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      Timing of Administration: For Commonly-Prescribed Medicines in Australia

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          Abstract

          Chronotherapy involves the administration of medication in coordination with the body’s circadian rhythms to maximise therapeutic effectiveness and minimise/avoid adverse effects. The aim of this study is to investigate the “time of administration” recommendations on chronotherapy for commonly-prescribed medicines in Australia. This study also aimed to explore the quality of information on the timing of administration presented in drug information sources, such as consumer medicine information (CMI) and approved product information (PI). Databases were searched for original research studies reporting on the impact of “time of administration” of the 30 most commonly-prescribed medicines in Australia for 2014. Further, time of administration recommendations from drug information sources were compared to the evidence from chronotherapy trials. Our search revealed 27 research studies, matching the inclusion and exclusion criteria. In 56% ( n = 15) of the research studies, the therapeutic effect of the medicine varied with the time of administration, i.e., supported chronotherapy. For some medicines (e.g., simvastatin), circadian-based optimal administration time was evident in the information sources. Overall, dedicated studies on the timing of administration of medicines are sparse, and more studies are required. As it stands, information provision to consumers and health professionals about the optimal “time” to take medications lags behind emerging evidence.

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          Prognostic accuracy of day versus night ambulatory blood pressure: a cohort study.

          Few studies have formally compared the predictive value of the blood pressure at night over and beyond the daytime value. We investigated the prognostic significance of the ambulatory blood pressure during night and day and of the night-to-day blood pressure ratio. We did 24-h blood pressure monitoring in 7458 people (mean age 56.8 years [SD 13.9]) enrolled in prospective population studies in Denmark, Belgium, Japan, Sweden, Uruguay, and China. We calculated multivariate-adjusted hazard ratios for daytime and night-time blood pressure and the systolic night-to-day ratio, while adjusting for cohort and cardiovascular risk factors. Median follow-up was 9.6 years (5th to 95th percentile 2.5-13.7). Adjusted for daytime blood pressure, night-time blood pressure predicted total (n=983; p or =0.07). Adjusted for the 24-h blood pressure, night-to-day ratio predicted mortality, but not fatal combined with non-fatal events. Antihypertensive drug treatment removed the significant association between cardiovascular events and the daytime blood pressure. Participants with systolic night-to-day ratio value of 1 or more were older, at higher risk of death, and died at an older age than those whose night-to-day ratio was normal (> or =0.80 to <0.90). In contrast to commonly held views, daytime blood pressure adjusted for night-time blood pressure predicts fatal combined with non-fatal cardiovascular events, except in treated patients, in whom antihypertensive drugs might reduce blood pressure during the day, but not at night. The increased mortality in patients with higher night-time than daytime blood pressure probably indicates reverse causality. Our findings support recording the ambulatory blood pressure during the whole day.
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            Circadian rhythm of glomerular filtration rate in normal individuals.

            1. In a group of 11 normal individuals we measured glomerular filtration rate (GFR) by inulin clearances and effective renal plasma flow (ERPF) by p-aminohippurate clearances during a period of 24 h and a regimen of bedrest, identical food intake per 3 h and normal sleep/wake and light/dark cycles. 2. All subjects had a circadian rhythm for GFR with a maximum of 122 ml/min (SD 22) in the daytime, a minimum of 86 ml/min (SD 12) at night and with a relative amplitude of 33% (SD 15). 3. ERPF had a circadian rhythm with a similar relative amplitude as the GFR rhythm, but with a different phase. Because of this difference in phase, the calculated filtration fraction (GFR/ERPF) followed a circadian rhythm as well. 4. The circadian rhythms of urine volume and sodium excretion were in phase with the GFR rhythm, but the potassium rhythm had a different phase, probably because urinary potassium is largely derived from tubular secretion. 5. Urinary albumin and beta 2-microglobulin excretion had a circadian rhythm in phase with the GFR rhythm. 6. The highest quantity of sodium, water and beta 2-microglobulin was reabsorbed in the daytime; tubular reabsorption, expressed as percentage of the filtered load (fractional reabsorption), had a rhythm with a reversed phase.
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              Chronobiology, drug delivery, and chronotherapeutics.

              Biological processes and functions are organized in space, as a physical anatomy, and time, as a biological time structure. The latter is expressed by short-, intermediate-, and long-period oscillations, i.e., biological rhythms. The circadian (24-h) time structure has been most studied and shows great importance to the practice of medicine and pharmacotherapy of patients. The phase and amplitude of key physiological and biochemical circadian rhythms contribute to the known predictable-in-time patterns in the occurrence of serious and life-threatening medical events, like myocardial infraction and stroke, and the manifestation and severity of symptoms of chronic diseases, like allergic rhinitis, asthma, and arthritis. Moreover, body rhythms can significantly affect responses of patients to diagnostic tests and, most important to the theme of this special issue, medications. Rhythmicity in the pathophysiology of disease is one basis for chronotherapeutics--purposeful variation in time of the concentration of medicines in synchrony with biological rhythm determinants of disease activity--to optimize treatment outcomes. A second basis is the control of undesired effects of medications, especially when the therapeutic range is narrow and the potential for adverse effects high, which is the case for cancer drugs. A third basis is to meet the biological requirements for frequency-modulated drug delivery, which is the case for certain neuroendocrine peptide analogues. Great progress has been realized with hydrogels, and they offer many advantages and opportunities in the design of chronotherapeutic systems for drug delivery via the oral, buccal, nasal, subcutaneous, transdermal, rectal, and vaginal routes. Nonetheless, innovative delivery systems will be necessary to ensure optimal application of chronotherapeutic interventions. Next generation drug-delivery systems must be configurable so they (i) require minimal volitional adherence, (ii) respond to sensitive biomarkers of disease activity that often vary in time as periodic (circadian rhythmic) and non-periodic (random) patterns to release medication to targeted tissue(s) on a real time as needed basis, and (iii) are cost-effective.
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                Author and article information

                Contributors
                Role: Academic Editor
                Journal
                Pharmaceutics
                Pharmaceutics
                pharmaceutics
                Pharmaceutics
                MDPI
                1999-4923
                15 April 2016
                June 2016
                : 8
                : 2
                : 13
                Affiliations
                [1 ]Faculty of Pharmacy, The University of Sydney, Camperdown NSW 2006, Australia; andrew.mclachlan@ 123456sydney.edu.au (A.J.M.); bandana.saini@ 123456sydney.edu.au (B.S.)
                [2 ]Woolcock Institute of Medical Research, University of Sydney, Glebe, NSW 2037, Australia; craig.phillips@ 123456sydney.edu.au (C.L.P.); keith.wong@ 123456sydney.edu.au (K.W.)
                [3 ]Department of Respiratory & Sleep Medicine, Royal North Shore Hospital, Sydney NSW 2065, Australia
                [4 ]Department of Respiratory & Sleep Medicine, Royal Prince Alfred Hospital, Camperdown NSW 2050, Australia
                [5 ]Centre for Education and Research on Ageing, Concord Hospital, Concord, NSW 2137, Australia
                Author notes
                [* ]Correspondence: gaga8947@ 123456uni.sydney.edu.au ; Tel.: +61-2-9351-3645; Fax: +61-2-9351-4391
                Article
                pharmaceutics-08-00013
                10.3390/pharmaceutics8020013
                4932476
                27092523
                f3424163-47a0-4fed-b746-eeba6db54124
                © 2016 by the authors; licensee MDPI, Basel, Switzerland.

                This article is an open access article distributed under the terms and conditions of the Creative Commons by Attribution (CC-BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 20 December 2015
                : 07 April 2016
                Categories
                Review

                chronotherapy,circadian rhythm,medicines,statins,antihypertensives,proton pump inhibitors,timing of drug administration,australia

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