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Biomedical subjects

F Lévi

Publications and source records attributed to F Lévi.

At least 73 records · Page 4Linked to original sources
PubMed1995

Rhythm alteration in patients with metastatic breast cancer and poor prognostic factors.

Circulating blood cell counts, serum cortisol, proteins, alkaline phosphatase, carcinoembryonic antigen and CA15.3 displayed significant circadian rhythms in a group of 13 women with metastatic breast cancer. Statistical significance (P < 0.05) was assessed with both analysis of variance and cosinor analysis. All patients had been previously treated with chemo-and/or radiotherapy and/or antiestrogens. All patients had been treatment-free for 1 month prior to the study. Each patient had blood drawn every 4 h for 48 h. Circadian rhythms were examined as a function of performance status, graded according to the World Health Organization, liver involvement and number of metastatic sites. Group circadian rhythms in serum cortisol or proteins were abolished in patients with liver metastases, and were altered in cases of poor performance status. Circulating leukocytes, neutrophils or platelets did not exhibit synchronized circadian rhythmicity in patients with poor performance status or liver metastases. The number of metastatic organs had a minor influence on circadian rhythmicity. These results suggest that rhythm alteration may be associated with both poor performance status and liver metastases in patients with advanced breast cancer. Such alteration of the normal circadian time structure may favor and/or result from cancer spread.

Adult↗
PubMed1995

Light-induced suppression of the rat circadian system.

In a constant environment, circadian rhythms persist with slightly altered period lengths. Results of studies with continuous light exposure are less clear, because of short exposure durations and single-variable monitoring. This study sought to characterize properties of the oscillator(s) controlling the rat's circadian system by monitoring both body temperature and locomotor activity. We observed that prolonged exposure of male Sprague-Dawley rats to continuous light (LL) systematically induced complete suppression of body temperature and locomotor activity circadian rhythms and their replacement by ultradian rhythms. This was preceded by a transient loss of coupling between both functions. Continuous darkness (DD) restored circadian synchronization of temperature and activity circadian rhythms within 1 wk. The absence of circadian rhythms in LL coincided with a mean sixfold decrease in plasma melatonin and a marked dampening but no abolition of its circadian rhythmicity. Restoration of temperature and activity circadian rhythms in DD was associated with normalization of melatonin rhythm. These results demonstrated a transient internal desynchronization of two simultaneously monitored functions in the rat and suggested the existence of two or more circadian oscillators. Such a hypothesis was further strengthened by the observation of a circadian rhythm in melatonin, despite complete suppression of body temperature and locomotor activity rhythms. This rat model should be useful for investigating the physiology of the circadian timing system as well as to identify agents and schedules having specific pharmacological actions on this system.

Animals↗
PubMed1995

In vitro chronopharmacology of recombinant mouse IL-3, mouse GM-CSF, and human G-CSF on murine myeloid progenitor cells.

Circadian changes in in vitro pharmacodynamic effects of recombinant mouse interleukin-3 (rmIL-3), rm granulocyte-macrophage colony-stimulating factor (rmGM-CSF), and recombinant human G-CSF (rhG-CSF) were investigated in 418 male B6D2F1 mice. Seven distinct experiments were staggered from July to December 1991. All mice were standardized for 3 weeks with a lighting schedule consisting of 12 hours of light and 12 hours of dark (LD12:12). In each experiment, bone marrow was sampled from separate groups of nine to 10 mice each every 4 hours for 24 hours. Data were analyzed with analysis of variance (ANOVA) and Cosinor. This latter method computes the probability of rhythm detection and its parameters. Femoral myeloid progenitors were quantified using the colony-forming units granulocyte/macrophage (CFU-GM) assay in the presence or absence of recombinant CSFs. For each CSF, the number of colonies is a function of circadian time of bone marrow exposure (ANOVA and Cosinor; p < 0.0001) with the values at peak time being double those found at the trough. Peak CSF efficacy occurred at 3 hours after light onset (HALO, early rest span) irrespective of CSF type or dose. Furthermore, in the absence of any added CSF, the number of clusters varied significantly according to sampling time, with a similar peak at 3 HALO (ANOVA and Cosinor; p < 0.001). Further in vivo chronopharmacologic experiments are needed to assess the relevance of these in vitro rhythms in bone marrow responsiveness to hematopoietic growth factors.

Animals↗
PubMed1995

[Chrono-chemotherapy and dose intensity].

Circadian (about 24 h) changes modulate cellular metabolism and proliferation in healthy tissues. As a result, the extent of toxicity of cancer chemotherapy varies by 50% or more according to dosing time in mice or rats. These experimental data led to test the principle of adapting chemotherapy delivery to circadian rhythms--so-called "chronotherapy"--in cancer patients. Clinical trials first aimed to assess toxicities and maximal tolerated dose of chronotherapy schedules. Programmable-in-time pumps became the indispensable tool for reliably testing this principle in a large enough patient population and without any need for hospitalization. Results from randomized clinical trials have indicated that chronotherapy allowed to increase dose intensity (DI, a secondary criterion in these trials) by 13 to 45% as compared to injecting the drug at another time (doxorubicin, cisplatin) or according to a flat rate (5-fluorouracil, floxuridine, oxaliplatin). A non-randomized trial further suggested this principle would also apply to cytokine delivery (interferon alpha). Two consecutive randomized trials have revealed that chronotherapy-related increase in 5-FU DI was further associated with a 20% increase in response rate of patients with metastatic colorectal cancer to the 3-drug association that was used (5-FU, folinic acid and oxaliplatin). In a subsequent phase II trial 5-FU daily dose and 3-drug treatment frequency were increased in 50 patients with this disease. Such intrapatient dose escalation protocol also disclosed a positive correlation between DI of 5-FU and response. New anticancer drugs should benefit from this approach so that both their clinical safety and patient's quality of life are improved, through ambulatory administration.

Animals↗
PubMed1995

Chronomodulated 5-day infusion of floxuridine and L-folinic acid in patients with advanced malignancies: a feasibility and tolerability study.

The best schedule for administering floxuridine (FUDR) has not yet been established. Duration of infusion, need (and dosage) of leucovorin (folinic acid, FA), and circadian timing need to be further specified. Nevertheless, FUDR delivery according to circadian rhythms has allowed increase of dose intensity without enhancing the side effects. A 5-day infusional schedule combining FUDR and L-FA was devised as an attempt to increase dose intensity and to provide therapy every 3 weeks to patients with advanced cancer. An ambulatory programmable-in-time pump was used for this purpose. Fourteen patients entered this trial. Two dose levels (mg/kg x 5 days) were evaluated: 0.5 mg/kg/day in six patients and 0.525 mg/kg/day in eight patients. Both patient groups received a concurrent infusion of L-FA 10 mg/m2/day i.v. The delivery patterns of both FUDR and L-FA varied sinusoidally during the 24 hours with a maximum at 18.00 hours. Courses were repeated every 3 weeks. Of 35 courses, treatment produced mucosites greater than grade 2 in only two of them. No severe diarrhea, the dose-limiting toxicity of FUDR when infused over 14 days, was encountered at the dose levels tested. This 5-day chronotherapy schedule allowed delivery of a larger amount of FUDR than the flat delivery described in a previous report. A daily dose of 0.525 mg/kg FUDR, combined with 10 mg/mg2 L-FA, with intraindividual dose escalation according to tolerance, is recommended for future investigations of the activity of this chronotherapy schedule.

Adult↗
PubMed1995

A phase I-II trial of five-day continuous intravenous infusion of 5-fluorouracil delivered at circadian rhythm modulated rate in patients with metastatic colorectal cancer.

The toxicity of 5-fluorouracil (5-FU) was decreased by two to eight-fold if this drug was injected in mice near the middle of the day (rest span) rather than in the middle of the night (activity span). If the rhythm in 5-FU toxicity is linked to the sleep-wakefulness endogenous circadian cycle across species, the least toxic time in man would correspond to 4.00 hours at night. The availability of a single-reservoir programmable-in-time external ambulatory pump (Chronopump, Autosyringe, Hooksett, USA) allowed us to perform a first test of this hypothesis. Five-FU was infused for 5 consecutive days, via an implanted venous access port, with peak drug delivery at 4.00 hours and no infusion from 18.00 to 22.00 hours. Each course was repeated after a free interval of 16 days. Intrapatient dose escalation was planned from 4 to 9 g/m2/course (800 to 1800 mg/m2/day x 5 days) if toxicity was less than grade 2 according to the World Health Organization (W.H.O.). Thirty-five patients with metastatic colorectal cancer were treated; 15 (41%) had received previous therapy, 22 (63%) had W.H.O. performance status of 2 or greater, and 19 (54%) had two or more sites involved. Grade 2 or greater toxicity was encountered in less than 5% of the courses, indicating an adequate control of toxicity via dose adjustment. Oral mucositis, diarrhea, and/or hand-foot syndrome limited dose escalation, and their incidence was dose dependent. Median maximal tolerated dose was 7.5 mg/m2/course in 30 patients assessed for this endpoint.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

Circadian changes in mitoxantrone toxicity in mice: relationship with plasma pharmacokinetics.

Circadian time-dependent differences in clinical toxicity of several anti-cancer agents were predicted from murine studies. Mitoxantrone is an anthracenedion (an anthracycline-related class of compounds) of increased clinical use, which may benefit from selective circadian timing. In 3 consecutive studies, a total of 428 male B6D2F1 mice aged from 8 to 10 weeks were synchronized by an alternation of 12 hr of light and 12 hr of darkness (LD 12:12). They received a single i.v. injection of mitoxantrone at one of 6 or 4 circadian stages differing by 4 or 6 hr. A dose-response relationship characterized body-weight loss and survival rate. Dose-toxicity relationship further closely depended upon circadian dosing time. Thus, a dose of 16 mg/kg killed 100% of the mice injected at 3 hr after light onset (HALO), and none of them at 11 or at 15 HALO (p from chi 2 < 0.001). Body-weight loss varied from 41% at 3 HALO to 32% at 15 HALO (p from ANOVA < 0.0001). Least hematologic toxicity and fastest recovery of a normal circulating leukocyte count corresponded to mitoxantrone injection near the middle of the dark-activity span, at 16 HALO. Similar findings characterized colonic and splenic lesions. Moreover, mitoxantrone was both distributed and eliminated faster after injection at 16 HALO. If such data apply to cancer patients, as was the case for other drugs investigated with this methodology, an afternoon infusion should enable high-dose mitoxantrone to be well tolerated.

Analysis of Variance↗
PubMed1994

Comparative pharmacokinetics of oxaliplatin (L-OHP) and carboplatin (CBDCA) in mice with reference to circadian dosing time.

Carboplatin (CBDCA) and oxaliplatin (I-OHP) are non-nephrotoxic platinum (Pt) compounds, which exert their main respective toxicities on the bone marrow and on the intestinal mucosa in mice. Plasma and red blood cell (RBC) drug dispositions were investigated in 324 male B6D2F1 mice after a single IV injection of CBDCA (72 mg kg-1) or I-OHP (17 mg kg-1). Since the toxicities of either drug largely depended upon circadian dosing time, such a pharmacokinetic study was performed following injection of either Pt complex at a time of low (16 h after light onset-HALO), intermediate (0 HALO) or high (8 HALO) toxicity. Pt concentrations in plasma ultrafiltrate (PUF) and in total plasma declined in parallel and became barely detectable by 2 h following CBDCA injection. Conversely, free Pt became undetectable 1 h after I-OHP injection, whereas sustained levels of total Pt were found 24 h post dosing. This suggested that I-OHP had a high binding affinity for plasma proteins. Mean values of t1/2 alpha and mean residence time (MRT) of free Pt for I-OHP (6.7 min and 9.7 min respectively) were half those of CBDCA (12.5 min and 18.1 min respectively). The two drugs had a similar initial volume of distribution (Vdi) of free Pt (10.5 mL) in mice. However, plasma clearance of I-OHP was twice as high (1.06 mL min-1) as that of CBDCA (0.58 mL min-1). Free Pt AUCs were eight to ten times lower for I-OHP than for CBDCA. In contrast, erythrocyte Pt AUCs were three to four times as high for I-OHP as for CBDCA. Circadian changes in pharmacokinetic parameters were large, yet limited to the initial distribution phase (C0, t1/2 alpha, Vdi) as well as mean residence time. The smallest Vdi and the fastest plasma elimination occurred when either drug was injected at 0 HALO. The largest Vdi and the longest elimination were however observed at 8 HALO for CBDCA and 16 HALO for I-OHP. No consistent relationship was found for both Pt complexes with regard to circadian changes in blood pharmacokinetics and in target organ toxicities. The major pharmacokinetics differences between CBDCA and I-OHP were related to both protein binding and RBC handling.

Animals↗
PubMed1994

Spontaneous or imposed circadian changes in plasma concentrations of 5-fluorouracil coadministered with folinic acid and oxaliplatin: relationship with mucosal toxicity in patients with cancer.

Pharmacokinetics of total platinum, 5-fluorouracil, l-folinic and d-folinic acid, and 5-methyltetrahydrofolate were studied in plasma from nine patients with advanced colorectal cancer treated with oxaliplatin (20 mg/m2/day), 5-fluorouracil (600 mg/m2/day), and folinic acid (300 mg/m2/day). Drugs were administered with a programmable-in-time pump by continuous infusion for 5 days. We compared two drug delivery schedules: constant rate versus chronomodulated rate with peak of oxaliplatin at 4 pm and peak of 5-fluorouracil and folinic acid at 4 am. In the chronomodulated schedule, plasma concentrations of the drugs paralleled the pump functioning: maximum platinum concentration near 4 pm, and maximum 5-fluorouracil and folate concentrations near 4 am. When drugs were administered at a constant rate, mean plasma concentration of 5-fluorouracil varied in a circadian manner each treatment day, that is, a peak at 4 am (approximately 800 ng/ml) and a trough at 1 pm (approximately 100 ng/ml). Mean plasma levels of total platinum and folate compounds increased over the first 24 hours. Total platinum mean level and that of the inactive d-folinic acid isomer reached a constant plasma concentration, whereas biologically active folates exhibited circadian variation in their plasma concentrations (peak around 7 am, trough near 6 pm, and amplitude approximately 10%). Severe mucositis was exhibited by all four patients on the flat schedule, but only by one on the chronomodulated schedule (p < 0.008). Individual pharmacokinetic and toxicity data showed that patients with circadian rhythms in 5-fluorouracil concentrations were least sensitive to 5-fluorouracil-related toxicity. Thus amplification or induction of such rhythm in 5-fluorouracil exposure may permit dose escalation.

Adult↗
PubMed1994

Chronotherapy of cancer: biological basis and clinical application.

Chronotherapy-administration of drugs according to biological rhythms-has recently followed a development similar to that of new drugs. Clinical phase I, II and III trials could reliabily be performed thanks to the avialability of specific tools for chronotherapy, e.g. programmable-in-time-pumps. In standardized and selected mice or rats, the toxicity of approximately 30 anticancer agents (anthracylines, Pt complexes, fluoropyrimidines, nitrosoureas, as well as TNF, IL-2 ...) varied 2 to 10 fold according to drug dosing time along the 24 h time scale, as a result of endogenous circadian rhythms. Dosing-time dependent changes in pharmacokinetics or tissue uptake of drug do not suffice to explain 24 hr rhythms in drug pharmacodynamic effects. Thus, cellular rhythms in target tissues, including enzymatic activities, reduced glutathione, cell division cycle, ... appear as the major mechanisms of rhythms in the cytotoxicity of cytostatic compounds. These "peripheral" mechanisms are coordinated or reset by central biological clocks. In cancer patients, the continuous infusion of 5-fluorouracil, adriamycin or vindesine at a constant rate resulted in large 24-hr changes in plasma drug levels. Mechanisms involve circadian changes in drug metabolism (e.g., dehydropyrimidine dehydrogenase for 5-FU), disposition (blood flow) or excretion (urine output). Extrapolation of times of least toxicity from nocturnally-active rodents to diurnally-active patients has been attempted through referring them to the sleep-wakefulness cycle of the considered species. Chronotherapy has allowed to significantly decrease drug toxicity and/or increase dose intensity of adriamycin, fluorouracil, FUdR, oxaliplatin and alpha-interferon.(ABSTRACT TRUNCATED AT 250 WORDS)

Antineoplastic Agents↗
PubMed1993

Chronopharmacology of high-dose busulfan in children.

In bone marrow transplantation, high-dose busulfan is given p.o., usually every 6 h over 4 consecutive days. Since this repeated administration might alter busulfan disposition, fluctuations in busulfan plasma levels were studied over the 4-day treatment period in 21 children (median age, 5 years) with malignant solid tumors. In addition, urinary excretion of unchanged busulfan was measured every 6 h in 4 patients. Busulfan (37.5 mg/m2 for 16 doses) was given on an empty stomach at 12 p.m., 6 p.m., midnight, and 6 a.m. for 4 consecutive days, starting at 12 p.m. Trough plasma levels, i.e., concentration 6 h after each dose and just before the next one, and urinary excretion of busulfan were measured using a gas chromatography-mass spectrometry assay. Busulfan trough plasma levels exhibited a significant circadian rhythm with a higher mean level at 6 a.m. compared to that at 12 p.m., 6 p.m., and midnight. This rhythm was characterized by a double amplitude (mean +/- SD) of 42 +/- 14% and an acrophase (maximum) occurring at 5:48 a.m. +/- 115 min. In addition, once the steady state was reached, no decreasing trend was observed in any patient. Busulfan renal clearance proved to be low since only 5.4 +/- 1.2% of the given dose were excreted unchanged in urine. In the 4 patients studied, busulfan urinary excretion exhibited a significant circadian rhythm which was apparently linked to the physiological circadian rhythm in urinary output. Ten of 20 evaluable patients developed hepatic venoocclusive disease (HVOD). A significant circadian rhythm in the plasma level was found in both HVOD and non-HVOD patients with no difference between the two groups with regard to the 24-h mean, amplitude, or acrophase. Thus, the circadian changes in busulfan trough plasma levels observed at the steady state were not related to the occurrence of HVOD in these children with solid tumors. Moreover, since this rhythm was stable from day 2 to day 4, it should not compromise dose adjustment.

Bone Marrow Transplantation↗
PubMed1993

Circadian rhythm-modulated chemotherapy with high-dose 5-fluorouracil: a pilot study in patients with pancreatic adenocarcinoma.

From November 1986 to April 1989, 16 patients with advanced measurable pancreatic carcinoma were involved in a pilot phase I-II study. 5-Fluorouracil was given every 3 weeks by 5-day continuous chronomodulated venous infusion (CMVI) with peak 5-FU delivery at 4 a.m. Intrapatient dose escalation started at 1200 mg/m2/day up to 1600 mg/m2/day in the absence of grade III (WHO) toxicity. Mucositis and diarrhoea were dose limiting in the 131 cycles given. Three partial responses (21%) and 5 stable diseases were seen in the 14 patients with measurable disease. Dose intensity after three or after six courses (1800 mg/m2/week) was significantly correlated with time to progression (Pearson r = 0.64; P < 0.004). These results, although modest, support a multicentre phase II trial with 5-FU CMVI.

Adenocarcinoma↗
PubMed1992

A chronopharmacologic phase II clinical trial with 5-fluorouracil, folinic acid, and oxaliplatin using an ambulatory multichannel programmable pump. High antitumor effectiveness against metastatic colorectal cancer.

A significant increase in the dose intensity of chemotherapy with fluoropyrimidines and platinum complexes has resulted from selective circadian timing and/or circadian modulation of the infusion rate. The relevance of such chronopharmacologic strategy for improving the outcome of metastatic colorectal cancer was evaluated in an extended Phase II clinical trial involving 93 patients. Of these, 49% previously had received chemotherapy and/or radiation therapy. The drugs 5-fluorouracil (5-FU, 700 mg/m2/d) and folinic acid (FA, 300 mg/m2/d) combined with oxaliplatin (l-OHP, a nonnephrotoxic platinum complex, 25 mg/m2/d) were infused continuously for 5 days every 3 weeks. In a pilot randomized study, the infusion of all three drugs at a constant rate resulted in World Health Organization (WHO) Grade 3 or 4 toxicity in all four patients compared with no such toxicity in four patients if the infusion rate was modulated according to circadian rhythms. In this Phase II trial, drug delivery was modulated sinusoidally over the 24-hour day with peak flow rates at 4 AM for 5-FU and FA and at 4 PM for l-OHP, using an ambulatory programmable-in-time pump. All patients and 784 of 839 courses (93%) were evaluable for toxicity. Dose-limiting toxicities (WHO Grade 2 to 4) included diarrhea (19% of courses) and vomiting (35% of courses). In addition, WHO Grade 2 to 4 hematologic or mucosal toxicity, respectively, occurred in 2.5% and 7% of courses. Two toxic deaths were encountered. Peripheral sensory neuropathy led to discontinuation of l-OHP in 14 patients after 7 to 12 courses; it completely disappeared within 3 months. Fifty-four of the 93 patients had an objective response (58%; 95% confidence limits, 48% to 68%), irrespective of previous treatment or prior documented progression while receiving standard chemotherapy with 5-FU and FA or continuous 5-FU. Complete responses (CR) were seen in 6 patients (4 of which were proved histologically) and, after surgery, in 12 additional patients (overall CR rate, 18 of 93 [19%]; 95% confidence limits, 11% to 27%). Median progression-free survival (PFS) and overall survival were, respectively, 10 and 15 months, irrespective of prior therapy. Both PFS and survival were significantly longer in patients with a good performance status (PS, 0 or 1, by WHO criteria; respectively, 12 and 21 months) than in patients with poor PS (respectively, 8 and 10 months; P less than 0.01, by log-rank test). This chronopharmacologic protocol may have circumvented, to some extent, both the natural and acquired resistance of colorectal cancer to chemotherapy.

Adult↗
PubMed1992

The in vitro effect of metyrapone on steroid synthesis in mice adrenals at different circadian stages.

The circadian rhythm of the in vitro biosynthesis of cortisol and cortisone in mice adrenals has been documented in the absence and presence of 0.1 mumol metyrapone, an inhibitor of steroid 11 beta-monooxygenase. After 3 weeks of synchronization with 12 h light:12 h darkness, adrenalectomy was performed at eight circadian stages: 0, 4, 9, 10, 13, 16, 21, and 22 h after light onset (HALO). Because it has been shown that mice adrenals could convert exogenous 11-deoxycortisol, the synthesis of 11-oxysteroids (cortisol+cortisone) in adrenal homogenates was studied from tritiated precursor. The pattern of steroid synthesis showed a maximum around the end (10 HALO) and a minimum at the beginning of the resting period (0 HALO); the variation was approximately 10%. A similar pattern was observed in the presence of a approximately 50% inhibiting dose of metyrapone. On the other hand, the percent inhibition of 11-oxysteroids synthesis was greater at the beginning of the resting period (0 HALO) and minimum around the end of the activity span (21 HALO), with an overall variation of 20%. However, the variations were statistically insignificant (unpaired t test).

Adrenal Glands↗
PubMed1991

[Is papilloma of the esophagus a preneoplastic lesion? Study of 33 cases].

The etiology of esophagus papilloma is much debated: some authors attach greater importance to irritation factors, while others give preference to the viral hypothesis and suggest that this disease could eventually lead to squamous cell carcinoma of the esophagus. To verify the viral hypothesis, we reviewed the histological slides of the 33 cases of esophageal papilloma diagnosed in our Institute of Pathology between 1973 and 1988. We evaluated the histological diagnosis using Winckler's criteria. HPV typing was done using probes of HPV DNA types 6-11, 16-18, 31-33-35 applied to paraffin sections according to the in-situ hybridization method. Clinical and endoscopic data of 15 cases (from the CHUV) are reviewed. Oncological data was provided by the Vaud Cantonal Tumor Register. No patient in our series fulfilled all the histological criteria set by Winckler to diagnose an HPV condition. Viral DNA 31-33-35 was found in a small minority of the papillomas. The clinical impact of esophageal papilloma on epidermoid carcinogenesis is nil.

DNA Probes, HPV↗
PubMed1991

When should the immune clock be reset? From circadian pharmacodynamics to temporally optimized drug delivery.

Immune defenses are organized along both 24-h and yearly time scales. Two circadian systems have been isolated in man, which can be desynchronized: (1) the circulation of T, B, or NK lymphocyte subsets in peripheral blood and (2) the density of epitope molecules (CD3, CD4, ...) at their surface, which may relate to cell reactivity to antigen exposure. The in vitro response of murine splenocytes to interleukin 2, interferon (IFN), or cyclosporin A strongly depended upon circadian time of exposure. Temporally optimized delivery of biologic response modifiers (BRM) may be guided by immunologic marker rhythms. An alternative yet complementary strategy was sought with IFN: since high doses were shown as more effective than low doses against several malignancies, this drug was given at the presumed less toxic time, so that its dose could be increased. Continuous drug delivery was circadian modulated in 8 cancer patients. Dose intensities twice to fourfold higher than those usually recommended were safely infused to ambulatory patients. Chronotherapy with BRM may represent a necessary step for optimizing the immunologic control of malignancies.

Animals↗