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17 pages, 3346 KiB

Open AccessArticle

Sex and Circadian Timing Modulate Oxaliplatin Hematological and Hematopoietic Toxicities

by Sandrine Dulong, Lucas Eduardo Botelho de Souza, Jean Machowiak, Benoit Peuteman, Gaelle Duvallet, Déborah Boyenval, Elise Roth, Afag Asgarova, Yunhua Chang, Xiao-Mei Li, Adlen Foudi and Annabelle Ballesta

Pharmaceutics 2022, 14(11), 2465; https://doi.org/10.3390/pharmaceutics14112465 - 15 Nov 2022

Cited by 4 | Viewed by 1697

Abstract

Oxaliplatin was nearly twice as hematotoxic, with optimal circadian timing differing by 6 h, in women as compared to men with colorectal cancers. Hence, we investigated sex- and timing-related determinants of oxaliplatin hematopoietic toxicities in mice. Body-weight loss (BWL), blood cell counts, bone [...] Read more.

Oxaliplatin was nearly twice as hematotoxic, with optimal circadian timing differing by 6 h, in women as compared to men with colorectal cancers. Hence, we investigated sex- and timing-related determinants of oxaliplatin hematopoietic toxicities in mice. Body-weight loss (BWL), blood cell counts, bone marrow cellularity (BMC) and seven flow-cytometry-monitored hematopoietic progenitor populations were evaluated 72 h after oxaliplatin chronotherapy administration (5 mg/kg). In control animals, circadian rhythms of circulating white blood cells showed a peak at ZT5 in both sexes, whereas BMC was maximum at ZT20 in males and ZT13h40 in females. All BM progenitor counts presented robust rhythms with phases around ZT3h30 in females, whereas only three of them rhythmically cycled in males with a ≈ −6 h phase shift. In treated females, chronotoxicity rhythms occurred in BWL, WBC, BMC and all BM progenitors with the best timing at ZT15, ZT21, ZT15h15 and ZT14h45, respectively. In males, almost no endpoints showed circadian rhythms, BWL and WBC toxicity being minimal, albeit with a substantial drop in BM progenitors. Increasing dose (10 mg/kg) in males induced circadian rhythms in BWL and WBC but not in BM endpoints. Our results suggest complex and sex-specific clock-controlled regulation of the hematopoietic system and its response to oxaliplatin. Full article

(This article belongs to the Special Issue Chronotherapy and Chronomodulated Drug Delivery)

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10 pages, 1204 KiB

Open AccessArticle

Biphasic Drug Release from Rolled-Up Gelatin Capsules with a Cylindrical Cavity

by Jihane Mzoughi, Thierry Vandamme and Valeriy Luchnikov

Pharmaceutics 2021, 13(12), 2040; https://doi.org/10.3390/pharmaceutics13122040 - 29 Nov 2021

Cited by 5 | Viewed by 2408

Abstract

Biphasic drug delivery systems are used for quick release of a specific amount of drug for immediate amelioration of a patient’s state, followed by sustained release, to avoid repeated administration. This type of delivery is often necessary for pain management and the treatment [...] Read more.

Biphasic drug delivery systems are used for quick release of a specific amount of drug for immediate amelioration of a patient’s state, followed by sustained release, to avoid repeated administration. This type of delivery is often necessary for pain management and the treatment of many pathologies, such as migraines, hypertension, and insomnia. In this work, we propose a novel architecture of a biphasic release media that does not need the rapidly disintegrating layer and that allows for easily setting the sustained release rate. A drug-containing capsule is made by rolling up a thermally crosslinked gelatin strip on which drug reservoirs are formed by casting. The quick-release reservoir (QRR) is placed at the strip’s extremity, from which the rolling starts, while the sustained-release reservoir (SRR) is formed in the middle part of the strip. The strip is rolled around a cylinder that is a few millimeters wide, which is removed after rolling. The roll is stabilized by transglutaminase-catalyzed crosslinking of the consecutive shells. A biphasic release is successfully demonstrated with the use of model fluorescent drugs for single-dye and double-dye systems in phosphate-buffered saline (PBS) solution with pH = 7.4. In vitro, the drug from the QRR, placed at the walls of the cavity of the roll, is released immediately upon the capsule’s contact with the PBS solution. The drug from the SRR, embedded between the roll’s layers, diffuses steadily, with the lag time defined by the radial position of the reservoir. Full article

(This article belongs to the Special Issue Chronotherapy and Chronomodulated Drug Delivery)

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19 pages, 1597 KiB

Open AccessArticle

Timing of Novel Drug 1A-116 to Circadian Rhythms Improves Therapeutic Effects against Glioblastoma

by Laura Lucía Trebucq, Georgina Alexandra Cardama, Pablo Lorenzano Menna, Diego Andrés Golombek, Juan José Chiesa and Luciano Marpegan

Pharmaceutics 2021, 13(7), 1091; https://doi.org/10.3390/pharmaceutics13071091 - 16 Jul 2021

Cited by 13 | Viewed by 2902

Abstract

The Ras homologous family of small guanosine triphosphate-binding enzymes (GTPases) is critical for cell migration and proliferation. The novel drug 1A-116 blocks the interaction site of the Ras-related C3 botulinum toxin substrate 1 (RAC1) GTPase with some of its guanine exchange factors (GEFs), [...] Read more.

The Ras homologous family of small guanosine triphosphate-binding enzymes (GTPases) is critical for cell migration and proliferation. The novel drug 1A-116 blocks the interaction site of the Ras-related C3 botulinum toxin substrate 1 (RAC1) GTPase with some of its guanine exchange factors (GEFs), such as T-cell lymphoma invasion and metastasis 1 (TIAM1), inhibiting cell motility and proliferation. Knowledge of circadian regulation of targets can improve chemotherapy in glioblastoma. Thus, circadian regulation in the efficacy of 1A-116 was studied in LN229 human glioblastoma cells and tumor-bearing nude mice. Methods. Wild-type LN229 and BMAL1-deficient (i.e., lacking a functional circadian clock) LN229E1 cells were assessed for rhythms in TIAM1, BMAL1, and period circadian protein homolog 1 (PER1), as well as Tiam1, Bmal1, and Rac1 mRNA levels. The effects of 1A-116 on proliferation, apoptosis, and migration were then assessed upon applying the drug at different circadian times. Finally, 1A-116 was administered to tumor-bearing mice at two different circadian times. Results. In LN229 cells, circadian oscillations were found for BMAL1, PER1, and TIAM1 (mRNA and protein), and for the effects of 1A-116 on proliferation, apoptosis, and migration, which were abolished in LN229E1 cells. Increased survival time was observed in tumor-bearing mice when treated with 1A-116 at the end of the light period (zeitgeber time 12, ZT12) compared either to animals treated at the beginning (ZT3) or with vehicle. Conclusions. These results unveil the circadian modulation in the efficacy of 1A-116, likely through RAC1 pathway rhythmicity, suggesting that a chronopharmacological approach is a feasible strategy to improve glioblastoma treatment. Full article

(This article belongs to the Special Issue Chronotherapy and Chronomodulated Drug Delivery)

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19 pages, 4885 KiB

Open AccessArticle

Modelling Hydrocortisone Pharmacokinetics on a Subcutaneous Pulsatile Infusion Replacement Strategy in Patients with Adrenocortical Insufficiency

by Ioannis G. Violaris, Konstantinos Kalafatakis, Eder Zavala, Ioannis G. Tsoulos, Theodoros Lampros, Stafford L. Lightman, Markos G. Tsipouras, Nikolaos Giannakeas, Alexandros Tzallas and Georgina M. Russell

Pharmaceutics 2021, 13(6), 769; https://doi.org/10.3390/pharmaceutics13060769 - 21 May 2021

Cited by 2 | Viewed by 2886

Abstract

In the context of glucocorticoid (GC) therapeutics, recent studies have utilised a subcutaneous hydrocortisone (HC) infusion pump programmed to deliver multiple HC pulses throughout the day, with the purpose of restoring normal circadian and ultradian GC rhythmicity. A key challenge for the advancement [...] Read more.

In the context of glucocorticoid (GC) therapeutics, recent studies have utilised a subcutaneous hydrocortisone (HC) infusion pump programmed to deliver multiple HC pulses throughout the day, with the purpose of restoring normal circadian and ultradian GC rhythmicity. A key challenge for the advancement of novel HC replacement therapies is the calibration of infusion pumps against cortisol levels measured in blood. However, repeated blood sampling sessions are enormously labour-intensive for both examiners and examinees. These sessions also have a cost, are time consuming and are occasionally unfeasible. To address this, we developed a pharmacokinetic model approximating the values of plasma cortisol levels at any point of the day from a limited number of plasma cortisol measurements. The model was validated using the plasma cortisol profiles of 9 subjects with disrupted endogenous GC synthetic capacity. The model accurately predicted plasma cortisol levels (mean absolute percentage error of 14%) when only four plasma cortisol measurements were provided. Although our model did not predict GC dynamics when HC was administered in a way other than subcutaneously or in individuals whose endogenous capacity to produce GCs is intact, it was found to successfully be used to support clinical trials (or practice) involving subcutaneous HC delivery in patients with reduced endogenous capacity to synthesize GCs. Full article

(This article belongs to the Special Issue Chronotherapy and Chronomodulated Drug Delivery)

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Review

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16 pages, 1399 KiB

Open AccessReview

An Overview of the Circadian Clock in the Frame of Chronotherapy: From Bench to Bedside

by Alan Vandenberghe, Marc Lefranc and Alessandro Furlan

Pharmaceutics 2022, 14(7), 1424; https://doi.org/10.3390/pharmaceutics14071424 - 06 Jul 2022

Cited by 5 | Viewed by 3348

Abstract

Most living organisms in both the plant and animal kingdoms have evolved processes to stay in tune with the alternation of day and night, and to optimize their physiology as a function of light supply. In mammals, a circadian clock relying on feedback [...] Read more.

Most living organisms in both the plant and animal kingdoms have evolved processes to stay in tune with the alternation of day and night, and to optimize their physiology as a function of light supply. In mammals, a circadian clock relying on feedback loops between key transcription factors will thus control the temporally regulated pattern of expression of most genes. Modern ways of life have highly altered the synchronization of human activities with their circadian clocks. This review discusses the links between an altered circadian clock and the rise of pathologies. We then sum up the proofs of concept advocating for the integration of circadian clock considerations in chronotherapy for health care, medicine, and pharmacotherapy. Finally, we discuss the current challenges that circadian biology must face and the tools to address them. Full article

(This article belongs to the Special Issue Chronotherapy and Chronomodulated Drug Delivery)

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21 pages, 1746 KiB

Open AccessReview

Recent Advances in Chronotherapy Targeting Respiratory Diseases

by Keshav Raj Paudel, Saurav Kumar Jha, Venkata Sita Rama Raju Allam, Parteek Prasher, Piyush Kumar Gupta, Rahul Bhattacharjee, Niraj Kumar Jha, Sukriti Vishwas, Sachin K. Singh, Jesus Shrestha, Mohammad Imran, Nisha Panth, Dinesh Kumar Chellappan, Majid Ebrahimi Warkiani, Philip M. Hansbro and Kamal Dua

Pharmaceutics 2021, 13(12), 2008; https://doi.org/10.3390/pharmaceutics13122008 - 25 Nov 2021

Cited by 17 | Viewed by 5231

Abstract

Respiratory diseases contribute to a significant percentage of mortality and morbidity worldwide. The circadian rhythm is a natural biological process where our bodily functions align with the 24 h oscillation (sleep–wake cycle) process and are controlled by the circadian clock protein/gene. Disruption of [...] Read more.

Respiratory diseases contribute to a significant percentage of mortality and morbidity worldwide. The circadian rhythm is a natural biological process where our bodily functions align with the 24 h oscillation (sleep–wake cycle) process and are controlled by the circadian clock protein/gene. Disruption of the circadian rhythm could alter normal lung function. Chronotherapy is a type of therapy provided at specific time intervals based on an individual’s circadian rhythm. This would allow the drug to show optimum action, and thereby modulate its pharmacokinetics to lessen unwanted or unintended effects. In this review, we deliberated on the recent advances employed in chrono-targeted therapeutics for chronic respiratory diseases. Full article

(This article belongs to the Special Issue Chronotherapy and Chronomodulated Drug Delivery)

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34 pages, 1947 KiB

Open AccessReview

Antidepressants and Circadian Rhythm: Exploring Their Bidirectional Interaction for the Treatment of Depression

by Soraia Silva, Joana Bicker, Amílcar Falcão and Ana Fortuna

Pharmaceutics 2021, 13(11), 1975; https://doi.org/10.3390/pharmaceutics13111975 - 21 Nov 2021

Cited by 13 | Viewed by 5803

Abstract

Scientific evidence that circadian rhythms affect pharmacokinetics and pharmacodynamics has highlighted the importance of drug dosing-time. Circadian oscillations alter drug absorption, distribution, metabolism, and excretion (ADME) as well as intracellular signaling systems, target molecules (e.g., receptors, transporters, and enzymes), and gene transcription. Although [...] Read more.

Scientific evidence that circadian rhythms affect pharmacokinetics and pharmacodynamics has highlighted the importance of drug dosing-time. Circadian oscillations alter drug absorption, distribution, metabolism, and excretion (ADME) as well as intracellular signaling systems, target molecules (e.g., receptors, transporters, and enzymes), and gene transcription. Although several antidepressant drugs are clinically available, less than 50% of depressed patients respond to first-line pharmacological treatments. Chronotherapeutic approaches to enhance the effectiveness of antidepressants are not completely known. Even so, experimental results found until this day suggest a positive influence of drug dosing-time on the efficacy of depression therapy. On the other hand, antidepressants have also demonstrated to modulate circadian rhythmicity and sleep–wake cycles. This review aims to evidence the potential of chronotherapy to improve the efficacy and/or safety of antidepressants. It includes pre-clinical and clinical studies that demonstrate the relevance of determining the most appropriate time of administration for antidepressant drugs. In parallel, their positive influence on the resynchronization of disrupted circadian rhythms is also herein discussed. It is expected that this review will promote the investigation of chronotherapy for the treatment of depression, contribute to a better understanding of the relationship between antidepressants and circadian rhythms, and consequently promote the development of new therapeutics. Full article

(This article belongs to the Special Issue Chronotherapy and Chronomodulated Drug Delivery)

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13 pages, 322 KiB

Open AccessReview

Chronobiology and Chronotherapy in Inflammatory Joint Diseases

by Francesco Ursini, Alfredo De Giorgi, Martina D’Onghia, Roberto De Giorgio, Fabio Fabbian and Roberto Manfredini

Pharmaceutics 2021, 13(11), 1832; https://doi.org/10.3390/pharmaceutics13111832 - 02 Nov 2021

Cited by 12 | Viewed by 2875

Abstract

Circadian rhythm perturbations can impact the evolution of different conditions, including autoimmune diseases. This narrative review summarizes the current understanding of circadian biology in inflammatory joint diseases and discusses the potential application of chronotherapy. Proinflammatory cytokines are key players in the development and [...] Read more.

Circadian rhythm perturbations can impact the evolution of different conditions, including autoimmune diseases. This narrative review summarizes the current understanding of circadian biology in inflammatory joint diseases and discusses the potential application of chronotherapy. Proinflammatory cytokines are key players in the development and progression of rheumatoid arthritis (RA), regulating cell survival/apoptosis, differentiation, and proliferation. The production and secretion of inflammatory cytokines show a dependence on the human day–night cycle, resulting in changing cytokine plasma levels over 24 h. Moreover, beyond the circadian rhythm of cytokine secretion, disturbances in timekeeping mechanisms have been proposed in RA. Taking into consideration chronotherapy concepts, modified-release (MR) prednisone tablets have been introduced to counteract the negative effects of night-time peaks of proinflammatory cytokines. Low-dose MR prednisone seems to be able to improve the course of RA, reduce morning stiffness and morning serum levels of IL-6, and induce significant clinical benefits. Additionally, methotrexate (MTX) chronotherapy has been reported to be associated with a significant improvement in RA activity score. Similar effects have been described for polymyalgia rheumatica and gout, although the available literature is still limited. Growing knowledge of chronobiology applied to inflammatory joint diseases could stimulate the development of new drug strategies to treat patients in accordance with biological rhythms and minimize side effects. Full article

(This article belongs to the Special Issue Chronotherapy and Chronomodulated Drug Delivery)

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