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      Chronopharmacodynamics and Chronopharmacokinetics of Pethidine in Mice

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          Abstract

          Background

          Many studies have demonstrated that the pharmacokinetics and pharmacodynamics of analgesic drugs vary according to the circadian time of drug administration. This study aims at determining whether the analgesic effect and pharmacokinetics of pethidine in male BALB/c mice are influenced by administration time.

          Methods

          A hot-plate test was used to evaluate the analgesic effect after pethidine (20 mg/kg) or saline injection at different dosing times. Mouse blood samples were collected at different intervals after dosing at 9:00 am and 9:00 pm, and were determined via liquid chromatography–tandem mass spectrometry (LC–MS/MS).

          Results

          A significant 24-h rhythm was observed in the latency to thermal response at 30 min after dosing, with the peak during the dark phase and the nadir during the light phase. Tolerance to analgesic effect was produced after chronic pethidine injection at 9:00 am or 9:00 pm, and the recovery from tolerance was faster during the dark phase. The peak concentration (C max) and area under the concentration–time curve (AUC) of pethidine and its metabolite norpethidine were significantly higher during the dark phase than during the light phase, but the total serum clearance (CL/F) exhibited the opposite trend. The rhythm of drug plasma concentration was positively correlated with the analgesic effect.

          Conclusion

          These results suggest that the pharmacodynamics and pharmacokinetics of pethidine in mice vary significantly according to the dosing time, which implies that the time of administration should be considered in the rational clinical use of pethidine to maximise analgesia and minimise the adverse effects.

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          Most cited references35

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          SCN outputs and the hypothalamic balance of life.

          The circadian clock in the suprachiasmatic nucleus (SCN) is composed of thousands of oscillator neurons, each dependent on the cell-autonomous action of a defined set of circadian clock genes. Still, the major question remains how these individual oscillators are organized into a biological clock producing a coherent output able to time all the different daily changes in behavior and physiology. In the present review, the authors discuss the anatomical connections and neurotransmitters used by the SCN to control the daily rhythms in hormone release. The efferent SCN projections mainly target neurons in the medial hypothalamus surrounding the SCN. The activity of these preautonomic and neuroendocrine target neurons is controlled by differentially timed waves of, among others, vasopressin, GABA, and glutamate release from SCN terminals. Together, the data on the SCN control of neuroendocrine rhythms provide clear evidence not only that the SCN consists of phenotypically (i.e., according to neurotransmitter content) different subpopulations of neurons but also that subpopulations should be distinguished (within phenotypically similar groups of neurons) based on the acrophase of their (electrical) activity. Moreover, the specialization of the SCN may go as far as a single body structure, that is, the SCN seems to contain neurons that specifically target the liver, pineal, and adrenal.
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            The mammalian pineal gland: known facts, unknown facets.

            In the mammalian pineal gland, information on environmental lighting conditions that is neuronally encoded by the retina is converted into nocturnally elevated synthesis of the hormone melatonin. Evolutionary pressure has changed the morphology of vertebrate pinealocytes, eliminating direct photoreception and the endogenous clock function. Despite these changes, nocturnally elevated melatonin synthesis has remained a reliable indicator of time throughout evolution. In the photo-insensitive mammalian pineal gland this message of darkness depends on the master circadian pacemaker in the hypothalamic suprachiasmatic nuclei. The dramatic change in vertebrate pinealocytes has received little attention; here, we therefore link the known evolutionary morphodynamics and well-investigated biochemical details responsible for rhythmic synthesis of melatonin with recently characterized patterns of gene expression in the pineal gland. We also address the enigmatic function of clockwork molecules in mammalian pinealocytes.
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              Rhythmic pattern in pain and their chronotherapy.

              Pain control is one of the most important therapeutic priorities; nonetheless, inadequate pain relief remains a significant health care issue. Thus, it is important to determine whether the analgesic effect can be improved by using the chronopharmacological approach. This paper reviews the data on the rhythmic patterns in pain level and their chronotherapy. It underlines the major issues and problems related to the development of chronotherapeutic strategies, and it examines emerging aspects of new drug-delivery systems for achieving such.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2014
                15 July 2014
                : 9
                : 7
                : e102054
                Affiliations
                [1 ]Department of Pharmacy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
                [2 ]Department of Clinical Pharmacy, College of Pharmacology, China Pharmaceutical University, Nanjing, China
                Karlsruhe Institute of Technology, Germany
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: CZ DL. Performed the experiments: CZ ZY XL YX. Analyzed the data: ZY XL. Contributed reagents/materials/analysis tools: XL. Contributed to the writing of the manuscript: CZ ZY DL. Provided experimental instrument: DL.

                Article
                PONE-D-14-11906
                10.1371/journal.pone.0102054
                4098901
                25025283
                5fe9d540-5ab6-4fb0-8cd4-7bfbebedac26
                Copyright @ 2014

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 17 March 2014
                : 13 June 2014
                Page count
                Pages: 6
                Funding
                The authors have no support or funding to report.
                Categories
                Research Article
                Biology and Life Sciences
                Chronobiology
                Neuroscience
                Toxicology
                Medicine and Health Sciences
                Pharmacology
                Research and Analysis Methods
                Chromatographic Techniques
                Custom metadata
                The authors confirm that all data underlying the findings are fully available without restriction. All data are available on request.

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