, Akio Fujimura, Hiroo Uchida, D R Xiu, Eiji Kobayashi
    Abstract:

    The Chronopharmacology of oral prednisolone (PSL) was studied in rat models. Differences in the dosing-time-dependent toxicity were evaluated at four time points (3, 9, 15 and 21 HALO) in adult male Wistar rats and confirmed in an inbred strain of Lewis rats (MHC haplotype; RTIl) at two time points (9 and 21 HALO). The total body weight and that of the immunologic-related organs were maximally reduced when PSL was repeatedly administered during the late active phase (21 HALO). This chronotoxicity was independent of plasma concentrations of PSL, adrenocorticotropic hormone, and corticosterone. Repeated administration of PSL prolonged cardiac allograft survival in a DA (RTIa) -to-Lewis combination, and there was a tendency to be more effective in the 21 HALO trial. These results suggested that single dose therapy of PSL at the selected point of the day may be less harmful, protecting against allograft rejection.

  • Chronopharmacology of enalapril in hypertensive patients
    European journal of clinical pharmacology, 1995
    Co-Authors: K. Sunaga, Akio Fujimura, T. Shiga, A. Ebihara
    Abstract:

    The pharmacokinetics and pharmacodynamics of enalapril, an angiotensin converting enzyme inhibitor, are reported to vary with the time of administration. The present study was undertaken to examine whether the effect of enalapril on plasma bradykinin (BK), substance P and prostaglandin E2 (PGE2), which are likely to be involved in the mechanism of enalaprilinduced cough, might also be affected by its time of administration. Enalapril 5 mg or placebo was given orally at 10:00 h (day trial) or 22:00 h (night trial) to 12 patients with essential hypertension. Serum concentrations of total drug (enalapril + enalaprilat, its active metabolite) during the day and night trials did not differ significantly at any time. However, serum enalaprilat tended to be higher and its maximum concentration greater in the day trial than in the night trial. Blood pressure 24 h after administration of enalapril was reduced at 22:00 h, but not at 10:00 h. Plasma BK tended to increase following enalapril administration at 10:00 h, but not at 22:00 h. Remarkable increases in plasma BK were observed in two patients in the day trial and one of them also complained of cough. However, no such increase in plasma BK or subsequent adverse effect were recorded in the night trial. Plasma substance P and PGE2 did not change significantly following enalapril administration either in the day or night trial. The results suggest that the response of BK to enalapril is affected by the time of administration. In patients who complain of cough during treatment with enalapril during the daytime, this adverse effect might be dminished or eliminated by a switch to night-time administration.

  • Chronopharmacology of amlodipine in rats.
    Life sciences, 1993
    Co-Authors: Akio Fujimura, Tsuyoshi Shiga, Kyoichi Ohashi, Akio Ebihara
    Abstract:

    The present study was undertaken to examine whether plasma concentrations of amlodipine, a calcium antagonist, and its diuretic effects vary with the time of dosage. Pharmacokinetic study; 20 mg/kg of amlodipine was given orally to rats at 10 am (day trial) or 10 pm (night trial), and blood samples were obtained during a 24-hour period. Pharmacodynamic study; two doses (10 and 20 mg/kg) of amlodipine were given orally at 10 am or 10 pm by a cross-over design, and urine was collected for 12 hours after dosage. Rats were maintained under condition of light from 7 am to 7 pm. The following results were obtained; The tmax of amlodipine was shorter and the Cmax was greater in the night trial than in the day trial. Its diuretic effects were greater in the night trial. These results suggest that the pharmacokinetic and pharmacodynamic profiles of amlodipine vary with its time of dosage.

  • Chronopharmacology of Furosemide in the Elderly
    Journal of clinical pharmacology, 1992
    Co-Authors: Akio Fujimura, Tsuyoshi Shiga, Kyoichi Ohashi, Hiroshi Ohira, Akio Ebihara
    Abstract:

    The authors have previously reported the time-dependent change in the diuretic effects of Furosemide, a loop diuretic agent, in young and middle-aged subjects. The current study was undertaken to examine an influence of aging on this chronopharmacologic phenomenon. Ten milligrams furosemide was given intravenously to 12 elderly subjects (>70 years of age) at 9:00 am (day trial) or at 9:00 pm (night trial) by a cross-over design. One-hour urine samples were collected for 3 hours after each administration, and urine volume and urinary excretions of sodium and furosemide were determined. Urine volume and urinary sodium excretion increased after furosemide administration. Contrary to the findings in the young and middle-aged subjects, no significant differences were observed in these parameters at any observation period between the day and night trials in the elderly subjects. Urinary furosemide excretion of the day and night trials did not significantly differ. These results suggest that the chronopharmacologic profiles of furosemide are altered in the elderly.

Alper Okyar - One of the best experts on this subject based on the ideXlab platform.

  • Models and Technologies Identification of Circadian Determinants of Cancer Chronotherapy through In Vitro Chronopharmacology and Mathematical Modeling
    2016
    Co-Authors: Rine Dulong, Annabelle Ballesta, Alper Okyar
    Abstract:

    Cancer chronotherapy aims at enhancing tolerability and efficacy of anticancer drugs through their delivery according to circadian clocks. However, mouse and patient data show that lifestyle, sex, genetics, drugs, and cancer can modify both host circadian clocks and metabolism pathways dynamics, and thus the optimal timing of drug administration. The mathemati-cal modeling of Chronopharmacology could indeed help mod-erate optimal timing according to patient-specific determinants. Here, we combine in vitro and in silico methods, in order to characterize the critical molecular pathways that drive the Chronopharmacology of irinotecan, a topoisomerase I inhibitor with complexmetabolism and known activity against colorectal cancer. Large transcription rhythms moderated drug bioactiva-tion, detoxification, transport, and target in synchronized colo-rectal cancer cell cultures. These molecular rhythms translated into statistically significant changes in pharmacokinetics and pharmacodynamics according to in vitro circadian drug timing. The top-up of the multiple coordinated Chronopharmacology pathways resulted in a four-fold difference in irinotecan-induced apoptosis according to drug timing. Irinotecan cyto-toxicity was directly linked to clock gene BMAL1 expression: The least apoptosis resulted from drug exposure near BMAL1mRNA nadir (P < 0.001), whereas clock silencing through siBMAL1 exposure ablated all the Chronopharmacology mechanisms. Mathematical modeling highlighted circadian bioactivation and detoxification as the most critical determinants of irinote-can Chronopharmacology. In vitro–in silico systems chronophar-macology is a new powerful methodology for identifying the main mechanisms at work in order to optimize circadian drug delivery. Mol Cancer Ther; 14(9); 1–11. 2015 AACR

  • Identification of Circadian Determinants of Cancer Chronotherapy through In Vitro Chronopharmacology and Mathematical Modeling
    Molecular cancer therapeutics, 2015
    Co-Authors: Sandrine Dulong, Alper Okyar, Annabelle Ballesta, Francis Lévi
    Abstract:

    Cancer chronotherapy aims at enhancing tolerability and efficacy of anticancer drugs through their delivery according to circadian clocks. However, mouse and patient data show that lifestyle, sex, genetics, drugs, and cancer can modify both host circadian clocks and metabolism pathways dynamics, and thus the optimal timing of drug administration. The mathematical modeling of Chronopharmacology could indeed help moderate optimal timing according to patient-specific determinants. Here, we combine in vitro and in silico methods, in order to characterize the critical molecular pathways that drive the Chronopharmacology of irinotecan, a topoisomerase I inhibitor with complex metabolism and known activity against colorectal cancer. Large transcription rhythms moderated drug bioactivation, detoxification, transport, and target in synchronized colorectal cancer cell cultures. These molecular rhythms translated into statistically significant changes in pharmacokinetics and pharmacodynamics according to in vitro circadian drug timing. The top-up of the multiple coordinated Chronopharmacology pathways resulted in a four-fold difference in irinotecan-induced apoptosis according to drug timing. Irinotecan cytotoxicity was directly linked to clock gene BMAL1 expression: The least apoptosis resulted from drug exposure near BMAL1 mRNA nadir (P < 0.001), whereas clock silencing through siBMAL1 exposure ablated all the Chronopharmacology mechanisms. Mathematical modeling highlighted circadian bioactivation and detoxification as the most critical determinants of irinotecan Chronopharmacology. In vitro-in silico systems Chronopharmacology is a new powerful methodology for identifying the main mechanisms at work in order to optimize circadian drug delivery.

  • Optimization of irinotecan chronotherapy with P-glycoprotein inhibition.
    Toxicology and applied pharmacology, 2013
    Co-Authors: Elisabeth Filipski, Elodie Berland, Narin Ozturk, Catherine Guettier, Gijsbertus T. J. Van Der Horst, Francis Lévi, Alper Okyar
    Abstract:

    The relevance of P-glycoprotein (P-gp) for irinotecan Chronopharmacology was investigated in female B6D2F1 mice. A three-fold 24h change in the mRNA expression of Abcb1b was demonstrated in ileum mucosa, with a maximum at Zeitgeber Time (ZT) 15 (p