WorldWideScience

Sample records for chronotherapy

  1. Glucocorticoids and chronotherapy in rheumatoid arthritis.

    Science.gov (United States)

    Cutolo, Maurizio

    2016-01-01

    It is evident that the morning symptoms of rheumatoid arthritis (RA) are linked to the circadian abnormal increase in night inflammation, favoured by inadequate cortisol secretion under conditions of active disease. Therefore, exogenous glucocorticoid treatment is recommended in RA at low doses since it may partially act like a 'replacement therapy'. The prevention/treatment of the night upregulation of the immune/inflammatory reaction (and related flare of cytokine synthesis) has been shown to be more effective when exogenous glucocorticoid administration is obtained with a night-time-release formulation. Large-scale trials documented that modified-release prednisone has greater efficacy then morning prednisone for long-term low-dose glucocorticoid treatment in patients with RA, showing at least a more significant reduction in morning joint stiffness. Interestingly, despite a considerably higher cost than conventional prednisone, chronotherapy with night-time-release prednisone was recognised as a cost-effective option for patients with RA not on glucocorticoids who are eligible for therapy with biological disease-modifying antirheumatic drugs (DMARDs). Moreover, since different cell populations involved in the inflammatory process are particularly activated during the night, other therapeutical approaches used in RA, for example, conventional DMARDs and non-steroidal anti-inflammatory drugs (NSAIDs), should follow the same concepts of glucocorticoid chronotherapy. Indeed, bedtime methotrexate chronotherapy was found to improve RA symptoms compared to the current standard dosing methods, and several available NSAIDs (ie, indomethacin, aceclofenac, ketoprofen, flurbiporfen, lornoxicam) have been very recently modified in their formulation, in order to obtain chronotherapeutical effects in RA. PMID:27042335

  2. Chronotherapy in the treatment of epilepsy

    Directory of Open Access Journals (Sweden)

    Stanley DA

    2014-11-01

    Full Text Available David A Stanley,1 Sachin S Talathi,2 Paul R Carney3 1Department of Mathematics and Statistics, Boston University, Boston, MA, USA; 2Qualcomm Research Center, San Diego, CA, USA; 3Departments of Pediatrics, Neurology, Neuroscience, and Biomedical Engineering, University of Florida, Gainesville, FL, USA Abstract: The presence of natural 24-hour oscillations within the body provides often overlooked opportunities for treatment of epilepsy. By simply tailoring the drug regimen to an individual's circadian rhythm, recent studies suggest one can improve the effectiveness of antiepileptic drugs, while reducing side effects. Daily variations in seizure occurrence and drug side effects create optimal timing windows for delivery of medication. Conversely, in certain epilepsy syndromes, there is growing evidence that both sleep and circadian rhythm can be distorted or misaligned. Thus, therapeutic re-entrainment of rhythms via application of zeitgebers (chronobiotics may represent an untapped opportunity for improving patient quality of life. Keywords: circadian, epilepsy, sleep, chronotherapy, chronopharmacology, personalized medicine

  3. Chronotherapy in practice: the perspective of the community pharmacist.

    Science.gov (United States)

    Kaur, Gagandeep; Gan, Yuh-Lin; Phillips, Craig L; Wong, Keith; Saini, Bandana

    2016-02-01

    Background Optimising the time of drug administration in alignment with circadian rhythms to enhance the clinical effect or minimise/avoid adverse effects is referred to as chronotherapy. Pharmacists have a key role in providing medicine related information, including counselling about the optimal time for medication administration. Where applicable, the principles of chronotherapy should underlie this aspect of medication counselling. Despite significant developments in the science of chronotherapy for specific pharmacological treatments, the perspective of pharmacists about their understanding and application of these principles in practice has not been explored. Objective To explore community pharmacist's viewpoints about and experience with the application of chronotherapy principles in practice. Setting Community pharmacies within metropolitan Sydney in New South Wales, Australia. Methods Semi-structured, face to face interviews with a convenience sample of community pharmacists were conducted. All interviews were audio-recorded, transcribed verbatim and thematically analyzed using a 'grounded theory' approach, given the novelty of this area. Main outcome measure Community pharmacists' awareness, current practice and future practice support requirements about the principles of chronotherapy. Results Twenty-five semi-structured interviews were conducted. Most participants reported encountering cases where clinical decision making about suggesting appropriate times of drug administration to patients was needed. Their approach was mainly pragmatic rather than based on theoretical principles of circadian variation in drug disposition or on current or emerging evidence; thus there was an evidence practice chasm in some cases. However, most participants believed they have an important role to play in counselling patients about optimal administration times and were willing to enact such roles or acquire skills/competence in this area. Conclusion Community pharmacists

  4. CHRONOTHERAPY: A NOVEL DRUG DELIVERY SYSTEM

    Directory of Open Access Journals (Sweden)

    Dubal Ashwini

    2011-06-01

    Full Text Available Recent advances in chronopharmacology and requirement of an appropriate technology to deliver the drug at specific time and site led to the development of novel type of drug delivery systems as “chronotropic or Pulsatile drug delivery systems”. Rationale behind designing these drug delivery systems is to release the drug at desired time (pathophysiological need of disease, which results into improved therapeutic efficacy and patient-compliance. These systems are meant for treatment of those diseases that are caused due to circadian changes in body like asthma, peptic ulcer, cardiovascular diseases, arthritis and when zero order drug release is not desired. These drug delivery systems are designed to release the drug within a short period of time, immediately after a predetermined lag time. The current article focuses on diseases requiring chronotropic systems and their chronological behavior, various approaches like time controlled chronotropic systems, stimuli induced pulsatile drug delivery systems, externally regulated pulsatile drug delivery systems to design them, recent technologies for chronotherapy and currently available marketed formulations.

  5. Sleep deprivation as a method of chronotherapy in the treatment of depression

    OpenAIRE

    Ewa Dopierała; Janusz Rybakowski

    2015-01-01

    Disturbances of circadian rhythms play an important role in the pathogenesis of affective illnesses, and their normalisation with methods of chronotherapy might become an important element of therapeutic treatment. Chronotherapy is based on a controlled exposure to environmental stimuli which affect biorhythms. One of the chronotherapeutic methods is sleep deprivation (SD). The article discusses the present status of SD in psychiatry, its methods and application in depression treatment. Prese...

  6. Robust Individual Circadian Parameter Estimation for Biosignal-based Personalisation of Cancer Chronotherapy

    OpenAIRE

    Schott, Benjamin; Stegmaier, Johannes; Arbaud, Alexandre; Reischl, Markus; Mikut, Ralf; Lévi, Francis

    2016-01-01

    In cancer treatment, chemotherapy is administered according a constant schedule. The chronotherapy approach, considering chronobiological drug delivery, adapts the chemotherapy profile to the circadian rhythms of the human organism. This reduces toxicity effects and at the same time enhances efficiency of chemotherapy. To personalize cancer treatment, chemotherapy profiles have to be further adapted to individual patients. Therefore, we present a new model to represent cycle phenomena in circ...

  7. Low-dose prednisone chronotherapy for rheumatoid arthritis: a randomised clinical trial (CAPRA-2)

    OpenAIRE

    Buttgereit, Frank; Mehta, Daksha; Kirwan, John; Szechinski, Jacek; Boers, Maarten; Alten, Rieke E; Supronik, Jerzy; Szombati, Istvan; Romer, Ulrike; Witte, Stephan; Saag, Kenneth G.

    2012-01-01

    Objective To assess the efficacy and safety of low-dose prednisone chronotherapy using a new modified-release (MR) formulation for the treatment of rheumatoid arthritis (RA). Methods In this 12-week, double-blind, placebo-controlled study, patients with active RA (n=350) were randomised 2:1 to receive MR prednisone 5 mg or placebo once daily in the evening in addition to their existing RA disease-modifying antirheumatic drug (DMARD) treatment. The primary end point was the percentage of patie...

  8. Sleep deprivation as a method of chronotherapy in the treatment of depression.

    Science.gov (United States)

    Dopierała, Ewa; Rybakowski, Janusz

    2015-01-01

    Disturbances of circadian rhythms play an important role in the pathogenesis of affective illnesses, and their normalisation with methods of chronotherapy might become an important element of therapeutic treatment. Chronotherapy is based on a controlled exposure to environmental stimuli which affect biorhythms. One of the chronotherapeutic methods is sleep deprivation (SD). The article discusses the present status of SD in psychiatry, its methods and application in depression treatment. Presently the most recommended pattern is combining total sleep deprivation (TSD), sleep phase advance (SPA), pharmacotherapy, and sometimes also phototherapy. Such proceedings have proven short-term and long-term effectiveness, and they may also have beneficial effect in drug resistant depression. Among the therapeutic mechanisms of the sleep deprivation treatment, the following are influenced: catecholaminergic, serotonergic and glutamatergic neurotransmission, neurotrophic factors (mainly the brain-derived neurotrophic factor - BDNF), the immune system, the endocrine system, metabolism of some brain structures (mostly the prefrontal cortex) and gene expression related to biological clock. On the grounds of the efficiency, simplicity and safety of this method, authors think that SD in its modern version with SPA should be used more often as an element of depression treatment. PMID:26276912

  9. INFLUENCE OF CHRONOTHERAPY WITH DIFFERENT ANTIHYPERTENSIVE DRUGS ON CIRCADIAN BLOOD PRESSURE PATTERN

    Directory of Open Access Journals (Sweden)

    V. M. Gorbunov

    2016-01-01

    Full Text Available Aim. To determine the value of different blood pressure (BP measurement methods for arterial hypertension (HT chronotherapy efficacy assessment. Material and methods. Two similar open, randomized, cross-over studies (morning vs evening intake were carried out. Duration of the initial wash-out period was 2 weeks; duration of both treatment courses — 3 weeks; the interval between courses — 1 week. Only patients with stable HT (mean day-time BP>135/85 mm Hg were included. Ambulatory BP monitoring (ABPM was carried out prior to treatment and at the end of both treatment courses. The patients performed home BP monitoring (HBPM throughout the study. Pharmacokinetics of verapamil (n=14, mean daily dose — 240.0±16.3 mg was studied to assess compliance with verapamil therapy. In ramipril trial (n=30 its mean daily dose was 8.9±0.7 mg. The following main ABPM variables were analyzed: ABPM means and variability, maximal and minimal values, nocturnal BP fall, parameters of Fourier transformation and smoothness index. The morning and evening BP means and morning BP surge (morning – evening BP were assessed by HBPM. Student’s t-value and Mahalanobis distance were used to evaluate individual value of each variable (“morning” vs “evening” effect. This analysis was first done separately for each trial. After that, combined data were analyzed. Results. Overall antihypertensive effect was more intense with morning ramipril (p<0.05 intake and evening verapamil intake. The t-values ranged 2.2-2.3 for nocturnal BP fall; 2.0-2.1 for night-time BP variability; 3.8-4.3 for morning BP surge. The t-values of office and 24-hour BP were low (0.2-1.7. Conclusion. Morning BP surge based on HBPM is a good instrument for chronotherapy effect assessment. Evening administration of antihypertensive drugs causes nocturnal BP fall shift towards “dipper” status.

  10. Adjunctive Triple Chronotherapy (Combined Total Sleep Deprivation, Sleep Phase Advance, and Bright Light Therapy) Rapidly Improves Mood and Suicidality in Suicidal Depressed Inpatients: An Open Label Pilot Study

    OpenAIRE

    Sahlem, Gregory L.; Kalivas, Benjamin; Fox, James B.; Lamb, Kayla; Roper, Amanda; Williams, Emily N.; Williams, Nolan R.; Korte, Jeffrey E.; Zuschlag, Zachary D.; El Sabbagh, Salim; Guille, Constance; Barth, Kelly S.; Uhde, Thomas W.; George, Mark S.; Short, E. Baron

    2014-01-01

    Previous studies have demonstrated that combined total sleep deprivation (Wake therapy), sleep phase advance, and bright light therapy (Triple Chronotherapy) produce a rapid and sustained antidepressant effect in acutely depressed individuals. To date no studies have explored the impact of the intervention on unipolar depressed individuals with acute concurrent suicidality. Participants were suicidal inpatients (N=10, Mean age=44±16.4SD, 6F) with unipolar depression. In addition to standard o...

  11. Adjunctive triple chronotherapy (combined total sleep deprivation, sleep phase advance, and bright light therapy) rapidly improves mood and suicidality in suicidal depressed inpatients: an open label pilot study.

    Science.gov (United States)

    Sahlem, Gregory L; Kalivas, Benjamin; Fox, James B; Lamb, Kayla; Roper, Amanda; Williams, Emily N; Williams, Nolan R; Korte, Jeffrey E; Zuschlag, Zachary D; El Sabbagh, Salim; Guille, Constance; Barth, Kelly S; Uhde, Thomas W; George, Mark S; Short, E Baron

    2014-12-01

    Previous studies have demonstrated that combined total sleep deprivation (Wake therapy), sleep phase advance, and bright light therapy (Triple Chronotherapy) produce a rapid and sustained antidepressant effect in acutely depressed individuals. To date no studies have explored the impact of the intervention on unipolar depressed individuals with acute concurrent suicidality. Participants were suicidal inpatients (N = 10, Mean age = 44 ± 16.4 SD, 6F) with unipolar depression. In addition to standard of care, they received open label Triple Chronotherapy. Participants underwent one night of total sleep deprivation (33-36 h), followed by a three-night sleep phase advance along with four 30-min sessions of bright light therapy (10,000 lux) each morning. Primary outcome measures included the 17 item Hamilton depression scale (HAM17), and the Columbia Suicide Severity Rating Scale (CSSRS), which were recorded at baseline prior to total sleep deprivation, and at protocol completion on day five. Both HAM17, and CSSRS scores were greatly reduced at the conclusion of the protocol. HAM17 scores dropped from a mean of 24.7 ± 4.2 SD at baseline to a mean of 9.4 ± 7.3 SD on day five (p = .002) with six of the ten individuals meeting criteria for remission. CSSRS scores dropped from a mean of 19.5 ± 8.5 SD at baseline to a mean of 7.2 ± 5.5 SD on day five (p = .01). The results of this small pilot trial demonstrate that adjunctive Triple Chronotherapy is feasible and tolerable in acutely suicidal and depressed inpatients. Limitations include a small number of participants, an open label design, and the lack of a comparison group. Randomized controlled studies are needed. PMID:25231629

  12. [Chronotherapy and relativity theory].

    Science.gov (United States)

    Polishchuk, N A

    2008-01-01

    The course of time itself in alive organisms is treated from positions of the special theory of the relativity created by A. Einstein in 1905 and added by the Nobel winners H.A.Lorentsem, M. Plankom, M. fon Laue. These achievements of fundamental physics have been put in a basis of special medical technology "Resonant chronophytotherapy" (SMT RCPT) which is applied in practice of treatment of chronic diseases for 27 years. Grass tinctures in various dosages are used in SMT RCPT, which patients take once a day during precisely designated time. Parameters "dosage-time" daily vary. SMT RCPT have been conducted in treatment of epilepsy bronchial asthma, rheumatism, sclerodermia, hypertension, chronic glomerulonephritis, vegeto-vascular dystonia, female sterility, circular alopecia, vitiligo, eczema, psoriasis, onychomycosis. SMT RCPT does have adverse events, has no contra-indications to its use, directed, first of all, on elimination of nonspecific signs of a disease, reduces dependence and complications of the use of chemical synthetic preparations. SMT RCPT can be combined with any kind of specific treatment. Internet-variant of SMT RCPT has been developed. Chronomedicine is priority tendency in industrialized countries of the world--the USA, the Great Britain, Germany, France, Russia, China, Japan and appears on lead positions among alternative methods of treatment, both traditional, and non-traditional. PMID:19145832

  13. Circadian rhythms of myocardial ischemia and chronotherapy%心肌缺血的昼夜节律性与时辰疗法

    Institute of Scientific and Technical Information of China (English)

    张恩晖; 王海峰; 陈莉; 刘佃花; 于剑光; 蔡国君

    2016-01-01

    The occurrence of the clinical manifestations of myocardial ischemia shows clear circadian rhythmicity ,and they are unevenly distributed during the 24 h with higher morbidity during the initial hours of the daily activity span and in the late afternoon or early evening .Such temporal patterns result from circadian rhythms in pathophysiological mechanisms plus cyclic environmental stressors that trigger these clinical events .β‐receptor antagonist medications ,oral nitrate ,and calcium channel blocker have been shown to be influenced by the circadian time of their administration .Here we briefly review the char‐acteristics of circadian rhythmicity in MI ,the pathophysiological mechanisms as well as the current chronotherapy ,and then discuss the future treatment strategies .%临床上心肌缺血(M I )的发作频率伴有昼夜变化,在清晨和傍晚是发病高峰期。产生这一现象主要是受到机体病理生理机制的昼夜节律性以及外界的环境因素影响。目前β‐受体阻断剂、硝酸酯类以及钙通道阻滞剂等药物的治疗作用已经被证明受到机体昼夜节律的影响。因此,笔者对MI发作的昼夜节律特点、病理生理机制以及目前临床上的时辰疗法进行综述,并对未来的治疗策略进行探讨。

  14. Optimization of irinotecan chronotherapy with P-glycoprotein inhibition

    Energy Technology Data Exchange (ETDEWEB)

    Filipski, Elisabeth; Berland, Elodie [INSERM, U776 “Rythmes biologiques et cancers”, CAMPUS CNRS, 7 rue Guy Môquet, F-94801 Villejuif (France); Univ Paris-Sud, UMR-S0776, Orsay F-91405 (France); Ozturk, Narin [INSERM, U776 “Rythmes biologiques et cancers”, CAMPUS CNRS, 7 rue Guy Môquet, F-94801 Villejuif (France); Univ Paris-Sud, UMR-S0776, Orsay F-91405 (France); Istanbul University Faculty of Pharmacy, Department of Pharmacology, Beyazit TR-34116, Istanbul (Turkey); Guettier, Catherine [Assistance Publique-Hôpitaux de Paris, Unité de Chronothérapie, Département de Cancérologie, Hôpital Paul Brousse, Villejuif F-94807 (France); Horst, Gijsbertus T.J. van der [Department of Genetics, Erasmus University Medical Center, 3000 CA Rotterdam (Netherlands); Lévi, Francis [INSERM, U776 “Rythmes biologiques et cancers”, CAMPUS CNRS, 7 rue Guy Môquet, F-94801 Villejuif (France); Univ Paris-Sud, UMR-S0776, Orsay F-91405 (France); Assistance Publique-Hôpitaux de Paris, Unité de Chronothérapie, Département de Cancérologie, Hôpital Paul Brousse, Villejuif F-94807 (France); and others

    2014-02-01

    The relevance of P-glycoprotein (P-gp) for irinotecan chronopharmacology was investigated in female B6D2F{sub 1} mice. A three-fold 24 h change in the mRNA expression of Abcb1b was demonstrated in ileum mucosa, with a maximum at Zeitgeber Time (ZT) 15 (p < 0.001). No rhythm was found for abcb1a in ileum mucosa, or for Abcb1a/b in Glasgow osteosarcoma (GOS), a mouse tumor cell line moderately sensitive to irinotecan. Non-tumor-bearing mice received irinotecan (50 mg/kg/day i.v. × 4 days) as a single agent or combined with P-gp inhibitor PSC833 (6.25 mg/kg/day i.p. × 4 days) at ZT3 or ZT15, respectively corresponding to the worst or the best irinotecan tolerability. Endpoints involved survival, body weight change and hematologic toxicity. Antitumor efficacy was studied in GOS-bearing mice receiving irinotecan (25, 30 or 40 mg/kg/day × 4 days) and +/− PSC833 at ZT3 or ZT15, with survival, body weight change, and tumor growth inhibition as endpoints. Non-tumor bearing mice lost an average of 17% or 9% of their body weight according to irinotecan administration at ZT3 or ZT15 respectively (p < 0.001). Dosing at ZT15 rather than ZT3 reduced mean leucopenia (9% vs 53%; p < 0.001). PSC833 aggravated irinotecan lethal toxicity from 4 to ∼ 60%. In tumor-bearing mice, body weight loss was ∼ halved in the mice on irinotecan or irinotecan–PSC833 combination at ZT15 as compared to ZT3 (p < 0.001). PSC833–irinotecan at ZT15 increased tumor inhibition by ∼ 40% as compared to irinotecan only at ZT15. In conclusion, P-gp was an important determinant of the circadian balance between toxicity and efficacy of irinotecan. - Highlights: • Irinotecan chronotolerance and chronoefficacy change as drug was applied with PSC833. • P-glycoprotein is an important player of the toxicity and efficacy of irinotecan. • Timing should be considered if chemotherapy is performed with a MDR1 inhibitor.

  15. Recent advances in chronotherapy for the management of asthma

    Directory of Open Access Journals (Sweden)

    Durrington HJ

    2014-11-01

    Full Text Available Hannah J Durrington,1 Stuart N Farrow,2,3 David W Ray2 1Institute of Inflammation and Repair, 2Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, Manchester, UK; 3Respiratory Therapy Area, GlaxoSmithKline, Stevenage, UK Abstract: Asthma is a common inflammatory disease of the airways, with a pronounced circadian variation in symptoms. A number of existing asthma treatments are “chronotherapies” designed to be delivered to coincide with the “morning dip” in lung function and corresponding worsening of symptoms. In the past decade, our knowledge of how circadian rhythms are regulated has increased immensely, and increasing evidence that the molecular clock plays a significant role in the immune system makes asthma an intriguing disease to study. The current trend toward once-daily dosing of asthma therapies reduces the need for careful timing of doses; however, patients are exposed to therapeutic levels of the drug and potential side effects for the entire day. Consequently, improved therapeutic benefit in asthma may be gained by understanding the molecular pathways that drive the predictable, diurnal worsening of symptoms. Furthermore, timing the delivery of therapy to coincide with pathway sensitivity may deliver maximum benefit. Defining the role of the molecular clock in these pathways could therefore lead to novel therapies and improved asthma control. Keywords: anticholinergic, beta agonist, corticosteroids, FEV1, PEFR, theophylline

  16. Design and development of colon specific microspheres for chronotherapy of hypertension

    Directory of Open Access Journals (Sweden)

    P Patel

    2012-01-01

    Full Text Available The purpose of this research was to design, and evaluate multiparticulate systems for Chronotherapeutic delivery of beta blocker containing biodegradable polymers coated with pH sensitive polymers in hypertension. Chitosan was used as a carrier for drug delivery and Eudragit S100 was used as an enteric coating polymer. 3 2 full factorial design was employed to optimize the proper formulation for Chronotherapeutic drug delivery.

  17. Design and development of colon specific microspheres for chronotherapy of hypertension

    OpenAIRE

    Patel, P; A Dhake

    2012-01-01

    The purpose of this research was to design, and evaluate multiparticulate systems for Chronotherapeutic delivery of beta blocker containing biodegradable polymers coated with pH sensitive polymers in hypertension. Chitosan was used as a carrier for drug delivery and Eudragit S100 was used as an enteric coating polymer. 3 2 full factorial design was employed to optimize the proper formulation for Chronotherapeutic drug delivery.

  18. Development and Evaluation of Dual Cross-Linked Pulsatile Beads for Chronotherapy of Rheumatoid Arthritis

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    Abanesh kumar Bansal

    2013-01-01

    Full Text Available In the present investigation, pulsatile release beads were prepared by ionic gelation technique. Lornoxicam dual cross-linked beads were prepared by dropping dispersed phase of lornoxicam, pectin, and sodium alginate into the dispersion phase of different concentrations of calcium chloride solution followed by aluminium chloride solution. The formulated beads were further coated by Eudragit L & S 100 in the ratio 1 : 2 w/w in order to achieve desired lag time. In vitro release study showed lag time of 5–8 h before release of lornoxicam from the formulated beads. Thus, formulated dual cross-linked beads when administered at bed time may release lornoxicam when needed most for chronotherapeutics of early morning rheumatoid arthritis attacks in chronic patients.

  19. Hepatic leukemia factor promotes resistance to cell death: Implications for therapeutics and chronotherapy

    International Nuclear Information System (INIS)

    Physiological variation related to circadian rhythms and aberrant gene expression patterns are believed to modulate therapeutic efficacy, but the precise molecular determinants remain unclear. Here we examine the regulation of cell death by hepatic leukemia factor (HLF), which is an output regulator of circadian rhythms and is aberrantly expressed in human cancers, using an ectopic expression strategy in JB6 mouse epidermal cells and human keratinocytes. Ectopic HLF expression inhibited cell death in both JB6 cells and human keratinocytes, as induced by serum-starvation, tumor necrosis factor alpha and ionizing radiation. Microarray analysis indicates that HLF regulates a complex multi-gene transcriptional program encompassing upregulation of anti-apoptotic genes, downregulation of pro-apoptotic genes, and many additional changes that are consistent with an anti-death program. Collectively, our results demonstrate that ectopic expression of HLF, an established transcription factor that cycles with circadian rhythms, can recapitulate many features associated with circadian-dependent physiological variation. - Highlights: ► Circadian-dependent physiological variation impacts therapeutic efficacy. ► Hepatic leukemia factor inhibits cell death and is a candidate circadian factor. ► Hepatic leukemia factor anti-death program is conserved in murine and human cells. ► Transcriptomics indicates the anti-death program results from a systems response

  20. Hepatic Leukemia Factor Promotes Resistance To Cell Death: Implications For Therapeutics and Chronotherapy

    Energy Technology Data Exchange (ETDEWEB)

    Waters, Katrina M.; Sontag, Ryan L.; Weber, Thomas J.

    2013-04-15

    Physiological variation related to circadian rhythms and aberrant gene expression patterns are believed to modulate therapeutic efficacy, but the precise molecular determinants remain unclear. Here we examine the regulation of cell death by hepatic leukemia factor (HLF), which is an output regulator of circadian rhythms and is aberrantly expressed in human cancers, using an ectopic expression strategy in JB6 mouse epidermal cells and human keratinocytes. Ectopic HLF expression inhibited cell death in both JB6 cells and human keratinocytes, as induced by serum-starvation, tumor necrosis factor alpha and ionizing radiation. Microarray analysis indicates that HLF regulates a complex multi-gene transcriptional program encompassing upregulation of anti-apoptotic genes, downregulation of pro-apoptotic genes, and many additional changes that are consistent with an anti-death program. Collectively, our results demonstrate that ectopic expression of HLF, an established transcription factor that cycles with circadian rhythms, can recapitulate many features associated with circadian-dependent physiological variation.

  1. Hepatic leukemia factor promotes resistance to cell death: Implications for therapeutics and chronotherapy

    Energy Technology Data Exchange (ETDEWEB)

    Waters, Katrina M. [Computational Biology and Bioinformatics, Pacific Northwest National Laboratory, Richland, WA 99354 (United States); Sontag, Ryan L. [Systems Toxicology Groups, Pacific Northwest National Laboratory, Richland, WA 99354 (United States); Weber, Thomas J., E-mail: Thomas.Weber@pnl.gov [Systems Toxicology Groups, Pacific Northwest National Laboratory, Richland, WA 99354 (United States)

    2013-04-15

    Physiological variation related to circadian rhythms and aberrant gene expression patterns are believed to modulate therapeutic efficacy, but the precise molecular determinants remain unclear. Here we examine the regulation of cell death by hepatic leukemia factor (HLF), which is an output regulator of circadian rhythms and is aberrantly expressed in human cancers, using an ectopic expression strategy in JB6 mouse epidermal cells and human keratinocytes. Ectopic HLF expression inhibited cell death in both JB6 cells and human keratinocytes, as induced by serum-starvation, tumor necrosis factor alpha and ionizing radiation. Microarray analysis indicates that HLF regulates a complex multi-gene transcriptional program encompassing upregulation of anti-apoptotic genes, downregulation of pro-apoptotic genes, and many additional changes that are consistent with an anti-death program. Collectively, our results demonstrate that ectopic expression of HLF, an established transcription factor that cycles with circadian rhythms, can recapitulate many features associated with circadian-dependent physiological variation. - Highlights: ► Circadian-dependent physiological variation impacts therapeutic efficacy. ► Hepatic leukemia factor inhibits cell death and is a candidate circadian factor. ► Hepatic leukemia factor anti-death program is conserved in murine and human cells. ► Transcriptomics indicates the anti-death program results from a systems response.

  2. Advanced technology in neurosurgery

    International Nuclear Information System (INIS)

    Technological improvements in neurosurgery are discussed. The use of surgical lasers, ultrasound aspirators, bipolar coagulator and operative microscopes for surgery of deep-seated neoplasms and vascular malformations is discussed. Intraoperative monitoring, chronotherapy, chronic neurostimulation and stereotactic interstitial irradiation are covered and indications for interventional neuroradiology are reviewed

  3. Advanced technology in neurosurgery

    Energy Technology Data Exchange (ETDEWEB)

    Pluchino, F.; Broggi, G.

    1987-01-01

    Technological improvements in neurosurgery are discussed. The use of surgical lasers, ultrasound aspirators, bipolar coagulator and operative microscopes for surgery of deep-seated neoplasms and vascular malformations is discussed. Intraoperative monitoring, chronotherapy, chronic neurostimulation and stereotactic interstitial irradiation are covered and indications for interventional neuroradiology are reviewed.

  4. FORMULATION AND EVALUATION OF PULSED DRUG DELIVERY OF 5- FLUOROURACIL IN TREATING COLO-RECTAL CANCER

    OpenAIRE

    Joshi V.G; Sutar P.S; Sutar K.P; Patil Prakash; Karigar A.A

    2012-01-01

    The proposed work aimed to develop a time dependent programmable pulsatile drug delivery system of 5-Fluorouracil, intended for chronotherapy in colorectal cancer. Various batches of tablets were prepared by direct compression method using microcrystalline cellulose (MCC). These tablets were coated with pH sensitive polymers like Eudragit S-100, cellulose acetate succinate(CAS) and Ethyl Cellulose (EC) at fixed concentration with different coating level (10% & 20%).The prepared tablets were e...

  5. Design and In Vitro Evaluation of Compression-coated Pulsatile Release Tablets of Losartan Potassium

    OpenAIRE

    Bajpai, M.; Singh, D. C. P.; Bhattacharya, A.; Singh, A.

    2012-01-01

    In majority of individuals blood pressure rises in the early morning hours, which lead to serious cardiovascular complications. Formulation of pulsatile system makes it possible to deliver drug at definite period of time when symptoms of the disease condition are most critical. The purpose of the present work was to develop pulsatile release tablet of losartan potassium for chronotherapy in hypertension. The prepared system consisted of a core tablet coated with versatile and safe hydrophilic...

  6. The circadian rest-activity rhythm, a potential safety pharmacology endpoint of cancer chemotherapy.

    Science.gov (United States)

    Ortiz-Tudela, Elisabet; Iurisci, Ida; Beau, Jacques; Karaboue, Abdoulaye; Moreau, Thierry; Rol, Maria Angeles; Madrid, Juan Antonio; Lévi, Francis; Innominato, Pasquale F

    2014-06-01

    The robustness of the circadian timing system (CTS) was correlated to quality of life and predicted for improved survival in cancer patients. However, chemotherapy disrupted the CTS according to dose and circadian timing in mice. A continuous and repeated measures longitudinal design was implemented here to characterize CTS dynamics in patients receiving a fixed circadian-based chemotherapy protocol. The rest-activity rhythm of 49 patients with advanced cancer was monitored using a wrist actigraph for 13 days split into four consecutive spans of 3-4 days each, i.e., before, during, right after and late after a fixed chronotherapy course. The relative amount of activity in bed vs. out of bed (Ihr amplitude (Amp), interdaily stability (IS) and intradaily variability (IV) were compared according to study span. Circadian disruption (Iimprovement (14.3%); alteration and complete recovery (31%) or sustained deterioration (45%), possibly due to inadequate chronotherapy dosing and/or timing. Improved clinical tolerability could result from the minimization of circadian disruption through the personalization of chronotherapy delivery. PMID:24510611

  7. Circadian variations and chronotherapeutic implications for cardiovascular management: a focus on COER verapamil.

    Science.gov (United States)

    Glasser, S P

    1999-01-01

    The circadian variation in biologic functions (chronobiology) may play a large role in the pathogenesis and exacerbation of many different diseases. Traditional treatment regimens for medical conditions associated with circadian variation often do not account for fluctuations in disease activity. A novel type of treatment approach, known as chronotherapy, is being evaluated in the treatment of many different disorders, including cardiovascular disease. Chronotherapeutic regimens are designed to provide pharmacologic intervention at the most appropriate time point in accordance with circadian rhythms, and may offer benefits over traditional regimens. This can be accomplished through appropriate dose scheduling (e.g., scheduling higher doses during greater disease activity and lower doses during low disease activity) or through unique drug-delivery systems. One chronotherapeutic formulation that uses a unique drug-delivery system, controlled-onset extended-release (COER) verapamil, aligns peak plasma drug levels with times when blood pressure, heart rate, and myocardial oxygen demand are at their highest levels. The efficacy and safety of COER verapamil have been evaluated in several clinical trials in patients with hypertension and angina. The purpose of this article is to review the concepts of chronobiology and chronotherapy and to review results of key efficacy and safety trials of COER verapamil. PMID:11720629

  8. Improving Therapeutic Ratio in Head and Neck Cancer with Adjuvant and Cisplatin-Based Treatments

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    Loredana G. Marcu

    2013-01-01

    Full Text Available Advanced head and neck cancers are difficult to manage despite the large treatment arsenal currently available. The multidisciplinary effort to increase disease-free survival and diminish normal tissue toxicity was rewarded with better locoregional control and sometimes fewer side effects. Nevertheless, locoregional recurrence is still one of the main reasons for treatment failure. Today, the standard of care in head and neck cancer management is represented by altered fractionation radiotherapy combined with platinum-based chemotherapy. Targeted therapies as well as chronotherapy were trialled with more or less success. The aim of the current work is to review the available techniques, which could contribute towards a higher therapeutic ratio in the treatment of advanced head and neck cancer patients.

  9. The role of sleep disturbances in attention deficit disorder symptoms: a case study.

    Science.gov (United States)

    Dahl, R E; Pelham, W E; Wierson, M

    1991-04-01

    Identified a 10-year-old girl with ADD and a 5-year history of sleep difficulties. Sleep difficulties (delayed sleep phase insomnia) were corrected while performing blind assessments of behavioral symptoms. The intervention (chronotherapy combined with a behavior modification program) resulted in an increase of sleep from 7.2 to 9.2 hours per night. Pre/postintervention behavioral measures indicated significant improvement in positive interactions with peers, increased productivity on a timed arithmetic task, and significantly increased percentage of assigned seatwork completed. Four-month follow-up in the natural school setting indicated improvement in teacher ratings and classroom performance. Despite the persistence of ADD symptomatology, the improvement in sleep apparently contributed to a clinically significant reduction in ADD. PMID:2061790

  10. Formulation and Evaluation of Chronomodulated Pulsatile Drug Delivery System of Salbutamol Sulphate

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    Anusha V

    2015-12-01

    Full Text Available Chronotherapy denotes the therapy in which the release of the drug in the body is allowed to match with the circadian rhythm of the disease, such that the required action of the drug is shown with minimal side effects. The main interesting fact of chronotherapy is its ability to deliver the drug in required concentrations during the time of its greatest need such that synchronizing circadian rhythm of diseases or symptoms. Pulsatile drug delivery system for Salbutamol sulphate was formulated initially as core tablets followed by formulation of pulsatile tablets using press-coated technology. Core tablets were formulated using various concentrations of superdisintegrant (Sodium starch glycolate, cross povidone and diluents (MCC & Dicalcium phosphate. The core tablets were then compressed into pulsatile tablets using combinations of HPMC K 100M and Eudragit L 100, Eudragit S 100 in various concentrations. Core tablets were evaluated and based on the dissolution studies trial T3was optimized as it shows lower disintegration time and faster drug release. Then the pulsatile tablets were evaluated for various tests and drug release studies were conducted for 2 hours in 0.1N HCl followed by pH 6.8 buffer and the trial S6 was optimized which showed satisfactory greater lag time of about 6 hours with satisfactory drug release which contains a combination of HPMC K15M (20mg, Eudragit L 100 (50mg, Eudragit S100 (60mg. Pulsatile tablets were formulated utilizing press coated technology and the combination of polymers provided required lag time with satisfactory dissolution profile.

  11. Prednisolone Delivery Platforms: Capsules and Beads Combination for a Right Timing Therapy

    Science.gov (United States)

    Cerciello, Andrea; Auriemma, Giulia; Morello, Silvana; Aquino, Rita P.; Del Gaudio, Pasquale

    2016-01-01

    In this work, a platform of alginate beads loaded with Prednisolone in hypromellose/gellan gum capsules (F6/Cps) able to delay steroidal anti-inflammatory drug (SAID) release as needed for chronotherapy of rheumatoid arthritis is proposed. Rheumatoid arthritis, showing a worsening in symptoms in the morning upon waking, is a pathology that can benefit from chronotherapy. With the aim to maximize prednisolone therapeutic action allowing the right timing of glucocorticoid therapy, different engineered microparticles (gel-beads) were manufactured using prilling (laminar jet break-up) as micro-encapsulation technique and Zn-alginate as gastroresistant carrier. Starting from various feed solutions and process parameters, the effect of the variables on particles size, morphology, solid state properties and drug release was studied. The optimization of operative and prilling/ionotropic gelation variables led to microspheres with almost spherical shape and a narrow dimensional range. The feed solution with the highest alginate (2.5% w/v) amount and drug/polymer ratio (1:5 w/w) gave rise to the highest encapsulation efficiency (78.5%) as in F6 formulation. As to drug release, F6 exhibited an interesting dissolution profile, releasing about 24% of the drug in simulated gastric fluid followed by a more sustained profile in simulated intestinal fluid. #F6, acting as a gastro-resistant and delayed release formulation, was selected for in vivo studies on male Wistar rats by means of a carrageenan-induced oedema model. Finally, this efficacious formulation was used as core material for the development of a final dosage form: F6/Cps allowed to significantly reduce prednisolone release in simulated gastric fluid (12.6%) and delayed drug release up to about 390 minutes. PMID:27472446

  12. Antihypertensive therapy: nocturnal dippers and nondippers. Do we treat them differently?

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    Mahabala C

    2013-03-01

    Full Text Available Chakrapani Mahabala,1 Padmanabha Kamath,2 Unnikrishnan Bhaskaran,3 Narasimha D Pai,2 Aparna U Pai41Department of Medicine, Kasturba Medical College, Manipal University, Mangalore, Karnataka State, India; 2Department of Cardiology, Kasturba Medical College, Manipal University, Mangalore, Karnataka State, India; 3Department of Community Medicine, Kasturba Medical College, Manipal University, Mangalore, Karnataka State, India; 4Department of Radiodiagnosis, Vivekananda Institute of Medical Sciences, Kolkata, West Bengal State, IndiaAbstract: Hypertension is a major independent risk factor for cardiovascular diseases. Management of hypertension is generally based on office blood pressure since it is easy to determine. Since casual blood pressure readings in the office are influenced by various factors, they do not represent basal blood pressure. Dipping of the blood pressure in the night is a normal physiological change that can be blunted by cardiovascular risk factors and the severity of hypertension. Nondipping pattern is associated with disease severity, left ventricular hypertrophy, increased proteinuria, secondary forms of hypertension, increased insulin resistance, and increased fibrinogen level. Long-term observational studies have documented increased cardiovascular events in patients with nondipping patterns. Nocturnal dipping can be improved by administering the antihypertensive medications in the night. Long-term clinical trials have shown that cardiovascular events can be reduced by achieving better dipping patterns by administering medications during the night. Identifying the dipping pattern is useful for decisions to investigate for secondary causes, initiating treatment, necessity of chronotherapy, withdrawal or reduction of unnecessary medications, and monitoring after treatment initiation. Use of this concept at the primary care level has been limited because 24-hour ambulatory blood pressure monitoring has been the only method

  13. Nerve growth factor, brain-derived neurotrophic factor, and the chronobiology of mood: a new insight into the "neurotrophic hypothesis"

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    Tirassa P

    2015-10-01

    Full Text Available Paola Tirassa,1 Adele Quartini,2 Angela Iannitelli2–4 1National Research Council (CNR, Institute of Cell Biology and Neurobiology (IBCN, 2Department of Medical-Surgical Sciences and Biotechnologies, Faculty of Pharmacy and Medicine – "Sapienza" University of Rome, 3Italian Psychoanalytical Society (SPI, Rome, Italy; 4International Psychoanalytical Association (IPA, London, UKAbstract: The light information pathways and their relationship with the body rhythms have generated a new insight into the neurobiology and the neurobehavioral sciences, as well as into the clinical approaches to human diseases associated with disruption of circadian cycles. Light-based strategies and/or drugs acting on the circadian rhythms have widely been used in psychiatric patients characterized by mood-related disorders, but the timing and dosage use of the various treatments, although based on international guidelines, are mainly dependent on the psychiatric experiences. Further, many efforts have been made to identify biomarkers able to disclose the circadian-related aspect of diseases, and therefore serve as diagnostic, prognostic, and therapeutic tools in clinic to assess the different mood-related symptoms, including pain, fatigue, sleep disturbance, loss of interest or pleasure, appetite, psychomotor changes, and cognitive impairments. Among the endogenous factors suggested to be involved in mood regulation, the neurotrophins, nerve growth factor, and brain-derived neurotrophic factor show anatomical and functional link with the circadian system and mediate some of light-induced effects in brain. In addition, in humans, both nerve growth factor and brain-derived neurotrophic factor have showed a daily rhythm, which correlate with the morningness–eveningness dimensions, and are influenced by light, suggesting their potential role as biomarkers for chronotypes and/or chronotherapy. The evidences of the relationship between the diverse mood-related disorders

  14. Sleep disorders and depression: brief review of the literature, case report, and nonpharmacologic interventions for depression

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    Luca A

    2013-08-01

    Full Text Available Antonina Luca,1 Maria Luca,2 Carmela Calandra2 1Department GF Ingrassia, Section of Neuroscience, 2Department of Medical and Surgery Specialties, Psychiatry Unit, University Hospital Policlinico-Vittorio Emanuele, Catania, Sicily, Italy Abstract: Sleep disorders are so frequently associated with depression that, in the absence of sleep complaints, a diagnosis of depression should be made with caution. Insomnia, in particular, may occur in 60%–80% of depressed patients. Depressive symptoms are important risk factors for insomnia, and depression is considered an important comorbid condition in patients with chronic insomnia of any etiology. In addition, some drugs commonly prescribed for the treatment of depression may worsen insomnia and impair full recovery from the illness. The aim of this paper is to review briefly and discuss the following topics: common sleep disturbances during depression (in particular pavor nocturnus, nightmares, hypersomnia, and insomnia; circadian sleep disturbances; and treatment of depression by manipulation of the sleep-wake rhythm (chronotherapy, light therapy, cycles of sleep, and manipulation of the sleep-wake rhythm itself. Finally, we present a case report of a 65-year-old Caucasian woman suffering from insomnia associated with depression who was successfully treated with sleep deprivation. Keywords: sleep disorders, depression, insomnia, sleep-wake rhythm

  15. Timing Matters: Circadian Rhythm in Sepsis, Obstructive Lung Disease, Obstructive Sleep Apnea, and Cancer.

    Science.gov (United States)

    Truong, Kimberly K; Lam, Michael T; Grandner, Michael A; Sassoon, Catherine S; Malhotra, Atul

    2016-07-01

    Physiological and cellular functions operate in a 24-hour cyclical pattern orchestrated by an endogenous process known as the circadian rhythm. Circadian rhythms represent intrinsic oscillations of biological functions that allow for adaptation to cyclic environmental changes. Key clock genes that affect the persistence and periodicity of circadian rhythms include BMAL1/CLOCK, Period 1, Period 2, and Cryptochrome. Remarkable progress has been made in our understanding of circadian rhythms and their role in common medical conditions. A critical review of the literature supports the association between circadian misalignment and adverse health consequences in sepsis, obstructive lung disease, obstructive sleep apnea, and malignancy. Circadian misalignment plays an important role in these disease processes and can affect disease severity, treatment response, and survivorship. Normal inflammatory response to acute infections, airway resistance, upper airway collapsibility, and mitosis regulation follows a robust circadian pattern. Disruption of normal circadian rhythm at the molecular level affects severity of inflammation in sepsis, contributes to inflammatory responses in obstructive lung diseases, affects apnea length in obstructive sleep apnea, and increases risk for cancer. Chronotherapy is an underused practice of delivering therapy at optimal times to maximize efficacy and minimize toxicity. This approach has been shown to be advantageous in asthma and cancer management. In asthma, appropriate timing of medication administration improves treatment effectiveness. Properly timed chemotherapy may reduce treatment toxicities and maximize efficacy. Future research should focus on circadian rhythm disorders, role of circadian rhythm in other diseases, and modalities to restore and prevent circadian disruption. PMID:27104378

  16. Disruption of Circadian Rhythms: A Crucial Factor in the Etiology of Depression

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    Roberto Salgado-Delgado

    2011-01-01

    Full Text Available Circadian factors might play a crucial role in the etiology of depression. It has been demonstrated that the disruption of circadian rhythms by lighting conditions and lifestyle predisposes individuals to a wide range of mood disorders, including impulsivity, mania and depression. Also, associated with depression, there is the impairment of circadian rhythmicity of behavioral, endocrine, and metabolic functions. Inspite of this close relationship between both processes, the complex relationship between the biological clock and the incidence of depressive symptoms is far from being understood. The efficiency and the timing of treatments based on chronotherapy (e.g., light treatment, sleep deprivation, and scheduled medication indicate that the circadian system is an essential target in the therapy of depression. The aim of the present review is to analyze the biological and clinical data that link depression with the disruption of circadian rhythms, emphasizing the contribution of circadian desynchrony. Therefore, we examine the conditions that may lead to circadian disruption of physiology and behavior as described in depressive states, and, according to this approach, we discuss therapeutic strategies aimed at treating the circadian system and depression.

  17. Carcinogenic effects ofcircadian disruption:an epigenetic viewpoint

    Institute of Scientific and Technical Information of China (English)

    Abbas Salavaty

    2015-01-01

    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, affects many biological processes within the body and results in different long-term diseases, including cancer. Circadian regulatory pathways result in rhythmic epigenetic modiifcations and the formation of circadian epigenomes. Aberrant epigenetic modiifcations, 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 effects of circadian disruption. In this review, I ifrst discuss some of the circadian genes and regulatory proteins. Then, I summarize the current evidence related to the epigenetic modiifcations that result in circadian disruption. In addition, I explain the carcinogenic effects of circadian disruption and highlight its potential role in different human cancers using an epigenetic view-point. Finally, the importance of chronotherapy in cancer treatment is highlighted.

  18. Dosing-time contributes to chronotoxicity of clofarabine in mice via means other than pharmacokinetics.

    Science.gov (United States)

    Luan, Jia-Jie; Zhang, Yu-Shan; Liu, Xiao-Yun; Wang, Ya-Qin; Zuo, Jian; Song, Jian-Guo; Zhang, Wen; Wang, Wu-San

    2016-05-01

    To evaluate the time- and dose-dependent toxicity of clofarabine in mice and to further define the chronotherapy strategy of it in leukemia, we compared the mortality rates, LD50s, biochemical parameters, histological changes and organ indexes of mice treated with clofarabine at various doses and time points. Plasma clofarabine levels and pharmacokinetic parameters were monitored continuously for up to 8 hours after the single intravenous administration of 20 mg/kg at 12:00 noon and 12:00 midnight by high performance liquid chromatography (HPLC)-UV method. Clofarabine toxicity in all groups fluctuated in accordance with circadian rhythms in vivo. The toxicity of clofarabine in mice in the rest phase was more severe than the active one, indicated by more severe liver damage, immunodepression, higher mortality rate, and lower LD50. No significant pharmacokinetic parameter changes were observed between the night and daytime treatment groups. These findings suggest the dosing-time dependent toxicity of clofarabine synchronizes with the circadian rhythm of mice, which might provide new therapeutic strategies in further clinical application. PMID:27316580

  19. FABRICATION OF PULSATILE DELIVERY MULTIPARTICULATE SYSTEM OF POORLY WATER SOLUBLE CARVEDILOL PHOSPHATE

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    Singh DK

    2012-09-01

    Full Text Available Pulsatile drug delivery system is required to satisfy the needs of chronotherapy. Among solids, multiparticulates have its own advantages. Pulsatile drug delivery system provides better therapy with many of the actives. Rupturable pulsatile drug delivery system consists of a drug core; swelling layer of a super disintegrant; and an insoluble, water-permeable polymeric coating. Upon water ingress, the swellable layer expands, resulting in the rupturing of outer membrane followed by drug release. The active pharmaceutical ingredient selected was Carvedilol Phosphate, deposited on sugar pellets as first layer. The second layer composed of swelling excipient, had crospovidone, L–substituted hydroxy propyl cellulose and sodium starch glycolate. Third and the outer most layer was based on ethyl cellulose. The release after lag time was fast and complete, when crospovidone was used as a swelling agent. In contrast, a sustained release was achieved after the lag time, when L–substituted hydroxy propyl cellulose and sodium starch glycolate were used as swelling agents. Fast release would be preferable in the present case. Optimal level of crospovidone to achieve a fast and complete release of Carvedilol phosphate was 33%. Outer membrane, formed using aqueous dispersion of ethyl cellulose was suitable enough to rupture sufficiently ensuring fast drug release, compared to stronger ethyl cellulose membrane formed using organic solution. It was possible to design multiparticulates of carvedilol phosphate having a suitable release profile.

  20. Non-invasive estimation of the circadian rhythm in serum cortisol in patients with ovarian or colorectal cancer.

    Science.gov (United States)

    Mormont, M C; Hecquet, B; Bogdan, A; Benavides, M; Touitou, Y; Levi, F

    1998-11-01

    The variability in toxicity or efficacy of cancer chronotherapy among patients may be due to differences in circadian rhythm. Adequate assessment of circadian rhythm often requires repeated blood sampling over at least a 24-hr period; this cannot be a routine procedure. We attempted to assess the reliability of a 2-timepoint estimate of the 24-hr rhythm of serum cortisol in 19 healthy subjects, 19 women with ovarian cancer and 18 patients with metastatic colorectal cancer. The difference between daily maximum and minimum values (MAX-MIN) was compared with that observed between values at 08.00 and at 16.00 (H8-H16). As significant correlations were found between both variables in all groups, we conclude that the magnitude of circadian changes in serum cortisol may be estimated from blood samples collected at 08.00 and at 16.00. The clinical relevance and the prognostic value of this method of assessment are currently under evaluation in a larger-scale clinical trial. PMID:9797128

  1. FORMULATION AND EVALUATION OF PULSED DRUG DELIVERY OF 5- FLUOROURACIL IN TREATING COLO-RECTAL CANCER

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    Joshi V.G

    2012-09-01

    Full Text Available The proposed work aimed to develop a time dependent programmable pulsatile drug delivery system of 5-Fluorouracil, intended for chronotherapy in colorectal cancer. Various batches of tablets were prepared by direct compression method using microcrystalline cellulose (MCC. These tablets were coated with pH sensitive polymers like Eudragit S-100, cellulose acetate succinate(CAS and Ethyl Cellulose (EC at fixed concentration with different coating level (10% & 20%.The prepared tablets were evaluated for lag time and in vitro drug release. FTIR studies revealed that there was no interaction between drug and polymer. Lag time with Eudragit S-100 at (20% coating level was 5 hrs, Cumulative drug released from the formulation ranged from 91-96% within 8-10 hrs. Drug released followed first order kinetics. The rapid release of the drug after a lag time consistent with requirement for chronotherapeutics was achieved. This approach provides a useful means for pulsatile/programmable release (with single pulse of 5-Fluorouracil and may be helpful for patients suffering from cancer.

  2. Design and in vitro evaluation of compression-coated pulsatile release tablets of losartan potassium

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    M Bajpai

    2012-01-01

    Full Text Available In majority of individuals blood pressure rises in the early morning hours, which lead to serious cardiovascular complications. Formulation of pulsatile system makes it possible to deliver drug at definite period of time when symptoms of the disease condition are most critical. The purpose of the present work was to develop pulsatile release tablet of losartan potassium for chronotherapy in hypertension. The prepared system consisted of a core tablet coated with versatile and safe hydrophilic cellulosic ethers such as, hydroxypropyl methylcellulose, hydroxypropyl cellulose and sodium carboxy methylcellulose to produce burst release after predetermined lag time. Various formulation factors were studied through series of test and in vitro dissolution study. It was found that core tablets containing superdisintegrant failed to produce burst drug release pattern while effervescent agent was able to do so. Results also reveal that coating composition and coating level affects lag time. Formulation containing effervescent agent in core and coated with 200 mg hydroxypropyl cellulose provide lag time of 4.5 h with 73% drug release in 6 h that followed a sigmoidal release pattern. These values were close to the desired objective of producing lag time of 5-6 h followed by fast drug release. This approach can thus provide a useful means for timed release of losartan and is helpful for patients with morning surge.

  3. OPTIMISATION OF CHRONOMODULATED DOSAGE FORM FOR ASTHMA USING FULL FACTORIAL DESIGN

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    SARDA R.R

    2015-06-01

    Full Text Available Chronotherapy is growing treatment method in various diseases. Various diseases like asthma, hypertension, and arthritis show circadian variation, that demand time scheduled drug release for effective drug action. In Asthma like diseases which follow circadian rhythms, it is necessary to modulate the drug release in synchrony with the circadian rhythm of nocturnal asthma. Different polymers like Ethyl cellulose 10, 20, 45 cps, Compritol, Sodium alginate, Sodium CMC and LH-21 were tried. The combination of Eudragit RSPO and HPMC K4M was selected for the study based on lag time and release characteristics. On the basis of the trial batches and their evaluation parameters, concentrations of the polymers were decided and the 23 full factorial design was applied for the formulation of tablets. Lag time prior to drug release and cumulative percentage drug release at 3hrs and 6hrs were selected as responses. Results revealed that both, the coating composition and coating level, are significant factors affecting drug release profile.

  4. Coffee and caffeine potentiate the antiamyloidogenic activity of melatonin via inhibition of Aβ oligomerization and modulation of the Tau-mediated pathway in N2a/APP cells

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    Zhang LF

    2014-12-01

    Full Text Available Li-Fang Zhang,1,2 Zhi-Wei Zhou,2 Zhen-Hai Wang,1 Yan-Hui Du,1 Zhi-Xu He,3 Chuanhai Cao,2 Shu-Feng Zhou2,31Department of Neurology, General Hospital of Ningxia Medical University, Yinchuan, Ningxia, People’s Republic of China; 2Department of Pharmaceutical Science, College of Pharmacy, University of South Florida, Tampa, FL, USA; 3Guizhou Provincial Key Laboratory for Regenerative Medicine, Stem Cell and Tissue Engineering Research Center and Sino-US Joint Laboratory for Medical Sciences, Guiyang Medical University, Guiyang, Guizhou, People’s Republic of ChinaAbstract: There is an increasing prevalence of Alzheimer’s disease (AD, which has become a public health issue. However, the underlying mechanisms for the pathogenesis of AD are not fully understood, and the current therapeutic drugs cannot produce acceptable efficacy in AD patients. Previous animal studies have shown that coffee (Coff, caffeine (Caff, and melatonin (Mel have beneficial effects on AD. Disturbed circadian rhythms are observed in AD, and chronotherapy has shown promising effects on AD. In this study, we examined whether a combination of Coff or Caff plus Mel produced a synergistic/additive effect on amyloid-ß (Aß generation in Neuro-2a (N2a/amyloid precursor protein (APP cells and the possible mechanisms involved. Cells were treated with Coff or Caff, with or without combined Mel, with three different chronological regimens. In regimen 1, cells were treated with Coff or Caff for 12 hours in the day, followed by Mel for 12 hours in the night. For regimen 2, cells were treated with Coff or Caff plus Mel for 24 hours, from 7 am to 7 am the next day. In regimen 3, cells were treated with Coff or Caff plus Mel with regimen 1 or 2 for 5 consecutive days. The extracellular Aβ40/42 and Aβ oligomer levels were determined using enzyme-linked immunosorbent assay (ELISA kits. The expression and/or phosphorylation levels of glycogen synthase kinase 3β (GSK3β, Erk1/2, PI3K

  5. Floating-pulsatile release multiparticulate system for chronopharmacotherapy: effect of some hydrophobic additives on the buoyancy and release behavior of particles.

    Science.gov (United States)

    Maghsoodi, M

    2014-01-01

    A blend of floating and pulsatile principles of a drug delivery system would have the advantage that a drug can be released in the upper gastrointestinal (GI) tract after a lag period, which is anticipated for chronotherapy. In this study, microballoons were prepared by an emulsion solvent diffusion technique using Eudragit S100, and hydrophobic additive (magnesium stearate, stearic acid or talc) for time- and site-specific drug release of piroxicam. The effect of hydrophobic additives on the production yield of floating microparticles, buoyant ability for 8 h, release of drug in simulated GI fluids (simulated gastric fluid [SGF] and simulated intestinal fluid [SIF]), mean particle size, apparent particle density, encapsulation efficiency of drug and physical state of incorporated drug were studied. Both production yield and buoyancy of the microballoons were affected by additives in the following order: magnesium stearate, stearic acid>free-additive>talc. The observed difference in yield and the buoyancy of the microballoons could be attributed to the hydrophobic character of the additives and the shell rigidity of the obtained microballoons. Incorporation of hydrophobic additives in the microballoons was found to impart the desired release properties to the microballoons by providing a 2-phase release pattern with initial slow release (5-6%) through 8 h in SGF followed by rapid pulse release (>92%) in SIF through 15 min. The microballoons co-formulated with magnesium stearate or stearic acid, combining excellent buoyancy and suitable drug release pattern of piroxicam, could be useful in chronopharmacotherapy in arthritis. PMID:23950100

  6. Formulation and optimization of chronomodulated press-coated tablet of carvedilol by Box–Behnken statistical design

    Directory of Open Access Journals (Sweden)

    Satwara RS

    2012-08-01

    promising alternative to control early morning hypertensive increase.Keywords: Box–Behnken, carvedilol, chronotherapy, hypertension, optimization, press coating

  7. Current status and approaches to developing press-coated chronodelivery drug systems.

    Science.gov (United States)

    Lin, Shan-Yang; Kawashima, Yoshiaki

    2012-02-10

    recent challenges for the press coating technique. We also provide a brief overview of press-coating approaches intended for chronotherapy. PMID:21968338

  8. Novel chronotherapeutic rectal aminophylline delivery system for therapy of asthma.

    Science.gov (United States)

    Shiohira, Hideo; Fujii, Makiko; Koizumi, Naoya; Kondoh, Masuo; Watanabe, Yoshiteru

    2009-09-01

    The aim of this study was to develop a new chronotherapeutic pharmaceutical preparation as a sustained-release suppository for prevention and therapeutic use against bronchial asthma in the early morning. Sustained-release hollow-type (SR-HT) suppositories using sodium alginate (Alg-Na), sodium polyacrylate (PANa) or polyacrylate-PANa co-polymer (PA-PANa) as gelling polymers (gel agent) were prepared and pharmaceutical characteristics of these suppositories were investigated. Type A SR-HT suppositories comprised a suppository shell prepared with oleaginous base and containing aminophylline only or aminophylline with Alg-Na or PANa in the cavity (hollow space). Type B SR-HT suppositories comprised a suppository shell prepared with oleaginous base and gel agent (30%), with aminophylline in the hollow space. In drug-release studies, the acrylate polymer-containing suppositories showed linearity of delayed release rate, providing significantly decreased the highest concentration of theophylline in plasma (C(max)) and delayed the time required to reach C(max) (t(max)) and the mean residence time (MRT) after rectal administrated in rabbits. In particular, suppositories containing PA-PANa maintained significantly higher theophylline concentrations than control suppositories at 12h after rectal administration. Furthermore, histopathological examination indicated that these suppositories using acrylate polymers did not result in rectal lesions. The SR-HT suppository, particularly using PA-PANa as a gel agent, may thus be useful against nocturnal symptoms of asthma. In this study, we confirmed new formulation of sustained-release suppository for chronotherapy of theophylline using oily base material in combination with polymer such as PA-PANa. The hollow-type suppository containing oleaginous base and hydrophilic polymer in the shell could be useful device for rectal administration of various drugs with prolongation of plasma concentration. PMID:19555748

  9. FORMULATION DESIGN AND OPTIMIZATION OF PULSATILE RELEASE TABLET OF ACEBROPHYLLINE WITH SWELLING AND ERODIABLE LAYERS FOR TREATMENT OF NOCTURNAL BRONCHIAL ASTHMA

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    Mohit D. Bauskar et al.

    2011-12-01

    Full Text Available Acebrophylline is a bronchodilator with mucosecrytolytic and anti-inflammatory activity. It is used to treat the bronchial asthma, and chronic obstructive pulmonary diseases. This work is based on the formulation and optimization of time dependant pulsatile release tablets of Acebrophylline having adequate mechanical strength of tablet and proper drug release of tablet. Pulsatile drug delivery system has an advantage as delivers the drug at right place, right time and right quantity. The crucial aspect in the formulation of pulsatile drug delivery system is to release the drug as pulse after a lag time has to be designed in such a way that rapid and complete drug release follows after lag time. Present work conceptualizes a specific technology, based on pulsatile principles to develop drug delivery system, intended for chronotherapy in bronchial asthma. This approach will be achieved by using a programmed delivery of acebrophylline. In this work rapid pulse to pulsatile drug delivery system can be achieved through immediate release tablet with good mechanical strength and proper disintegration. Lag time in pulsatile drug delivery system can be maintained by using coating with time responsive polymer having good mechanical strength. In this study immediate release tablet can be prepared by using two super disintegrants as Cross carmellose sodium and Cross-povidone to give rapid pulse of drug. The lag time of pulsatile drug delivery system can be maintained by coating using extended release polymer as HPMC E 50 (Methocel E 50. The programmable pulsatile release of Acebrophylline was consistent with the demands of bronchial asthma.

  10. Chronomodulated press-coated pulsatile therapeutic system for aceclofenac: optimization of factors influencing drug release and lag time

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    et al

    2011-02-01

    Full Text Available Sumit Patil1, Swati Pund2, Amita Joshi2, Chamanlal J Shishoo2, Aliasgar Shahiwala11Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER, Ahmedabad, India; 2Department of Pharmaceutics, BV Patel PERD Centre, Ahmedabad, IndiaBackground: The objective of this study was to develop and evaluate a press-coated pulsatile drug delivery system intended for treatment of early morning stiffness and symptomatic relief from pain in patients with rheumatoid arthritis.Methods: The formulation involved press coating of a rupturable coat around a rapidly disintegrating core tablet of aceclofenac. A three-factor, two-level, full factorial design was used to investigate the influence of amount of glyceryl behenate, amount of sodium chloride in the coating composition, and the coating level on the responses, ie, lag time to release and amount of aceclofenac released in 450 minutes.Results: Glyceryl behenate and the coating level had a significant influence on lag time, while sodium chloride helped in the rupture of the coat by acting as a channeling agent. After the coat was ruptured, the core tablet showed a rapid release of aceclofenac due to the presence of Ac-Di-Sol®. Graphical analysis of effects by Lenth's method and Bayesian analysis of coefficients enabled identification of variables active on the selected responses. The optimized formulation comprised 20% w/w glyceryl behenate and 2.2% w/w sodium chloride with a 650 mg coating level, and showed a desired lag time of 358.23 minutes, which mimics the fluctuating symptoms of rheumatoid arthritis, followed by rapid release of aceclofenac.Keywords: chronotherapy, pulsatile delivery, rupturable coat, aceclofenac 

  11. Formulation and process optimization of multiparticulate pulsatile system delivered by osmotic pressure-activated rupturable membrane.

    Science.gov (United States)

    Hung, Sheng-Feng; Hsieh, Chien-Ming; Chen, Ying-Chen; Lin, Cheng-Mao; Ho, Hsiu-O; Sheu, Ming-Thau

    2015-03-01

    In this study, a multiparticulate pulsatile drug delivery system activated by a rupturable controlled-release membrane (Eudragit(®) RS) via osmotic pressure (with NaCl as the osmogent) was developed and characterized for omeprazole, omeprazole sodium, and propranolol HCl which have different water solubilities. Multiparticulates in pellet form for incorporation with or without the osmogent were manufactured by three methods and then used to coat a polymeric membrane. Results demonstrated that drug/osmogent-containing pellets manufactured by the extrusion/spheronization method with incorporation of the osmogent were optimal. The lag time (tL) to initiate pulsatile release is regulated by tL=l(2)/(6×D), which is dependent on the coating levels (l(2)) and plasticizer content (D). The pulsatile release pattern was found to be dependent on the osmotic pressure (osmogent), drug solubility, and mechanical properties of the polymeric membrane (elasticity and toughness). Omeprazole with lower water solubility could not generate sufficient osmotic pressure to create a crack in the membrane to activate pulsatile release, whereas the two other model drugs with higher solubilities could. But adsorption of omeprazole sodium on Eudragit(®) RS via charge-charge interactions led the its incomplete release. Finally, with 4% osmogent of NaCl added, a lag time in a range from 0 to 12h proportionally regulated by varying both the membrane thickness and plasticizer level initiated the complete pulsatile release of propranolol HCl. In conclusion, a multiparticulate pulsatile drug delivery system activated by a rupturable controlled-release membrane via osmotic pressure was successfully developed, and clinical applications of chronotherapy with drugs like propranolol HCl are expected. PMID:25575473

  12. Retrospective analysis of chronomodulated chemotherapy versus conventional chemotherapy with paclitaxel, carboplatin, and 5-fluorouracil in patients with recurrent and/or metastatic head and neck squamous cell carcinoma

    Directory of Open Access Journals (Sweden)

    Chen D

    2013-10-01

    5-Fu may be a new and effective therapy for patients with recurrent and/or metastatic HNSCC as compared with conventional chemotherapy. Keywords: chronotherapy, chronomodulated chemotherapy, head and neck cancer, palliative chemotherapy, paclitaxel, 5-fluorouracil, carboplatin

  13. Prevalence, putative mechanisms, and current management of sleep problems during chemotherapy for cancer

    Directory of Open Access Journals (Sweden)

    Palesh O

    2012-12-01

    Full Text Available Oxana Palesh,1 Luke Peppone,2 Pasquale F Innominato,3–5 Michelle Janelsins,2 Monica Jeong,1 Lisa Sprod,7 Josee Savard,6 Max Rotatori,1 Shelli Kesler,1 Melinda Telli,1 Karen Mustian21Stanford University School of Medicine, Stanford, CA, USA; 2University of Rochester School of Medicine and Dentistry, Rochester, NY, USA; 3INSERM, UMRS 776, Biological Rhythms and Cancers, Villejuif, France; 4Faculty of Medicine, Universite Paris Sud, le Kremlin-Bicêtre, France; 5APHP, Chronotherapy Unit, Department of Oncology, Paul Brousse Hospital, Villejuif, France; 6Laval University, Quebec, Canada; 7University of North Carolina, Wilmington, NC, USAAbstract: Sleep problems are highly prevalent in cancer patients undergoing chemotherapy. This article reviews existing evidence on etiology, associated symptoms, and management of sleep problems associated with chemotherapy treatment during cancer. It also discusses limitations and methodological issues of current research. The existing literature suggests that subjectively and objectively measured sleep problems are the highest during the chemotherapy phase of cancer treatments. A possibly involved mechanism reviewed here includes the rise in the circulating proinflammatory cytokines and the associated disruption in circadian rhythm in the development and maintenance of sleep dysregulation in cancer patients during chemotherapy. Various approaches to the management of sleep problems during chemotherapy are discussed with behavioral intervention showing promise. Exercise, including yoga, also appear to be effective and safe at least for subclinical levels of sleep problems in cancer patients. Numerous challenges are associated with conducting research on sleep in cancer patients during chemotherapy treatments and they are discussed in this review. Dedicated intervention trials, methodologically sound and sufficiently powered, are needed to test current and novel treatments of sleep problems in cancer patients

  14. Preparation of gastric retenting and chronopharmacologic drug delivery tablets of sinomenine hydrochloride%盐酸青藤碱胃滞留型择时释药片的研制

    Institute of Scientific and Technical Information of China (English)

    张瑜; 武亚玲; 耿燕娜; 彭兴娟

    2009-01-01

    material in coating layer. The compressing pressure and preparation method of coat material had minor influence on the lag-time of the tablets. Coating layer erosion and tablet core swelling were involved in the mechanism of drug release. Conclusion: The tablets had typical chronopharmacologic drug delivery properties. A suitable lag-time can be achieved by adjusting formulation of coating layer to meet the requirement of chronotherapy.