Use this URL to cite or link to this record in EThOS: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.781881
Title: In vitro and in vivo chronopharmacology of a new generation of an organometallic anticancer drug complex
Author: Abraham, Kristin
ISNI:       0000 0004 7967 4947
Awarding Body: University of Warwick
Current Institution: University of Warwick
Date of Award: 2018
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Abstract:
The research presented in this thesis has highlighted the complementary and consistent links between in vitro and in vivo chronopharmacology findings, as shown for the anticancer drug candidate FY26. The use of 24-hour temperature schedules as an effective synchroniser of circadian clocks in vitro and that of core body temperature rhythm as a circadian biomarker in vivo has enabled the precise determination of the endogenous circadian times of best tolerability. This was achieved, as physiological rhythm had been introduced into cell culture conditions. Should these results be applicable to humans, least FY26 toxicity could occur at night, shortly after the physiological nadir in core body temperature. More generally, the synchronisation of healthy and cancer cells with 24-h periodic temperature schedules mimicking physiological cycles could have a high potential to identify optimal drug timing options and underlying chronopharmacokinetics and chronopharmacodymics mechanisms, whilst reducing and replacing animal experiments, as illustrated here. This could indeed encourage the integration of chronotherapy concepts into drug development strategies. In such context, the objectives of animal chronotherapy studies might hence become mostly confirmatory. Thus, the use of core body temperature circadian cycle appears not only as crucial for the determination of the circadian timing resulting in best drug tolerability, antitumour efficacy, and quality of life, but it is also in agreement with the principles of the 3 R's (reduction, refinement and replacement) and the public ethical opinion on animal experiments.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.781881  DOI: Not available
Keywords: RM Therapeutics. Pharmacology
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