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Development of cryptotanshinone-loaded pellets for angina chronotherapy:In vitro/in vivo prediction and evaluation

Asian Journal of Pharmaceutical Sciences 2018年第4期13卷 310-316页

作者： Zhenghua Li Shuangshuang Zhang Hongxiang Yan Jianping Liu Department of Pharmaceutics China Pharmaceutical University

The clinical manifestations of variant angina is unevenly distributed during the 24 h, thusthe in vivo performance of drugs should be tailored according to the angina circadianrhythm. Cryptotanshinone(CTN) is one of the representative bioactive lipid-soluble com-ponents of Danshen which has been commonly used for cardiovascular diseases such asangina pectoris. The aim of this study was to develop a novel CTN sustained-released pel-lets(CTN-SRPs) to precisely synchronize the CTN plasma concentrations with predictedoccurrence of angina pectoris for angina chronotherapy. A deconvolution-based methodwas applied to develop and optimize the CTN-SRPs. The plasma concentration-time curveof CTN immediate-released formulation after oral administration in rats was used as theweight function. The predicted plasma concentration-time curve of CTN-SRPs simulatedaccording to the incidence of variant angina during 24 h was used as the response func-tion. Then the desired drug release profile of CTN-SRPs was calculated based on deconvo-lution using weight function and response function, and subsequently used for guiding theformulation optimization. CTN-SRPs were prepared with the combinations of PVP, polox-amer 127 and EC as matrix using fluidized bed technology. An orthogonal design was em-ployed to obtain the optimal formulation with its release profile similar with the desiredone. Pharmacokinetic studies validated that the actual plasma concentration-time curve ofthese optimized CTN-SRPs was similar with the predicted one. In addition, the percent er-rors(%PE) of CTN plasma concentrations in 8–12 h were less than 10%. In conclusion, thisdeconvolution-based method could be applied to adjust the in vivo performance of drugs forangina chronotherapy.

关键词： chronotherapy Deconvolution Angina pectoris Cryptotanshinone In vitro/in vivo performance Control release

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Effects of chronotherapy of Benazepril on the Diurnal Profile of RAAS and Clock Genes in the Kidney of 5/6 Nephrectomy Rats

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Journal of Huazhong University of Science and Technology(Medical Sciences) 2013年第3期33卷 368-374页

作者：黄小妹袁静萍曾星若彭彩霞梅啓慧陈文莉 Department of Nephrology Wuhan Central Hospital Department of Pathology Wuhan Central Hospital Department of Science and Education Wuhan Central Hospital

Summary： This study investigated the effects of benazepril administered in the morning or evening on the diurnal variation of renin-angiotensin-aldosterone system （RAAS） and clock genes in the kidney. The male Wistar rat models of 5/6 subtotal nephrectomy （STNx） were established. Animals were ran- domly divided into 4 groups： sham STNx group （control）, STNx group, morning benazepril group （MB） and evening benazepril group （EB）. Benazepril was intragastfically administered at a dose of 10 mg/kg/day at 07：00 and 19：00 in the MB group and EB group respectively for 12 weeks. All the animals were synchronized to the light：dark cycle of 12：12 for 12 weeks. Systolic blood pressure （SBP）, 24-h urinary protein excretion and renal function were measured at 11 weeks. Blood samples and kidneys were collected every 4 h throughout a day to detect the expression pattern of renin activity （RA）, angio- tensin Ⅱ （Ang Ⅱ ） and aldosterone （Aid） by radioimmunoassay （RIA） and the mRNA expression profile of clock genes （bmall, dbp and per2） by real-time PCR at 12 weeks. Our results showed that no signifi- cant differences were noted in the SBP, 24-h urine protein excretion and renal function between the MB and EB groups. There were no significant differences in average Aid and RA content of a day between the MB group and EB group. The expression peak of bmall mRNA was phase-delayed by 4 to 8 h, and the diurnal variation of per2 and dbp mRNA diminished in the MB and EB groups compared with the control and STNx groups. It was concluded when the similar SBP reduction, RAAS inhibition and clock gene profile were achieved with optimal dose of benazepril, morning versus evening dosing of benazepril has the same renoprotection effects.

关键词： chronotherapy benazepril RAAS circadian clock genes 5/6 subtotal nephrectomy

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A New Approach: chronotherapy in Acute Blood Purification for Septic Shock

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Journal of Biosciences and Medicines 2017年第7期5卷 32-36页

作者： Masafumi Yamato Yusuke Minematsu Department of Nephrology Osaka National Hospital Osaka Japan Department of Clinical Engineering Osaka National Hospital Osaka Japan

Circadian rhythms are daily oscillations of multiple biological processes. Recently, relationships between circadian rhythms and immune functions have also been described. In a mouse sepsis model, the death rate due to lipopolysaccharide (LPS)-induced endotoxic shock was found to be dependent on LPS administration as determined by circadian time. In humans, a pronounced inflammatory response to endotoxemia differs depending on whether it is daytime or night-time: Levels of tumor necrosis factor-alpha and interleukin-6 were higher during the night. Therefore, it is reasonable to assume that circadian rhythms influence not only organ dysfunction and the prognosis induced by LPS, but also the therapeutic effect of anti-LPS therapy such as Polymyxin-B direct hemoperfusion. We herein postulate the concept that it is important to discuss septic shock treatment in terms of whether or not the treatment is adjusted for the optimal time window as determined by circadian rhythms.

关键词： chronotherapy PMX-DHP Septic Shock

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Investigation of drug administration times in conventional intestinal cancer therapy and chronotherapy review

Investigation of drug administration times in conventional i...

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2016年广东省药师周大会

作者： Shu Liu Rongxin Chen Tao Liu Xiaoquan Lin Xiaohua Zeng Chuanzhong Lin Hongbing Huang Sun Yat-sen University Cancer Center State Key Laboratory of Oncology in South ChinaCollaborative Innovation Center for Cancer Medicine State Key Laboratory of Ophthalmology Zhongshan Ophthalmic CenterSun Yat-sen University

Object Studies in mice and humans have suggested that chemotherapy may be more effective and less toxic when administered at carefully selected times,but this management of administration has been long overlooked in hospital *** The aim of this study was to investigate the difference between the actual drug administration time in hospitalized cancer patients and the optimal time according to *** reviewed the clinical outcomes and drug delivery schedules of chronotherapy for intestinal cancer and then retrospectively analyzed data on the time of treatment for patients hospitalized for one month at Sun Yat-sen University Cancer Center,the largest integrated cancer center in southern *** The percentage of the medication orders inputted the day before treatment were 57.5%,but the targeted admixture times directed by physicians were concentrated in the *** courses of antineoplastic agents were admixed via the hospital pharmacy intravenous admixture service from 07:30 to 12:00,and most(87.18%) courses of drugs were started to be administrated between 10:00 and 17:*** for a small percentage of oxaliplatin,any drugs were started to be administrated close to the optimal *** habitual duration of drug infusion also differed greatly from thereported optimal *** The treating physicians and other health care personnel did not give adequate importance to the time of drug *** studies demonstrating the benefits of chronotherapy and definite time of administration are *** study provides data to support future studies of chronotherapy as well as practical advice for physicians and pharmacists to improve the quality of medical care using chronotherapy.

关键词： Drug administration time conventional cancer therapy chronotherapy intestinal cancer

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时间治疗学(chronotherapy)——生物节律在临床医学上的应用

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中国医院药学杂志 1984年第6期 13-16页

作者：孙定人北京部队总医院

一切存在的基本形式是时间和空间。时间既没有开始也没有结束。人们计量时间必须以某种客观现象作为参考体,如日月的升落,季节的变化等。人体自身的节律性活动,行为和生理过程,也可以起到自动计时

关键词：时间治疗学时间医学 chronotherapy 节律性生物节律生物节奏生物调节

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The role of circadian clocks in cancer:Mechanisms and clinical implications

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Genes & Diseases 2023年第4期10卷 1279-1290页

作者： Huiwen Liu Ying Liu Rihan Hai Weihua Liao Xiangjian Luo Key Laboratory of Carcinogenesis and Invasion Chinese Ministry of EducationDepartment of RadiologyXiangya HospitalCentral South UniversityChangshaHunan 410078China Cancer Research Institute School of Basic MedicineCentral South UniversityChangshaHunan 410078China Department of Medicine Hunan Traditional Chinese Medical CollegeZhuzhouHunan 412000China Molecular Imaging Research Center of Central South University ChangshaHunan 410078China Hunan Key Laboratory of Oncotarget Gene Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of MedicineCentral South UniversityChangshaHunan 410078China National Clinical Research Center for Geriatric Disorders Xiangya HospitalCentral South UniversityChangshaHunan 410078China

Circadian rhythm refers to the inherent 24-h cycle oscillation of biochemical,phys-iological and behavioral functions,which is almost universal in *** least 14 core clock genes have been reported to form multiple chain feedback loops that confer intrinsic circadian rhythmicity onto the molecular *** evidence has shown that the circadian gene dysfunction resulted from single nucleotide polymorphisms(SNPs),deletions,epigenetic modification,and deregulation is strongly associated with cancer *** the pre-sent review,we describe the composition of circadian rhythm *** highlight the func-tion and mechanism of clock genes in cancer pathogenesis and ***,their potential clinical implications as prognostic biomarkers and therapeutic targets have been ad-dressed.

关键词： Cancer Cancer metabolism Circadian clock Circadian rhythm chronotherapy Tumor microenvironment

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Carcinogenic efects of circadian disruption: an epigenetic viewpoint

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Chinese Journal of Cancer 2015年第9期34卷 1-9页

作者： Abbas Salavaty Department of Genetics Faculty of ScienceShahid Chamran University of Ahvaz

Circadian rhythms refer to the endogenous rhythms that are generated to synchronize physiology and behavior with 24-h environmental cues. These rhythms are regulated by both external cues and molecular clock mechanisms in almost all cells. Disruption of circadian rhythms, which is called circadian disruption, afects many biological processes within the body and results in diferent long-term diseases, including cancer. Circadian regulatory pathways result in rhythmic epigenetic modiications and the formation of circadian epigenomes. Aberrant epigenetic modiications, such as hypermethylation, due to circadian disruption may be involved in the transformation of normal cells into cancer cells. Several studies have indicated an epigenetic basis for the carcinogenic efects of circadian disruption. In this review, I irst discuss some of the circadian genes and regulatory proteins. Then, I summarize the current evidence related to the epigenetic modiications that result in circadian disruption. In addition, I explain the carcinogenic efects of circadian disruption and highlight its potential role in diferent human cancers using an epigenetic viewpoint. Finally, the importance of chronotherapy in cancer treatment is highlighted.

关键词： Cancer, Epigenetics, Circadian rhythms, Circadian disruption, chronotherapy

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Circadian rhythm in prostate cancer: time to take notice of the clock

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Asian Journal of Andrology 2023年第2期25卷 184-191页

作者： Wei-Zhen Zhu Qi-Ying He De-Chao Feng Qiang Wei Lu Yang Department of Urology Institute of UrologyWest China HospitalSichuan UniversityChengdu 610041China

The circadian clock is an evolutionary molecular product that is associated with better adaptation to changes in the external *** of the circadian rhythm plays a critical role in tumorigenesis of many kinds of cancers,including prostate cancer(PCa).Integrating circadian rhythm into PCa research not only brings a closer understanding of the mechanisms of PCa but also provides new and effective options for the precise treatment of patients with *** review begins with patterns of the circadian clock,highlights the role of the disruption of circadian rhythms in PCa at the epidemiological and molecular levels,and discusses possible new approaches to PCa therapy that target the circadian clock.

关键词： chronotherapy circadian clock circadian rhythm prostate cancer

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The role of circadian rhythm in breast cancer

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Chinese Journal of Cancer Research 2013年第4期25卷 442-450页

作者： Shujing Li Xiang Ao Huijian Wu The School of Life Science and Biotechnology Dalian University of Technology

The circadian rhythm is an endogenous time keeping system shared by most organisms. The circadian clock is comprised of both peripheral oscillators in most organ tissues of the body and a central pacemaker located in the suprachiasmatic nucleus （SCN） of the central nervous system. The circadian rhythm is crucial in maintaining the normal physiology of the organism including, but not limited to, cell proliferation, cell cycle progression, and cellular metabolism; whereas disruption of the circadian rhythm is closely related to multi-tumorigenesis. In the past several years, studies from different fields have revealed that the genetic or functional disruption of the molecular circadian rhythm has been found in various cancers, such as breast, prostate, and ovarian. In this review, we will investigate and present an overview of the current research on the influence of circadian rhythm regulating proteins on breast cancer.

关键词： Circadian rhythm breast cancer circadian proteins chronotherapy

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The interaction between circadian rhythm and epilepsy

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Acta Epileptologica 2022年第3期5卷 156-168页

作者： Mingsu Liu Jing Ding Xin Wang Department of Neurology Zhongshan HospitalFudan UniversityShanghaiChina CAS Center for Excellence in Brain Science and Intelligence Technology ShanghaiChina Department of The State Key Laboratory of Medical Neurobiology The Institutes of Brain Science and the Collaborative Innovation Center for Brain ScienceFudan UniversityShanghaiChina

Evidence about the interaction between circadian rhythms(CR)and epilepsy has been expanded with the application of advanced detection *** adequate understanding of how circadian system and epilepsy interact with each other could contribute to more accurate seizure prediction as well as rapid development of potential treatment timed to specific phases of *** this review,we present the reciprocal relationship between CR and epileptic activities from aspects of sleep effect,genetic modulation and brain *** has been found that sleep-wake patterns,circadian timing systems and multidien rhythms have essential roles in seizure activities and interictal epileptiform discharge(IED).For instance,specific distribution patterns of seizures and IED have been reported,i.e.,lighter non-rapid eye movement(NREM)sleep stage(stage 2)induces seizures while deeper NREM sleep stage(stage 3)activates ***,the epilepsy type,seizure type and seizure onset zone can significantly affect the rhythms of seizure *** from the common seizure types,several specific epilepsy syndromes also have a close correlation with sleep-wakefulness *** influences the epilepsy rhythm,and conversely,epilepsy alters the sleep rhythm through multiple *** genes accompanied by two feedback loops of regulation have an important role in cortical excitability and seizure occurrence,which may be involved in the *** suprachiasmatic nuclei(SCN)has a rhythm of melatonin and cortisol secretion under the circadian pattern,and then these hormones can feed back into a central oscillator to affect the SCN-dependent rhythms,leading to variable but prominent influence on ***,we discuss the precise predictive algorithms and chronotherapy strategies based on different temporal patterns of seizure occurrence for patients with epilepsy,which may offer a valuable indication for non-invasive closed-loop treatment *** of the

关键词： Epilepsy Circadian rhythm Sleep Mechanisms chronotherapy

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